Synthesis of (9R,12S)- and (9S,12S)-cycloisodityrosine and their N-methyl derivatives

Article abstract of DOI:10.1021/jo961346o

Full details of the synthesis of (9R,12S)- and (9S,12S)-cycloisodityrosine and their N-methyl derivatives are detailed based on an intramolecular nucleophilic aromatic substitution reaction for formation of the key biaryl ether with 14-membered ring macrocyclization. Their comparison with prior samples and the documentation of a facile C9 epimerization within the natural 9S series are described.

Full text of DOI:10.1021/jo961346o

2054
J . Org. Chem. 1997, 62, 2054-2069
Syn th esis of (9R,12S)- a n d (9S,12S)-Cycloisod ityr osin e a n d Th eir
N-Meth yl Der iva tives
Dale L. Boger,* J iacheng Zhou, Robert M. Borzilleri, Seiji Nukui, and Steven L. Castle
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road,
La J olla, California 92037
Received J uly 16, 1996 (Revised Manuscript Received J anuary 29, 1997X)
Full details of the synthesis of (9R,12S)- and (9S,12S)-cycloisodityrosine and their N-methyl
derivatives are detailed based on an intramolecular nucleophilic aromatic substitution reaction
for formation of the key biaryl ether with 14-membered ring macrocyclization. Their comparison
with prior samples and the documentation of a facile C9 epimerization within the natural 9S series
are described.
Deoxybouvardin (1) and RA-VII (2), bicyclic hexapep-
tides containing an unusual N-methylcycloisodityrosine
subunit, constitute prototypical members of a growing
class of naturally occurring potent antitumor agents
(Figure 1).1-3 In recent communications,4,5 we and Inoue
disclosed the assessment of the stereochemistry of prior
cycloisodityrosine intermediates employed in the total
synthesis of 1 and 26,7 which resulted in the reassignment
of the stereochemistry of our past intermediates. This
was carried out concurrent with efforts8 on the develop-
ment of an alternative synthesis of the cycloisodityrosine
subunit of 1 and 2 based on an intramolecular nucleo-
philic aromatic substitution reaction9 for formation of the
biaryl ether modeled on our original Ullmann coupling
reaction.10 Herein, we report full details of this work and
the extension of the studies to the preparation of the
partially N-methylated derivatives including cycloisodi-
tyrosine itself and their comparison with our previously
reported samples. In these studies, we provide docu-
F igu r e 1.
mentation of a remarkably facile and efficient base-
catalyzed epimerization that went undetected in our prior
efforts.
X Abstract published in Advance ACS Abstracts, March 1, 1997.
(1) J olad, S. D.; Hoffmann, J . J .; Torrance, S. J .; Wiedhopf, R. M.;
Cole, J . R.; Arora, S. K.; Bates, R. B.; Gargiulo, R. L.; Kriek, G. R. J .
Am. Chem. Soc. 1977, 99, 8040.
(2) Review: Itokawa, H.; Takeya, K. Heterocycles 1993, 35, 1467.
(3) Itokawa, H.; Takeya, K.; Mori, N.; Sonobe, T.; Mihashi, S.;
Hamanaka, T. Chem. Pharm. Bull. 1986, 34, 3762. Itokawa, H.;
Takeya, K.; Mihara, K.; Mori, N.; Hamanaka, T.; Sonobe, T.; Iitaka,
Y. Chem. Pharm. Bull. 1983, 31, 1424.
(4) Inoue, T.; Sasaki, T.; Takayanagi, H.; Harigaya, Y.; Hoshino, O.;
Hara, H.; Inaba, T. J . Org. Chem. 1996, 61, 3936.
(5) Boger, D. L.; Zhou, J . J . Org. Chem. 1996, 61, 3938. Boger, D.
L.; Zhou, J .; Borzilleri, R. M.; Nukui, S. Bioorg. Med. Chem. Lett. 1996,
61, 1089.
(6) Inaba, T.; Umezawa, I.; Yuasa, M.; Inoue, T.; Mihashi, S.;
Itokawa, H.; Ogura, K. J . Org. Chem. 1987, 52, 2957. Inoue, T.; Inabe,
T.; Umezawa, I.; Yuasa, M.; Itokawa, H.; Ogura, K.; Komatsu, K.; Hara,
H.; Hoshino, O. Chem. Pharm. Bull. 1995, 43, 1325.
(7) Boger, D. L.; Yohannes, D.; Zhou, J .; Patane, M. A. J . Am. Chem.
Soc. 1993, 115, 3420. Boger, D. L.; Yohannes, D. J . Am. Chem. Soc.
1991, 113, 1427.
(8) 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.
P r ep a r a tion a n d Ch a r a cter iza tion of th e Am in o
Acid a n d Dip ep tid e Bu ild in g Block s. (S)- and (R)-
3-Fluoro-4-nitrophenylalanine methyl ester (6) were
prepared by benzylic bromination11 of 2-fluoro-4-meth-
ylnitrobenzene12 effected by treatment with 1,3-dibromo-
5,5-dimethylhydantoin and alkylation with both enanti-
omers of the higher order cuprate of Scho¨llkopf’s reagent
413 to provide the enantiomers of 5 with high diastereo-
selectivity (g99:1). In our hands, the best conversions
achieved with this procedure were 40-45% which do not
approach those disclosed in related efforts.14 Although
the corresponding lithium reagent provided 5 in lower
conversions (30-35%), it makes more effective use of the
valuable chiral reagent, and this was generally employed
in our preparations of 6. Hydrolysis of 5 followed by
liberation of the free amine provided the (S)- and (R)-
65,14 directly (Scheme 1).
(9) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J .;
Zhu, J . J . Org. Chem. 1994, 59, 5535. Beugelmans, R.; Bigot, A.; Zhu,
J . Tetrahedron Lett. 1994, 35, 7391. Beugelmans, R.; Zhu, J .; Husson,
N.; Bois-Choussy, M.; Singh, G. P. J . Chem. Soc., Chem. Commun.
1994, 439. Rama Rao, A. V.; Reddy, K. L.; Rao, A. S. Tetrahedron Lett.
1994, 35, 8465. Beugelmans, R.; Bourdet, S.; Zhu, J . Tetrahedron Lett.
1995, 36, 1279. Bois-Choussy, M.; Beugelmans, R.; Bouillon, J .-P.; Zhu,
J . Tetrahedron Lett. 1995, 36, 4781. Zhu, J .; Bouillon, J .-P.; Singh, G.
P.; Chastanet, J .; Beugelmans, R. Tetrahedron Lett. 1995, 36, 7081.
Zhu, J .; Beugelmans, R.; Bourdet, S.; Chastanet, J .; Roussi, G. J . Org.
Chem. 1995, 60, 6389. Beugelmans, R.; Neuville, L.; Bois-Choussy, M.;
Zhu, J . Tetrahedron Lett. 1995, 36, 8787. Beugelmans, R.; Bois-
Choussy, M.; Vergne, C.; Bouillon, J .-P.; Zhu, J . J . Chem. Soc., Chem.
Commun. 1996, 1029. Rama Rao, A. V.; Reddy, K. L.; Rao, A. S.; Vittal,
T. V. S. K.; Reddy, M. M.; Pathi, P. L. Tetrahedron Lett. 1996, 37, 3023.
Evans, D. A.; Watson, P. S. Tetrahedron Lett. 1996, 37, 3251.
(10) Boger, D. L.; Yohannes, D. J . Org. Chem. 1991, 56, 1763. Boger,
D. L.; Zhou, J . J . Am. Chem. Soc. 1993, 115, 11426. Boger, D. L.; Sakya,
S. M.; Yohannes, D. J . Org. Chem. 1991, 56, 4204. Boger, D. L.;
Nomoto, Y.; Teegarden, B. R. J . Org. Chem. 1993, 58, 1425. Boger, D.
L.; Yohannes, D. Tetrahedron Lett. 1989, 30, 2053. Boger, D. L.;
Yohannes, D. J . Org. Chem. 1989, 54, 2498. Boger, D. L.; Yohannes,
D. Tetrahedron Lett. 1989, 30, 5061. Boger, D. L.; Yohannes, D. J . Org.
Chem. 1990, 55, 6000.
(11) In our efforts dibromodimethylhydantoin was more effective
than NBS.
(12) Commercially available from Aldrich.
(13) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed. Engl.
1981, 20, 798.
(14) Beugelmans, R.; Bigot, A.; Bois-Choussy, M.; Zhu, J . J . Org.
Chem. 1996, 61, 771.
S0022-3263(96)01346-1 CCC: $14.00 © 1997 American Chemical Society

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2055
Sch em e 1
F igu r e 2.
resolution of the enantiomers of 11 on an analytical
ChiralCel OD-H HPLC column (tR ) 17.9 min for L and
16.0 min for D, 4% i-PrOH/hexane, 1.0 mL/min).
Both (S)- and (R)-3-fluoro-4-nitrophenylalanine methyl
ester (6) were coupled with L- and D-BOC-NMe-Tyr-
OC6F5 (11) in THF (25 °C, 4 h, 80-90%), and this reaction
exhibited a significant kinetic preference for formation
of the (S,R)- or (R,S)-diastereomer (Scheme 3). The use
of excess amounts of optically enriched but impure active
ester (47-55% ee) in the formation of the (S,S)- or (R,R)-
diastereomer was found to preferentially provide the
mixed (S,R)- or (R,S)-diastereomer, respectively.
Sch em e 2
Ma cr ocycliza tion of 13 a n d 14. Consistent with
prior observations8 on the 14-membered ring macrocy-
clization reaction with formation of a biaryl ether,9
treatment of 13 and 14 with either K2CO3 (5 equiv, 0.008
M DMF, 45-50 °C, 2-4 h) or NaH (2.2 equiv, 0.004 M
THF, 0-25 °C, 2-6 h) led to smooth 14-membered ring
closure under remarkably mild conditions (Scheme 4). In
the case of (R,S)- or (S,R)-14, both conditions provided a
single product 15 in superb conversions (76-78%), and
the relative stereochemistry of the former was unam-
biguously established upon N-BOC deprotection and
X-ray analysis of crystals grown from CH3OH-acetone
(Figure 2).17 The closure of (R,S)-14 was found to occur
even at 25 °C in the presence of K2CO3, albeit requiring
24 h (72%), and the reaction could be accelerated by the
addition of 0.1 equiv of 18-crown-6 (25 °C, 8 h, 70%). CsF
also proved to be an excellent reagent for promoting the
macrocyclization reaction and provided results compa-
rable to those observed with K2CO3 (Table 1). Both KF
and NaHCO3 were less effective.
The preparation of L- and D-BOC-NMe-Tyr-OH (10)
and their conversion to the corresponding active esters,
L- and D-BOC-NMe-Tyr-OC6F5 (11), were accomplished
as outlined in Scheme 2. Direct N-methylation15 of L- or
D-BOC-Tyr(OBn)-OH16 conducted in THF-DMF (20:1)
with limiting amounts of NaH (2.2 equiv) provided 8
(90%, 92% ee). This proved much more effective than
N-methylation of the corresponding benzyl ester (82-
89%, 47-55% ee) or when this reaction was run using
excess NaH (1:10 DMF-THF) under conditions that
generate the corresponding methyl ester (82% ee). In the
latter efforts, substantial racemization was observed.
This was most easily assessed by direct chromatographic
In contrast, (S,S)- or (R,R)-13 only provided the desired
macrocyclization product diastereomer 16 under carefully
defined reaction conditions where potential epimerization
was minimized (2.2 equiv of NaH, 0.004 M THF, 0-25
(17) The atomic coordinates for this structure have been deposited
with the Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EW, UK.
(15) Coggins, J . R.; Benoiton, N. L. Can. J . Chem. 1971, 49, 1968.
(16) Commercially available from Sigma.

2056 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
Sch em e 3
Sch em e 4
Ta ble 1. Rep r esen ta tive Resu lts of th e Ma cr ocycliza tion
Rea ction of 14 To P r ovid e 15a
mixture provided a much faster reaction and significantly
improved conversions at 25 °C, but with product epimer-
ization, and the isolated ratio of undesired diastereomer
15 to desired 16 was 2.5-3 to 1 under such conditions.
Equilibration studies conducted on (9S,12S)-16 con-
firmed the unusually facile epimerization which could be
effected by treatment with K2CO3, K2CO3/18-c-6, or KF
in DMF as well as DBU or Et3N in THF. However, the
epimerization of 16 was found to occur with greater
facility in the reaction itself, indicating that the liberated
fluoride in the reaction mixture may be contributing to
the generation of 15. The studies also established an
equilibrium ratio of g97:3 in favor of the unnatural
diastereomer 15 and that this epimerization occurs at
the C9 center adjacent to the methyl ester (eq 1). This
facile epimerization of 16 is analogous to similar but
temp
(°C)
time
(h)
yield
(%)
entry base (equiv) catalyst (equiv)
1
2
3
4
5
6
7
8
9
K2CO3 (3)
K2CO3 (3)
K2CO3 (3)
NaH (2.2)b
CsF (3)
CsF (3)
KF (3)
KF (3)
NaHCO3 (6)
NaHCO3 (6)
none
none
18-c-6 (0.1)
none
none
18-c-6 (0.1)
none
18-c-6 (0.1)
none
25
45
25
24
3
8
72
76
70
0-25
4-6 76-78
24
25
25
25
25
25
25
74
68
8
24
24
24
24
15-20
55c
trace
17d
10
18-c-6 (0.1)
a
All reactions were run in 0.007-0.008 M anhydrous, degassed
DMF. The reaction was run in 0.008 M anhydrous THF. c <10%
recovered 14. >50% recovered 14.
b
d
°C, 2-6 h, 50-61%). Moreover, increasing amounts of
the diastereomer 15 were observed if the reaction was
extended to longer reaction times or conducted with
excess NaH. Conducting this reaction under the appar-
ently milder conditions of K2CO3-DMF (5.0 equiv, 45-
50 °C, 0.008 M, 3-4 h) provided the undesired and
epimerized diastereomer 15 nearly exclusively (45-55%)
with only a trace of the desired product 16 (5-10%) being
detected at any time during the course of the reaction.
Even more remarkable, the epimerized diastereomer 15
was detected as the major cyclization product when this
reaction was conducted at 25 °C (5.0 equiv of DMF, 0.008
M K2CO3, 25 °C, 36 h). Under such conditions, the
macrocyclization reaction was found to proceed very
slowly and provided mainly recovered starting material
(>60%) without its epimerization. Addition of a catalytic
amount of 18-crown-6 (0.1-0.2 equiv) to the reaction
unrecognized observations made in closely related ef-
forts14 but is in sharp contrast to the observations made
in systems which are not constrained to the cycloisodi-
tyrosine 14-membered ring where epimerization is mini-
mal under comparable8,9 or more vigorous reaction con-
ditions10 (Figure 3).
(S,S)-N-Meth ylcycloisod ityr osin e Meth yl Ester
(22) a n d Its Un n a tu r a l Dia ster eom er , (R,S)-N-Meth -

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2057
Sch em e 5
F igu r e 3.
ylcycloisod ityr osin e Meth yl Ester (27). Conversions
of (9S,12S)-16 and (9R,12S)-15 to (S,S)-N-methylcyclo-
isodityrosine methyl ester (9S,12S)-22 and its unnatural
(R,S)-diastereomer, (9R,12S)-27, were accomplished as
outlined in Schemes 5 and 6. N10-Methylation (1.2 equiv
of NaH, 10 equiv of CH3I, 20:1 THF-DMF, 0-25 °C, 3
h, 84-92%) of 16 and 15 provided 18 and 23, respectively.
No epimerization of 23 was detected under the reaction
conditions while the more sensitive 18 suffered trace
detectable epimerization (e3%). Increasing amounts of
diastereomer 23 were observed if the latter reaction was
conducted with excess NaH (1.5-2.0 equiv), with increas-
ing amounts of DMF (THF-DMF 10:1), or if the reaction
time was extended. Nitro reduction to the aryl amines
19 and 24 (H2, 10% Pd-C, 95%) followed by diazotization
(2 equiv of t-BuONO, 2 equiv of HBF4, THF-H2O, 0 °C,
1 h) and subsequent oxidative hydrolysis of the diazo-
nium salt using Cu(NO3)2-Cu2O (0-25 °C, 1 h) afforded
the phenols 20 and 25 (40-50%) accompanied by minor
amounts of N-BOC deprotection and competitive forma-
tion of the reduced products (10-20%). Although not
extensively examined, the use of THF versus CH3OH18
as the reaction solvent provided significant improvements
in the relative ratio of phenol to reduction products and
limiting the amount of HBF4 diminished competitive
N-BOC deprotection. O-Methylation provided 21 and 26,
respectively, and subsequent acid-catalyzed N-BOC depro-
tection followed by liberation of the free amines provided
22 and 27. With care, (S,S)-16 could be taken through
this sequence without competitive epimerization. With
the samples of 21, 22 and 26, 27 in hand, their compari-
son with our prior intermediates7 and those reported by
Inoue4,6 revealed that our past intermediates possess the
(R,S)-stereochemistry of 26 and 27.7,19-21
(9S,12S)-21 was subjected to epimerization (DBU,
toluene) which established an equilibrium ratio of >3:1
in favor of the (R,S)- versus (S,S)-isomer with epimer-
ization occurring cleanly at the C9 center adjacent to the
methyl ester (eq 2). This epimerization study of 21,
which was not driven to equilibrium, was slower and less
effective than that of 16 but did confirm that it occurs
(19) Boger, D. L.; Myers, J . B.; Yohannes, D.; Kitos, P. A.; Suntorn-
wat, O.; Kitos, J . C. Bioorg. Med. Chem. Lett. 1991, 1, 313. Boger, D.
L.; Patane, M. A.; J in, Q.; Kitos, P. A. Bioorg. Med. Chem. 1994, 2, 85.
(20) Boger, D. L.; Zhou, J . J . Am. Chem. Soc. 1995, 117, 7364.
(21) Boger, D. L.; Patane, M. A.; Zhou, J . J . Am. Chem. Soc. 1995,
117, 7357.
(18) Cohen, T.; Dietz, A. G.; Miser, J . R. J . Org. Chem. 1977, 42,
2053.

2058 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
Sch em e 6
Sch em e 7
mixtures with one conformation dominating. For one
1
conformation, the 2D H-1H ROESY NMR spectrum of
the free amine 22 exhibited diagnostic H-9/N10-CH3,
H-12/N10-CH3, and H-19/N10-CH3 NOE cross peaks and
lacked a strong H-9/H-12 NOE establishing the trans
amide configuration and the N-CH3 orientation proxi-
mate to C19 analogous to that found in the X-ray
structures of 17, 26, and 45. For the second conforma-
tion, an intense H′-12/H′-9 NOE was observed and is
diagnostic of a cis amide central to the 14-membered ring.
Thus, 22 adopts two rigid conformations, one of which
possesses a cis amide in the 14-membered ring analogous
to that found in the natural products 1 and 2. Moreover,
the two conformational isomers of 22 are sufficiently
stable to be chromatographically detected (TLC) and even
separated although they rapidly reequilibrate at 25 °C
upon isolation. For 18-21, the major conformation (3-
4:1) adopted corresponds to the cis amide conformation
central to the 14-membered ring analogous to that found
in 1 and 2 and was established with the observation of
the characteristic H-9/H-12 and H-9/H-19 NOEs in the
1H-1H ROESY NMR spectra.
cleanly at the ester center. A similar treatment of 26
led to recovered starting material with little or no
detection of 21, indicating the true equilibrium ratio lies
close to that observed with 15/16 and explains why prior
attempts at deliberate epimerization with our original
samples7 did not afford a second diastereomer.
The intermediates 15 and 23-27 were all found to
exist in a single, rigid solution conformation that is
analogous to that observed with the X-ray structures of
17 and 264 which possess a trans amide central to the
14-membered ring. Thus, N10-methylation of 15 did not
alter this inherent preference for a central trans amide.
Similarly, 16 adopts a single rigid solution conformation
containing a trans secondary amide central to the 14-
membered ring, and its backbone conformation proved
nearly identical with that of 15. Although this was
Nr-Meth ylcycloisod ityr osin e Meth yl Ester (31).
The partially methylated agents 29-31 containing a
secondary amide central to the 14-membered ring and a
C12 N-methyl group were prepared following an identical
sequence (Scheme 7). Without optimization, reduction
of (9S,12S)-16 followed by conversion to the diazonium
salt and its immediate conversion to a phenol provided
29. Subsequent O-methylation provided N-BOC-NR-
methylcycloisodityrosine methyl ester (30) and N-BOC
deprotection followed by liberation of the free amine
afforded 31. The intermediates 29-31 adopt a single
rigid solution conformation possessing a trans secondary
amide central to the 14-membered ring. The comparison
of 30 and 31 with our prior intermediates revealed that
those previously disclosed7,19-20,22 possess the (R,S)-
versus (S,S)-stereochemistry.
1
established by H NMR and is consistent with modeling
studies of the low energy conformations available to 15,
16 and 23-27, it is most apparent in the comparison
X-ray of 45.17 Superimposition of 17 and 45 revealed that
the adopted backbone conformations are essentially
indistinguishable (RMS ) 0.23 Å excluding substituents).
In contrast, 18-22 derived from N-methylation of 16
adopt two rigid solution conformations. This was more
closely examined with the free amine 22 which was found
to exist as a near 1:1 mixture of the two conformations
in CDCl3 and acetone-d6 whereas 18-21 exist as 3-4:1

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2059
Sch em e 8
Na tu r a l (9S,12S)-Cycloisod ityr osin e Meth yl Ester
(40) a n d Its Un n a tu r a l (9R,12S)-Dia ster eom er 44.
The parent cycloisodityrosine derivatives 38-40 lacking
both the N10 and C12 N-methylation were prepared and
required the dipeptide macrocyclization substrate 33. For
this purpose and in efforts to distinguish the extent and
site of epimerization, both L- and D-6 were coupled (THF,
25 °C, 4 h, 90-95%) with L-BOC-NH-Tyr-OC6F5 (12) to
provide (S,S)-33 and (R,S)-34 (Scheme 8). When this
reaction was conducted with L-BOC-Tyr-OH activated for
coupling with EDCI-HOBt, a 4:1 mixture of (S,S)-33 and
(S,R)-34 was obtained resulting from the kinetic prefer-
ence for formation of the mixed (S,R)- or (R,S)-diastere-
omer. Unrecognized, but analogous, observations have
been made in closely related efforts.14,23
Smooth macrocyclization of (R,S)-34 was observed
upon exposure to K2CO3 (5 equiv, 0.005 M DMF, 70 °C,
10 h, 63%) to provide a single, stable diastereomer, (9R,-
12S)-35, in excellent conversions. Exposure of (S,S)-33
to the same reaction conditions provided an approximate
1:1 mixture of (9S,12S)-36 and the epimerized diastere-
omer (9R,12S)-35 in 50-60% combined yield (Scheme 9).
Conducting this latter reaction at 25 °C (3 equiv of K2-
CO3, 0.01 M DMF, 20-24 h, 59%, 1:1 35:36) provided
similar results but required a more extended reaction
time for completion. Analogous, but unrecognized, ob-
servations have been disclosed in the work of Zhu and
Beugelmans.24 Similar to our observations with 13,
macrocyclization of (S,S)-33 effected by treatment with
NaH (3.3 equiv, 0.004 M THF, 6-12 h, 0-25 °C) under
conditions that minimize epimerization provided pre-
dominately the desired (9S,12S)-36 (50-60%) and smaller
but significant amounts of the undesired (9R,12S)-
diastereomer (15-20%). The pure diastereomers were
obtained by chromatographic separation.
F igu r e 4.
(9R,12S)-35, and epimerization studies conducted on
(9S,12S)-36 confirmed the unusually facile epimerization,
established an equilibrium ratio of g2:1 in favor of the
unnatural diastereomer 35, and established that this
epimerization occurs at the C9 center adjacent to the
methyl ester (eq 3). The true equilibrium ratio was not
able to be assessed due to base-catalyzed decomposition
derived from nucleophilic attack of the deprotonated
central amide onto the C-12 NR-BOC in a reaction that
is not competitive upon C-12 N-methylation.7,10 The
structure of 36 was unambiguously established upon
N-BOC deprotection and subsequent single-crystal X-ray
structure determination of the resulting HCl salt (Figure
4). The comparison of the X-ray structure conformation
of 45 with that of 17 revealed the structural origin of the
preferential epimerization of the (9S,12S) diastereomers
to the more stable (9R,12S) diastereomers. Both 45 and
17 exist in rigid conformations containing a trans second-
ary amide central to the 14-membered ring and contain
nearly indistinguishable backbone conformations (RMS
) 0.23 Å excluding substituents). Both adopt perpen-
dicular arrangements of the two aryl rings with the
strongly shielded C19-H imbedded in the face of the right-
hand aryl ring which is slightly puckered to accommodate
the strain in the macrocyclic ring. In 17, as well as 26,4
which are representative of the (9R,12S)-diastereomers,
the C9 methyl ester adopts a pseudoequatorial position
on the rigid 14-membered ring avoiding transannular
Characterization of the minor diastereomer 35 derived
from closure of (S,S)-33, its comparison with authentic
(22) Boger, D. L.; Yohannes, D.; Myers, J . B. J . Org. Chem. 1992,
57, 1319.
(23) Similar, but unrecognized, observations with EDCI-HOBt were
disclosed, lit.14 [R]25 +12 (c 0.13, CHCl3) versus [R]25 +18 (c 0.16,
D
D
CHCl3) for (S,S)-33.
(24) Identical, but unrecognized, observations were disclosed14 but
misrepresented as thermally stable, noninterconvertable atropisomers.
The report14 that the starting materials and products are stable to
base and the macrocyclization conditions is incorrect and the two
diastereomers are related by C9 epimerization. The 1H NMR spectra
disclosed in this work14 for atropisomers match those of the diaster-
eomers 35 and 36. However, the specific rotations are not coincident
with those disclosed herein: (9S,12S)-36 [R]25 +48 (c 2.0, CHCl3)
D
versus +35 (c 0.28, CHCl3)14 and (9R,12S)-35 [R]25D -31 (c 1.0, CHCl3)
versus -9 (c 0.1, CHCl3).14 This would seem to further confirm the
contamination of (S,S)-33 with (S,R)-34 which was derived from
epimerization during coupling to provide 3323 (HOBt-EDCI, C12
center) in addition to that which occurs upon macrocyclization (C9
center).

2060 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
Sch em e 9
Sch em e 10
Sch em e 11
In early studies, we had also examined the prospect
that 36 might also serve as a precursor to 18 and thus
the N-methylcycloisodityrosine derivatives required of
the natural products 1 and 2. Although this was not
investigated in detail, the double N-methylation of 36 was
problematic (2.2 equiv of NaH, 10 equiv, CH3I, 10:1
THF-DMF, 0-25 °C, 12 h) and provided only low yields
of 18 (20-30%) along with at least three other com-
pounds, presumably representing the two monomethy-
lated derivatives accompanied by epimerization. Efforts
to drive this reaction to completion using more vigorous
conditions were not pursued due to this sensitivity to
epimerization. In contrast, the unnatural diastereomer
(9R,12S)-35 proved more amenable to permethylation,
requiring a shorter reaction period and providing a
satisfactory yield of (9R,12S)-23 (50%) under similar
conditions (2.2 equiv NaH, 10 equiv of CH3I, 10:1 THF-
DMF, 0-25 °C, 3 h).
Rela ted Stu d ies. The final agents in the series
examined were 51-53 which selectively differentiates
and protects the C12 amine and in principle would permit
the preparation of N10-methylcycloisodityrosine. Its prepa-
ration incorporated the use of L-BOC-NBn-Tyr-OH (49)
which allows for protection and subsequent release of a
C12 free amine. Coupling of L-49 which was prepared
as shown in Scheme 12 with L-6 cleanly provided (S,S)-
interactions and adopting an anti relationship to the C7-
C8 bond. In 45, which is representative of the (9S,12S)-
diastereomers, the C9 methyl ester adopts a pseudoaxial
position on the rigid 14-membered ring exposing it to
destabilizing transannular interactions and forcing it to
adopt a strongly destabilizing gauche/eclipsed relation-
ship with the C7-C8 bond (dihedral angle ) 44°).
Transformation of 36 and 35 into the (9S,12S)-cyclo-
isodityrosine derivatives 38-40 and their unnatural (9R,-
12S)-diastereomers 42-44 was accomplished as outlined
in Schemes 10 and 11. Thus, nitro reduction (97-98%),
diazotization, and oxidative hydrolysis of the in situ-
generated diazonium salt (40-55%), followed by selective
O-methylation (90-91%), provided 39 and 43, respec-
tively. Subsequent N-BOC deprotection provided the free
amines 40 and 44. With care, 36 could be taken through
this sequence without epimerization. Analogous to 15-
17 and 45, 35-44 adopt a single rigid solution conforma-
tion possessing a trans secondary amide central to the
cycloisodityrosine structure. The comparisons of 39, 40
and 43, 44 with our prior reported samples19,20,25 required
their reassignment to the diastereomer 43 and 44 ster-
eochemistry.
(25) Boger, D. L.; Zhou, J . Bioorg. Med. Chem. 1995, 3, 1579.

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2061
Sch em e 12
Sch em e 13
50 (78%) along with a trace of the separable (R,S)-
diastereomer (5%). Treatment of (S,S)-50 with NaH (2.2
equiv, 20:1 THF:DMF, 0 to 25 °C, 4.5 h) cleanly provided
(S,S)-51 (63%) without detection of the epimerized dias-
tereomer (R,S)-52.
has not yet proven sufficiently successful for implemen-
tation.
Subjection of (S,S)-51 to epimerization (DBU, THF, 50
°C) led to rapid and complete epimerization to (R,S)-52
(eq 4). These observations are analogous to those made
with 15 and 16. Both 51 and 52 adopt a single, rigid
solution conformation containing a trans amide central
to the cyclic structure.
The protected 3(S)-â-hydroxy-BOC-NMe-L-Tyr re-
quired for incorporation into 54 was prepared from 3(S)-
â-hydroxy-L-Tyr(OBn)-OMe (57) which in turn is avail-
able in two steps as shown in Scheme 13. The direct
condensation of 4-(benzyloxy)benzaldehyde with the
lithium anion of the Scho¨llkopf reagent (R)-4 (THF, -78
to -30 °C, 1.5 h) provided a separable mixture (86%) of
the diastereomers 55 and 56 epimeric at the alcohol
center. Without optimization, independent hydrolysis (2
equiv of 0.25 N aqueous HCl, 1:3 CH3CN-THF, 25 °C, 5
h, 56-60%) provided the free amino alcohols 57 and 58
which were converted (1.2 equiv of carbonyldiimidazole,
C6H6, 60 and 25 °C, 12-14 h) to the corresponding cyclic
carbamates 59 and 60, respectively. The large (J ) 9.0
Hz) and small (J ) 5.1 Hz) C4-H/C5-H coupling constants
of 59 and 60, respectively, established the erythro (cis)
and threo (trans) stereochemistry of the respective in-
termediates.
Similar to efforts with 16, N10-methylation was effected
by NaH-CH3I and could be accomplished without C9
epimerization (Scheme 12). However, extending the
reaction times, use of higher reaction temperatures (25
°C) or excess NaH, and employment of larger amounts
of DMF cosolvent led to increased levels of C9 epimer-
ization.
Attem p ted P r ep a r a tion of th e Cycloisod ityr osin e
Su bu n it of Bou va r d in : (9S,12S,13S)-N10,Nr-Dim eth -
yl-13-h yd r oxycycloisod ityr osin e. In preliminary ef-
forts, the extension of these studies to the preparation
of 54, a protected derivative of the N,N-dimethyl-13(S)-
hydroxycycloisodityrosine subunit found in bouvardin1
Without optimization, 57 was converted to 65 for
coupling with L-6 (Scheme 14). Thus, TBDMS protection
of the alcohol (5.0 equiv of TBDMSOTf, 6.0 equiv of Et3N,

2062 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
Sch em e 14
DMF led to a complex mixture including products of
elimination, and no N-methylated products were ob-
served.
The ramifications of these studies are under investiga-
tion and will be disclosed in due course. Most notable of
these is the accessible adoption of a conformation pos-
sessing a cis tertiary amide central to the 14-membered
ring of the 9S,12S diastereomers of the N10-methylcy-
cloisodityrosines analogous to that found in the natural
products 1 and 2.
Exp er im en ta l Section
3-Flu or o-4-n itr o-N-[N-(ter t-bu tyloxyca r bon yl)-N-m eth -
yl-L-tyr osyl]-L-p h en yla la n in e Meth yl Ester ((S,S)-13). A
solution of L-6 (203 mg, 0.84 mmol) in anhydrous THF (5 mL)
was treated with L-11 (426 mg, 0.924 mmol, 1.1 equiv, 92%
ee) at 25 °C under Ar, and the resulting reaction mixture was
stirred at 25 °C for 4 h under Ar before the solvent was
removed in vacuo. Flash chromatography (SiO2, 2 × 10 cm,
20-50% EtOAc-hexane gradient elution) afforded (S,S)-13
(376 mg, 436 mg theoretical, 86%) as a pale-yellow oil which
solidified upon standing and (S,R)-14 (18.2 mg, 436 mg
theoretical, 4%) as a pale-yellow oil which solidified upon
CH2Cl2, -10 to 4 °C, 24 h, 75-86%), N-BOC protection
(1.1 equiv of BOC2O, 2.0 equiv of K2CO3, 1:1 THF-H2O,
25 °C, 3 h, 83%), methyl ester hydrolysis (2.0 equiv of
LiOH, 2:1 t-BuOH-H2O, 5-25 °C, 4.5 h, 95%), and
N-methylation (2.2 equiv of NaH, 5.0 equiv of CH3I, THF,
-20 to 25 °C, 7 h, 30-40%) provided 64. In the latter
reaction, significant amounts (23-30%) of OTBDMS
elimination was observed. Benzyl ether deprotection by
hydrogenolysis (H2, 10% Pd-C, CH3OH, 3-4 h, 99%)
provided 65 and, for comparison purposes, the pentafluo-
rophenyl ester 66 was prepared from 65.
Coupling of either 65 (1.6 equiv of EDCI, 1.1 equiv
HOBt, DMF, 0-25 °C, 14 h, 80%) or 66 (1:1 THF-DMF,
60 °C, 18 h, 48%) with L-6 provided the key cyclization
substrate 67 (Scheme 15). In both instances, an ap-
proximately 4:1 mixture of separable diastereomers was
obtained upon coupling resulting from epimerization of
65 or 66 upon activation and prior to coupling. Treat-
ment of 67 with NaH (2.2 equiv, 0.008 M THF, 25 °C, 6
h, <10%) or K2CO3 (5 equiv, 0.008 M DMF, 45 °C, 6 h
(no reaction), 80 °C, 12 h, < 10%) provided only trace
amounts of 68 and predominantly the degradation prod-
uct 69. Thus, 68 presently fails to withstand the condi-
tions utilized to effect ring closure and these observations
are in interesting contrast to the stability of 15/16, 35/
36 and the related products successfully prepared in a
set of vancomycin ring systems.8,9
In an alternative approach to 54 which entails the
reverse macrocyclization reaction with closure conducted
with formation of the O2-C1 biaryl ether bond and
ultimately with reductive removal of the aryl nitro group,
the preparation of 80 was also examined (Scheme 16).
Analogous to the route employed for 65 and without
optimization, the erythro â-hydroxy amino acid 73 was
prepared and the stereochemistry confirmed upon cyclic
carbamate formation. However, following conversion of
73 to 79, exposure of 79 to the successful N-methylation
conditions above (2.2 equiv of NaH, 5 equiv CH3I, THF-
DMF 20:1, -10 to 25 °C, 6 h) afforded only recovered
starting material and trace amounts of methyl ester 78.
Increasing the amount of DMF cosolvent to 13:1 THF:
standing. For (S,S)-13: [R]25 -49 (c 0.5, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) mixture of two rotamers, δ 7.95 and 7.93
(two t, 1H, J ) 7.8 Hz, C5-H), 6.90-7.04 (m, 5H), 6.51-6.72
(m, 3H), 4.75-4.83 (m, 1H, ArCH2CH), 4.72 (dd, 1H, J ) 7.0,
9.0 Hz, ArCH2CH), 3.74 and 3.68 (two s, 3H, CO2CH3), 3.24
(dd, 1H, J ) 5.2, 14.0 Hz, ArCHH), 3.11 (dd, 1H, J ) 7.3, 14.0
Hz, ArCHH), 3.03 (dd, 1H, J ) 7.6, 13.4 Hz, ArCHH), 2.84
(dd, 1H, J ) 8.0, 13.4 Hz, ArCHH), 2.76 and 2.66 (two s, 3H,
NCH3), 1.40 and 1.30 (two s, 9H, CO2C(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ (major rotamer) 170.6 (2C), 155.3 (d, J )
263.0 Hz, C3), 154.6, 145.8 (d, J ) 9.0 Hz, C1), 145.4, 135.9
(d, J ) 20 Hz, C4), 130.3 (2C), 128.6, 126.2, 125.4, 119.1 (d, J
) 20 Hz, C2), 115.3 (2C), 81.1, 59.8, 52.7, 52.6, 37.6, 33.3, 31.0,
28.2 (3C); IR (neat) νmax 3342, 3016, 2978, 1744, 1670, 1605,
1518, 1441, 1392, 1349, 1222, 1163, 840, 753 cm-1; FABHRMS
(NBA-CsI) m/e 652.1093 (M+ + Cs, C25H30N3O8F requires
652.1071).
(R,R)-13: [R]25 +47 (c 0.5, CHCl3).
D
3-Flu or o-4-n itr o-N-[N-(ter t-bu tyloxyca r bon yl)-N-m eth -
yl-L-tyr osyl]-D-p h en yla la n in e Meth yl Ester ((R,S)-14).
Following the procedure described for (S,S)-13, D-6 (100 mg,
0.41 mmol) and L-11 (210 mg, 0.45 mmol, 1.1 equiv, 92% ee)
afforded (R,S)-14 (192 mg, 213 mg theoretical, 90%) and (R,R)-
13 (8 mg, 213 mg theoretical, 4%). For (R,S)-14: [R]25 -50
D
(c 1.1, CHCl3); 1H NMR (CDCl3, 400 MHz) mixture of two
rotamers, δ 7.95 and 7.87 (two t, 1H, J ) 7.8 Hz, C5-H), 6.44-
7.06 (m, 7H), 5.14 (br s, 1H, ArOH), 4.71-4.86 (m, 2H, two
ArCH2CH), 3.75 and 3.71 (two s, 3H, CO2CH3), 3.24 (dd, 1H,
J ) 5.6, 14.0 Hz, ArCHH), 3.14 (dd, 1H, J ) 5.0, 14.0 Hz,
ArCHH), 3.03 (dd, 1H, J ) 6.2, 13.7 Hz, ArCHH), 2.78 (dd,
1H, J ) 8.4, 13.7 Hz, ArCHH), 2.77 and 2.74 (two s, 3H,
NCH3), 1.39 and 1.31 (two s, 9H, CO2C(CH3)3); IR (KBr) νmax
3410, 2968, 2929, 1742, 1670, 1609, 1521, 1442, 1388, 1344,
1250, 1221, 1162, 838 cm-1; FABHRMS (NBA-CsI) m/e
652.1051 (M+ + Cs, C25H30FN3O8 requires 652.1071). Anal.
Calcd for C25H30N3O8F: C, 57.80; H, 5.78; N, 8.09. Found: C,
57.48; H, 5.99; N, 7.89.
(S,R)-14: [R]25 +53 (c 0.3, CHCl3).
D
Sch em e 15

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2063
CO2CH3), 3.28 (t, 1H, J ) 12.0 Hz, C13-HR), 2.98-3.03 (m,
2H, C8-Hâ and C13-Hâ), 2.99 (s, 3H, NCH3), 2.75 (dd, 1H, J
) 11.8, 16.8 Hz, C8-HR), 1.49 (s, 9H, CO2C(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ 171.0, 169.8, 156.4, 156.3, 155.6, 145.2,
136.7, 135.8, 133.8, 131.6, 125.6, 123.9, 123.7, 121.6, 116.4,
80.7, 61.1, 52.7, 52.1, 35.2, 34.8, 30.1, 28.4 (3C); IR (KBr) νmax
3279, 2958, 2919, 1750, 1670, 1589, 1522, 1432, 1364, 1347,
Sch em e 16
1255, 1227, 1196, 1142, 1093, 985, 882, 839, 749 cm-1
;
FABHRMS (NBA-CsI) m/e 632.0985 (M+ + Cs, C25H29N3O8
requires 632.1009). Anal. Calcd for C25H29N3O8: C, 60.12; H,
5.81; N, 8.42. Found: C, 59.86; H, 6.25; N, 8.11.
(9S,12R)-15: [R]25 +81 (c 0.7, CHCl3).
D
Met h yl 12(S)-[N-(ter t-Bu t yloxyca r b on yl)-N-m et h yl]-
a m in o-4-n it r o-11-oxo-10-a za -2-oxa t r icyclo[12.2.2.13,7]-
n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r b oxyla t e
((9S,12S)-16). A solution of (S,S)-13 (156 mg, 0.3 mmol) in
anhydrous THF (2 mL) was added dropwise to a suspension
of NaH (60% dispersion in mineral oil, 26.4 mg, 0.66 mmol,
2.2 equiv) in anhydrous THF (73 mL) at 0 °C under Ar, and
the resulting reaction mixture was stirred at 0 °C for 30 min
before being warmed to 25 °C for 6 h. The reaction was
quenched with the addition of H2O (5.0 mL) and EtOAc (50
mL). The aqueous solution was extracted with EtOAc (3 ×
10 mL), and the combined organic solution was washed with
H2O (15 mL) and saturated aqueous NaCl (10 mL), dried
(MgSO4), and concentrated in vacuo. Chromatography (SiO2,
3 × 10 cm, 20-40% EtOAc-hexane gradient elution) afforded
(9S,12S)-16 (81.3 mg, 150 mg theoretical, 54%) and (9R,12S)-
15 (21.4 mg, 150 mg theoretical, 14%). For (9S,12S)-16: pale-
yellow oil, which solidified upon standing; [R]25 -91 (c 0.5,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, 1H, J ) 8.4 Hz,
C5-H), 7.51 (dd, 1H, J ) 2.6, 8.4 Hz, C15- or C18-H), 7.46 (dd,
1H, J ) 2.6, 8.4 Hz, C18- or C15-H), 7.15 (dd, 1H, J ) 2.6, 8.4
Hz, C16- or C17-H), 7.13 (dd, 1H, J ) 2.6, 8.4 Hz, C17- or
C16-H), 6.67 (dd, 1H, J ) 1.3, 8.4 Hz, C6-H), 5.56 (d, 1H, J )
1.3 Hz, C19-H), 5.35 (br s, 1H, N10-H), 4.54 (dd, 1H, J ) 4.4,
11.9 Hz, C12-H), 4.27 (m, 1H, C9-H), 3.55 (s, 3H, CO2CH3),
3.22 (t, 1H, J ) 12.2 Hz, C13-HR), 3.15 (dd, 1H, J ) 6.3, 12.2
Hz, C13-Hâ), 3.13 (dd, 1H, J ) 5.4, 16.8 Hz, C8-HR), 3.07 (s,
3H, NCH3), 2.98 (dd, 1H, J ) 3.1, 16.8 Hz, C8-Hâ), 1.45 (s,
9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 171.2, 168.5,
156.6, 156.0, 155.9, 142.9, 136.8, 135.7, 133.8, 130.7, 125.9,
125.7, 124.0, 121.8, 119.5, 80.6, 61.8, 52.9, 52.1, 36.5, 34.9, 31.0,
28.4 (3C); IR (neat) νmax 3363, 3012, 2976, 2931, 1760, 1682,
1611, 1588, 1519, 1502, 1440, 1391, 1349, 1229, 1193, 1169,
1148, 1098, 1055, 992, 844, 755 cm-1; FABHRMS (NBA-CsI)
m/e 632.0985 (M+ + Cs, C25H29N3O8 requires 632.1009).
Following the K2CO3 procedure described for (R,S)-14, (S,S)-
13 (38 mg, 0.073 mmol) afforded the expected (9S,12S)-16 (4.0
mg, 36.4 mg theoretical, 11%) and its diastereomer (9R,12S)-
15 (19.7 mg, 36.4 mg theoretical, 54%).
(9R,12R)-16: [R]25 +91 (c 0.2, CHCl3).
D
Equ ilibr a tion Ep im er iza tion of (9S,12S)-16. A solution
of (9S,12S)-16 (12.3 mg, 0.025 mmol, [R]25D -91 (c 0.5, CHCl3)),
in anhydrous THF (2 mL), was treated with DBU (37.5 mg,
37 µL, 0.25 mmol, 10.0 equiv) at 25 °C, and the resulting
mixture was warmed at 50-55 °C for 36 h under Ar. The
solvent was removed in vacuo, and the residue was purified
by flash chromatography (SiO2, 1 × 10 cm, 20-40% EtOAc-
hexane gradient elution) to afford (9R,12S)-15 (10.5 mg, 12.3
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o ]-4-n it r o -11-o x o -10-a za -2-o x a t r ic y c lo [12.2.2.13 ,7 ]-
n on a d eca -3,5,7(19),14,16,17-h exa en e-9(R)-ca r b oxyla t e
((9R,12S)-15). A solution of (R,S)-14 (104 mg, 0.2 mmol) in
anhydrous DMF (25 mL, 0.008 M) was treated with K2CO3
(138 mg, 1.0 mmol, 5.0 equiv) at 25 °C under Ar. The resulting
reaction mixture was warmed to 45-50 °C for 4 h before the
solvent was removed in vacuo. Flash chromatography (SiO2,
1 × 10 cm, 15-30% EtOAc-hexane gradient elution) afforded
(9R,12S)-15 (77.8 mg, 99.8 mg theoretical, 78%) as a white
mg theoretical, 85.4%) as a white solid ([R]25 -82 (c 0.38,
D
CHCl3)), which was identical in all respects to an authentic
sample, and recovered (9S,12S)-16 (0.3 mg, 2.4%).
Meth yl 12(S)-(N-Meth yla m in o)-4-n itr o-11-oxo-10-a za -
2-oxa t r icyclo[12.2.2.13,7]-n on a d e ca -3,5,7(19),14,16,17-
h exa en e-9(R)-ca r boxyla te ((9R,12S)-17). A solution of
(9R,12S)-15 (27 mg, 0.054 mmol) in 2.2 N HCl -EtOAc (2 mL)
was stirred at 25 °C for 30 min before the volatiles were
removed in vacuo. The residue was then dried thoroughly
under vacuum to afford the crude HCl salt (23.5 mg, 23.5 mg
theoretical, 100%) as a white solid, which afforded white
crystals after recrystallization from CH3OH.
The crude HCl salt (20 mg, 0.046 mmol) was dissolved in
saturated aqueous NaHCO3 (2 mL), and the aqueous solution
was extracted with EtOAc (4 × 5 mL). The combined EtOAc
extracts were washed with H2O (2 mL) and saturated aqueous
solid: mp 228-230 °C (white powder, EtOAc-hexane); [R]25
D
-83 (c 0.36, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.87 (d, 1H,
J ) 8.4 Hz, C5-H), 7.50 (dd, 1H, J ) 2.2, 8.4 Hz, C18-H),
7.32 (dd, 1H, J ) 2.2, 8.4 Hz, C15-H), 7.09 (dd, 1H, J ) 2.2,
8.4 Hz, C17-H), 7.00 (dd, 1H, J ) 2.2, 8.4 Hz, C16-H), 6.73
(dd, 1H, J ) 2.2, 8.4 Hz, C6-H), 5.96 (d, 1H, J ) 8.3 Hz, N10-
H), 5.41 (d, 1H, J ) 2.2 Hz, C19-H), 4.56 (dd, 1H, J ) 5.0,
12.0 Hz, C12-H), 4.23 (t, 1H, J ) 10.0 Hz, C9-H), 3.67 (s, 3H,

2064 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
NaCl (2 mL), dried (MgSO4), and concentrated in vacuo. Flash
chromatography (SiO2, 1 × 10 cm, 0-5% CH3OH-CHCl3
gradient elution) afforded the free amine (17.0 mg, 18.4 mg
theoretical, 93%) as a white solid: 1H NMR (CDCl3, 400 MHz)
δ 7.85 (d, 1H, J ) 8.4 Hz, C5-H), 7.38 (dd, 1H, J ) 2.4, 8.4 Hz,
C15- or C18-H), 7.23 (dd, 1H, J ) 2.4, 8.4 Hz, C18- or C15-H),
7.02-7.05 (m, 2H, C16- and C17-H), 6.72 (dd, 1H, J ) 1.5, 8.4
Hz, C6-H), 5.68 (d, 1H, J ) 7.2 Hz, N10-H), 5.34 (d, 1H, J )
1.5 Hz, C19-H), 4.20 (dd, 1H, J ) 8.0, 10.4 Hz, C9-H), 3.72 (s,
3H, CO2CH3), 3.26 (dd, 1H, J ) 4.9, 12.2 Hz, C12-H), 3.04 (dd,
1H, J ) 4.9, 11.3 Hz, C13-Hâ), 2.99 (d, 1H, J ) 17.4 Hz, C8-
Hâ), 2.80 (dd, 1H, J ) 11.3, 17.4 Hz, C8-HR), 2.75 (t, 1H, J )
11.8 Hz, C13-HR), 2.44 (s, 3H, NCH3); IR (neat) νmax 3297,
3026, 2953, 2851, 1746, 1663, 1590, 1519, 1436, 1349, 1228,
1196, 1106, 988, 840, 753 cm-1; FABHRMS (NBA-CsI) m/e
532.0468 (M+ + Cs, C20H21N3O6 requires 532.0485).
boxyla te ((9S,12S)-20). Colorless oil, which solidified upon
standing; [R]25 -133 (c 0.3, CHCl3); 1H NMR (CDCl3, 400
D
MHz) mixture of two conformational isomers (conformer A:B
) 3:1), δ (for conformer A) 7.46 (dd, 1H, J ) 2.1, 8.3 Hz, C15-
or C18-H), 7.26 (dd, 1H, J ) 2.1, 8.3 Hz, C18- or C15-H), 7.15
(dd, 1H, J ) 2.2, 8.3 Hz, C16- or C17-H), 6.83 (dd, 1H, J )
2.2, 8.3 Hz, C17- or C16-H), 6.80 (d, 1H, J ) 8.3 Hz, C5-H),
6.53 (dd, 1H, J ) 1.6, 8.3 Hz, C6-H), 5.55 (br s, 1H, ArOH),
4.87 (dd, 1H, J ) 2.6, 11.2 Hz, C9- or C12-H), 4.67 (dd, 1H, J
) 3.9, 12.2 Hz, C12- or C9-H), 4.40 (d, 1H, J ) 1.6 Hz, C19-
H), 3.66 (s, 3H, CO2CH3), 3.62 (dd, 1H, J ) 5.0, 11.2 Hz, C13-
HR), 3.29 (dd, 1H, J ) 3.6, 17.8 Hz, C8-Hâ), 2.90 (s, 3H, NCH3),
2.83-2.88 (m, 1H, C8-HR), 2.70 (dd, 1H, J ) 2.4, 11.2 Hz, C13-
Hâ), 2.54 (s, 3H, NCH3), 1.46 (s, 9H, CO2C(CH3)3); δ (for
conformer B) 7.51 (dd, 1H, J ) 2.1, 8.3 Hz, C15- or C18-H),
7.34 (dd, 1H, J ) 2.1, 8.3 Hz, C18- or C15-H), 6.96 (dd, 1H, J
) 2.2, 8.3 Hz, C16- or C17-H), 6.88 (dd, 1H, J ) 2.2, 8.3 Hz,
C17- or C16-H), 6.77 (d, 1H, J ) 8.3 Hz, C5-H), 6.57 (dd, 1H,
J ) 1.6, 8.3 Hz, C6-H), 5.55 (br s, 1H, ArOH), 5.48 (dd, 1H, J
) 4.9, 12.2 Hz, C9- or C12-H), 4.91 (d, 1H, J ) 1.6 Hz, C19-
H), 4.40 (m, 1H, C12- or C9-H), 3.63 (s, 3H, CO2CH3), 3.38
(dd, 1H, J ) 4.4, 11.4 Hz, C8- or C13-H), 2.84-3.18 (m, 3H,
C8- and C13-H), 2.89 (s, 3H, NCH3), 2.67 (s, 3H, NCH3), 1.48
(s, 9H, CO2C(CH3)3); IR (neat) νmax 3344, 2923, 2852, 1742,
A single crystal X-ray structure determination conducted
on the HCl salt confirmed the structure and relative stereo-
chemistry of 17.17
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o ]-10-m e t h y l-4-n it r o -11-o x o -10-a za -2-o x o t r ic y c lo -
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r -
boxyla te ((9S,12S)-18). Following the procedure described
for 23, (9S,12S)-16 (81 mg, 0.16 mmol, 20:1 THF-DMF, 0-25
°C, 1 h) afforded (9S,12S)-18 (73 mg, 80 mg theoretical, 91%),
which was contaminated with ca. 3% of 23, as a colorless oil
1657, 1586, 1441, 1282, 1256, 1178, 1096, 1021, 860, 756 cm-1
;
FABHRMS (NBA-CsI) m/e 617.1286 (M+ + Cs, C26H32N2O7
requires 617.1264).
which solidified upon standing: [R]25 -146 (c 0.55, CHCl3);
D
1H NMR (CDCl3, 400 MHz) mixture of two conformational
isomers (conformer A:B ) 3.8:1), δ (for conformer A) 7.87 (d,
1H, J ) 8.4 Hz, C5-H), 7.49 (dd, 1H, J ) 1.9, 8.4 Hz, C15- or
C18-H), 7.29 (dd, 1H, J ) 1.9, 8.4 Hz, C18- or C15-H), 7.17
(dd, 1H, J ) 2.3, 8.4 Hz, C16- or C17-H), 6.90 (dd, 1H, J )
2.3, 8.4 Hz, C17- or C16-H), 6.72 (dd, 1H, J ) 1.6, 8.4 Hz, C6-
H), 4.88 (d, 1H, J ) 2.8, 11.2 Hz, C9- or C12-H), 4.71 (dd, 1H,
J ) 3.6, 12.0 Hz, C12- or C9-H), 4.63 (d, 1H, J ) 1.6 Hz, C19-
H), 3.68 (s, 3H, CO2CH3), 3.65 (dd, 1H, J ) 3.8, 14.8 Hz, C13-
Hâ), 3.42 (dd, 1H, J ) 3.3, 18.4 Hz, C8-Hâ), 3.03 (dd, 1H, J )
12.8, 18.4 Hz, C8-HR), 2.93 (s, 3H, NCH3), 2.73 (dd, 1H, J )
12.3, 14.8 Hz, C13-HR), 2.53 (s, 3H, NCH3), 1.45 (s, 9H, CO2C-
(CH3)3); δ (for conformer B) 7.83 (d, 1H, J ) 8.3 Hz, C5-H),
7.56 (dd, 1H, J ) 1.9, 8.4 Hz, C15- or C18-H), 7.37 (dd, 1H, J
) 1.9, 8.4 Hz, C18- or C15-H), 7.28 (dd, 1H, J ) 2.3, 8.4 Hz,
C16- or C17-H), 7.01 (dd, 1H, J ) 2.3, 8.4 Hz, C17- or C16-H),
6.77 (dd, 1H, J ) 1.6, 8.4 Hz, C6-H), 5.51 (dd, 1H, J ) 5.0,
12.0 Hz, C9- or C12-H), 5.10 (d, 1H, J ) 1.6 Hz, C19-H), 4.62
(m, 1H, C12- or C9-H, partially obscured by C19-H of con-
former A), 3.64 (s, 3H, CO2CH3), 3.16-3.27 (m, 2H, C8- and/
or C13-H), 2.92-3.11 (m, 2H, C8- and/or C13-H), 2.91 (s, 3H,
NCH3), 2.76 (s, 3H, NMe), 1.48 (s, 9H, CO2C(CH3)3); IR (neat)
νmax 2927, 2851, 1745, 1686, 1655, 1589, 1522, 1495, 1441,
For the reduced product, methyl 12(S)-[N-(tert-butyloxy-
ca r bon yl)-N -m et h yla m in o]-10-m et h yl-11-oxo-10-a za -2-
oxatricyclo[12.2.2.13,7]nonadeca-3,5,7(19),14,16,17-hexaene-
9(S)-carboxylate: colorless oil; 1H NMR (CDCl3, 400 MHz)
mixture of two conformational isomers (conformer A:B ) 3:1),
δ (for conformer A) 7.44 (dd, 1H, J ) 1.8, 8.3 Hz, C15- or C18-
H), 7.25 (dd, 1H, J ) 1.8, 8.3 Hz, C18- or C15-H), 7.14 (t, 1H,
J ) 7.8 Hz, C5-H), 6.96 (dd, 2H, J ) 2.0, 8.3 Hz, C16- and
C17-H), 6.84 (dd, 1H, J ) 2.1, 8.3 Hz, C4-H), 6.62 (dd, 1H, J
) 2.1, 8.3 Hz, C6-H), 4.89 (dd, 1H, J ) 2.7, 11.3 Hz, C9- or
C12-H), 4.72 (dd, 1H, J ) 3.4, 12.0 Hz, C12- or C9-H), 4.39 (d,
1H, J ) 2.1 Hz, C19-H), 3.66 (s, 3H, CO2CH3), 3.61 (m, 1H,
C13-Hâ), 3.36 (dd, 1H, J ) 2.8, 18.2 Hz, C8-Hâ), 3.18 (t, 1H,
J ) 12.0 Hz, C13-HR), 2.95 (dd, 1H, J ) 12.0, 18.2 Hz, C8-
HR), 2.92 (s, 3H, NCH3), 2.55 (s, 3H, NCH3), 1.46 (s, 9H, CO2C-
(CH3)3); δ (for conformer B) 7.51 (dd, 1H, J ) 1.8, 8.3 Hz, C15-
or C18-H), 7.32 (dd, 1H, J ) 1.8, 8.3 Hz, C18- or C15-H), 7.12
(t, 1H, J ) 7.8 Hz, C5-H), 6.96 (dd, 2H, J ) 2.0, 8.3 Hz, C16-
and C17-H), 6.89 (dd, 1H, J ) 2.1, 8.3 Hz, C4-H), 6.67 (dd,
1H, J ) 2.1, 8.3 Hz, C6-H), 5.49 (dd, 1H, J ) 5.0, 12.0 Hz, C9-
or C12-H), 4.87 (d, 1H, J ) 2.1 Hz, C19-H), 4.46 (dd, 1H, J )
2.7, 11.2 Hz, C12- or C9-H), 3.62 (s, 3H, CO2CH3), 3.42 (dd,
1H, J ) 4.2, 11.4 Hz, C13-Hâ), 2.90-3.23 (m, 3H, C8-H2 and
C13-HR), 2.91 (s, 3H, NCH3), 2.70 (s, 3H, NCH3), 1.49 (s, 9H,
CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ (for major confor-
mational isomer) 171.3, 170.9, 164.0, 157.7, 155.5, 137.0, 136.1,
132.6, 131.1, 129.1, 125.9, 124.0, 121.0, 114.1, 112.7, 80.1, 57.0,
56.8, 52.6, 37.3, 33.5, 31.2, 29.8, 28.5 (3C); IR (neat) νmax 2973,
2929, 2854, 1747, 1688, 1650, 1587, 1492, 1445, 1367, 1335,
1313, 1281, 1257, 1208, 1143, 1096, 1020, 964, 898, 863, 837,
1347, 1278, 1221, 1196, 1168, 1145, 1096, 1026, 840, 713 cm-1
;
FABHRMS (NBA-CsI) m/e 646.1184 (M+ + Cs, C26H31N3O8
requires 646.1165).
Meth yl 4-Am in o-12(S)-[N-(ter t-bu tyloxyca r bon yl)-N-
m et h yla m in o]-10-m et h yl-11-oxo-10-a za -2-oxa t r icyclo-
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r -
boxyla te ((9S,12S)-19). Following the procedure detailed for
the reduction of 15, (9S,12S)-18 (67 mg, 0.16 mmol) afforded
19 (60 mg, 63 mg theoretical, 95%) as a pink oil, which
solidified upon standing: 1H NMR (CDCl3, 400 MHz) mixture
of two conformational isomers, δ (for major isomer) 7.41 (dd,
1H, J ) 1.9, 8.4 Hz, C15- or C18-H), 7.29 (dd, 1H, J ) 1.9, 8.4
Hz, C18- or C15-H), 7.21 (dd, 1H, J ) 2.1, 8.4 Hz, C16- or
C17-H), 7.11 (dd, 1H, J ) 2.1, 8.4 Hz, C17- or C16-H), 6.77 (d,
1H, J ) 8.4 Hz, C5-H), 6.48 (dd, 1H, J ) 1.6, 8.4 Hz, C6-H),
4.85 (dd, 1H, J ) 2.4, 11.2 Hz, C9- or C12-H), 4.64 (dd, 1H, J
) 3.4, 14.9 Hz, C12- or C9-H), 4.34 (d, 1H, J ) 1.6 Hz, C19-
H), 3.64 (s, 3H, CO2CH3), 2.56-3.29 (m, 4H, C8-H2 and C13-
H2), 2.89 (s, 3H, NCH3), 2.52 (s, 3H, NCH3), 1.44 (s, 9H,
CO2C(CH3)3); IR (neat) νmax 3365, 2927, 2851, 1743, 1686, 1654,
1589, 1519, 1500, 1445, 1367, 1335, 1304, 1210, 1144, 1026,
866, 837, 736, 705 cm-1; FABHRMS (NBA-CsI) m/e 616.1450
(M+ + Cs, C26H33N3O6 requires 616.1424).
793, 736 cm-1; FABHRMS (NBA-CsI) m/e 601.1287 (M+
+
Cs, C26H32N2O6 requires 601.1315).
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o]-4-m et h oxy-10-m et h yl-11-oxo-10-a za -2-oxa t r icyclo-
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r -
boxyla te ((9S,12S)-21). Following the procedure described
for 26, (9S,12S)-20 (12 mg, 0.025 mmol) afforded (9S,12S)-21
(10.5 mg, 12.5 mg theoretical, 84%) as a white solid: [R]25
D
-161 (c 0.2, CHCl3); 1H NMR (CDCl3, 400 MHz) mixture of
two conformational isomers (conformer A:B ) 3.6:1), δ (for
conformer A) 7.44 (dd, 1H, J ) 1.8, 8.3 Hz, C15- or C18-H),
7.32 (dd, 1H, J ) 1.8, 8.3 Hz, C18- or C15-H), 7.15 (dd, 1H, J
) 2.2, 8.3 Hz, C16- or C17-H), 6.87 (dd, 1H, J ) 2.2, 8.3 Hz,
C17- or C16-H), 6.79 (d, 1H, J ) 8.3 Hz, C5-H), 6.59 (dd, 1H,
J ) 1.6, 8.3 Hz, C6-H), 4.88 (dd, 1H, J ) 2.7, 11.2 Hz, C9- or
C12-H), 4.68 (dd, 1H, J ) 3.7, 12.2 Hz, C12- or C9-H), 4.40 (d,
1H, J ) 1.6 Hz, C19-H), 3.93 (s, 3H, ArOCH3), 3.66 (s, 3H,
CO2CH3), 3.62 (t, 1H, J ) 12.0 Hz, C13-HR), 3.31 (dd, 1H, J )
3.3, 18.0 Hz, C8-Hâ), 2.93 (dd, 1H, J ) 12.0, 18.0 Hz, C8-HR),
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o]-4-h yd r oxy-10-m et h yl-11-oxo-10-a za -2-oxa t r icyclo-
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r -

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2065
2.91 (s, 3H, NCH3), 2.70 (dd, 1H, J ) 2.7, 12.0 Hz, C13-Hâ),
2.55 (s, 3H, NCH3), 1.45 (s, 9H, CO2C(CH3)3); δ (for conformer
B) 7.53 (dd, 1H, J ) 1.8, 8.3 Hz, C15- or C18-H), 7.22 (dd, 1H,
J ) 1.8, 8.3 Hz, C18- or C15-H), 7.03 (dd, 1H, J ) 2.2, 8.3 Hz,
C16- or C17-H), 6.91 (dd, 1H, J ) 2.2, 8.3 Hz, C17- or C16-H),
6.73 (d, 1H, J ) 8.3 Hz, C5-H), 6.63 (dd, 1H, J ) 1.6, 8.3 Hz,
C6-H), 5.51 (dd, 1H, J ) 4.8, 12.2 Hz, C9- or C12-H), 4.79 (d,
1H, J ) 1.6 Hz, C19-H), 4.30 (dd, 1H, J ) 3.7, 12.2 Hz, C12-
or C9-H), 3.92 (s, 3H, ArOCH3), 3.61 (s, 3H, CO2CH3), 3.40
(dd, 1H, J ) 4.2, 11.4 Hz, C13-Hâ), 2.67-3.22 (m, 3H, C8-H2
and C13-HR), 2.85 (s, 3H, NCH3), 2.74 (s, 3H, NCH3), 1.49 (s,
9H, CO2C(CH3)3); IR (neat) νmax 2972, 2932, 2855, 1747, 1683,
1652, 1585, 1517, 1443, 1368, 1335, 1312, 1263, 1211, 1144,
1096, 1027, 899, 862, 838, 798, 756 cm-1; FABHRMS (NBA-
CsI) m/e 631.1448 (M+ + Cs, C27H34N2O7 requires 631.1420).
Meth yl 4-Meth oxy-12(S)-(N-m eth yla m in o)-10-m eth yl-
11-oxo-10-aza-2-oxatr icyclo[12.2.2.13,7]n on adeca-3,5,7(19),-
14,16,17-h exa en e-9(S)-ca r boxyla te ((9S,12S)-22). Follow-
ing the procedure described for 27, (9S,12S)-21 (10.5 mg, 0.021
mmol) afforded (9S,12S)-22 (7.8 mg, 8.4 mg theoretical, 93%)
as a white solid, which consisted of two separable conforma-
tional isomers (conformer A: Rf 0.36, 5.2 mg, 62%; conformer
B: Rf 0.29, 2.6 mg, 31%; 5% CH3OH-CHCl3) and each
separated conformer slowly reverted to an equilibrium mixture
of two conformational isomers when they were allowed to stand
in CHCl3 solution: [R]25D +17 (c 0.12, CHCl3), -10 (c 0.12, CH3-
OH); 1H NMR (CDCl3, 400 MHz) mixture of two conforma-
tional isomers (conformer A:B ) 9:8), δ (for conformer A) 7.35
(dd, 1H, J ) 2.0, 8.4 Hz, C15- or C18-H), 7.25 (dd, 1H, J )
2.1, 8.3 Hz, C18- or C15-H), 7.14 (dd, 1H, J ) 2.2, 8.3 Hz, C16-
or C17-H), 6.91 (dd, 1H, J ) 2.2, 8.4 Hz, C17- or C16-H), 6.80
(d, 1H, J ) 8.3 Hz, C5-H), 6.60 (dd, 1H, J ) 2.0, 8.3 Hz, C6-
H), 4.34 (dd, 1H, J ) 3.4, 11.4 Hz, C9-H), 4.26 (d, 1H, J ) 2.0
Hz, C19-H), 3.93 (s, 3H, ArOCH3), 3.70 (s, 3H, CO2CH3), 3.47
(dd, 1H, J ) 3.9, 10.3 Hz, C12-H), 2.72-3.26 (m, 4H, C8-H2
and C13-H2), 2.72 (s, 3H, N10-CH3), 2.39 (s, 3H, C12-NCH3);
δ (for conformer B) 7.43 (dd, 1H, J ) 2.0, 8.4 Hz, C15- or C18-
H), 7.21 (dd, 1H, J ) 2.1, 8.4 Hz, C18- or C15-H), 7.19 (dd,
1H, J ) 2.2, 8.4 Hz, C16- or C17-H), 7.04 (dd, 1H, J ) 2.1, 8.4
Hz, C17- or C16-H), 6.74 (d, 1H, J ) 8.1 Hz, C5-H), 6.60 (dd,
1H, J ) 2.0, 8.3 Hz, C6-H), 4.70 (d, 1H, J ) 2.0 Hz, C19-H),
3.92 (s, 3H, ArOCH3), 3.92 (m, 1H, C9-H, partially obscured
by ArOCH3), 3.67 (s, 3H, CO2CH3), 3.53 (dd, 1H, J ) 3.7, 10.2
Hz, C12-H), 2.72-3.26 (m, 4H, C8-H2 and C13-H2), 2.69 (s,
3H, N10-CH3), 2.49 (s, 3H, C12-NCH3); IR (neat) νmax 3344,
2922, 2841, 1741, 1641, 1517, 1442, 1253, 1201, 1128, 1024,
838, 805 cm-1; FABHRMS (NBA-CsI) m/e 399.1908 (con-
former A) and 399.1914 (conformer B) (M+ + H, C22H26N2O5
requires 399.1920).
1H, J ) 12.0, 18.6 Hz, C8-HR), 2.98 (dd, 1H, J ) 5.0, 12.0 Hz,
C13-Hâ), 2.92 (s, 3H, C12-NCH3), 2.78 (s, 3H, N10-CH3), 1.50
(s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 170.9,
170.6, 156.6, 156.0, 154.9, 145.0, 136.1, 133.8, 131.4, 130.8,
125.5, 124.1, 122.9, 121.2, 115.0, 80.5, 56.7, 55.3, 52.6, 35.6,
31.4, 30.3, 29.8, 28.3 (3C); IR (KBr) νmax 2968, 2919, 1742, 1683,
1653, 1590, 1521, 1442, 1344, 1255, 1221, 1201, 1172, 1147,
1019, 902, 838 cm-1; FABHRMS (NBA-CsI) m/e 646.1139 (M+
+ Cs, C26H31N3O8 requires 646.1165).
Following the procedure described above, (9R,12S)-35 (9.7
mg, 0.02 mmol) treated with 2.2 equiv of NaH (1.8 mg, 0.044
mmol) afforded (9R,12S)-23 (5.1 mg, 10.3 mg theoretical, 50%).
Meth yl 4-Am in o-12(S)-[N-(ter t-bu tyloxyca r bon yl)-N-
m et h yla m in o]-10-m et h yl-11-oxo-10-a za -2-oxa t r icyclo-
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(R)-ca r -
boxyla te ((9R,12S)-24). A solution of (9R,12S)-23 (51.3 mg,
0.1 mmol) in anhydrous CH3OH (5 mL) was treated with 10%
Pd-C (10 mg, 20% wt equiv) at 25 °C and stirred under an
atmosphere of H2 (1 atm) for 1 h. The reaction mixture was
filtered through Celite (CH3OH wash), concentrated in vacuo,
and dried thoroughly under vacuum to afford (9R,12S)-24 (46
mg, 48.3 mg theoretical, 95%) as a white foam: 1H NMR
(acetone-d6, 400 MHz) mixture of two rotamers, δ 7.52 and
7.45 (two dd, 1H, J ) 2.2, 8.0 Hz, C18-H), 7.24 (dd, 1H, J )
2.2, 8.0 Hz, C15-H), 7.03 (dd, 1H, J ) 2.2, 8.0 Hz, C17-H),
6.95 (dd, 1H, J ) 2.2, 8.0 Hz, C16-H), 6.78 and 6.64 (two d,
1H, J ) 8.2 Hz, C5-H), 6.58 and 6.48 (two dd, 1H, J ) 2.2, 8.2
Hz, C6-H), 5.97 and 4.67 (two m, 1H, C12-H), 5.36 and 5.17
(two m, 1H, C9-H), 4.74 and 4.51 (two d, 1H, J ) 2.2 Hz, C19-
H), 4.72 and 4.68 (two s, 2H, C4-NH2), 3.61 (s, 3H, CO2CH3),
3.23 (t, 1H, J ) 11.0 Hz, C13-HR), 2.85-3.00 (m, 3H, C13-Hâ
and C8-H2), 2.83 (s, 3H, C12-NCH3), 2.79 (s, 3H, N10-CH3),
1.54 and 1.48 (two s, 9H, CO2C(CH3)3); IR (neat) νmax 3405,
2954, 2862, 1698, 1615, 1538, 1462, 1431, 1348, 1242, 1195,
1082, 1005, 913, 826, 790 cm-1; FABHRMS (NBA-CsI) m/e
616.1451 (M+ + Cs, C26H33N3O6 requires 616.1424).
Meth yl (12S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o]-4-h yd r oxy-10-m et h yl-11-oxo-10-a za -2-oxa t r icyclo-
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(R)-ca r -
boxyla te ((9R,12S)-25). A solution of (9R,12S)-24 (22 mg,
0.046 mmol) in anhydrous THF (1.0 mL) was treated dropwise
with HBF4 (48% aqueous solution, 17 mg, 12 µL, 0.092 mmol,
2.0 equiv) at 0 °C under Ar, and the resulting mixture was
stirred at 0 °C for 30 min before being warmed to 25 °C for 1
h. The reaction mixture was recooled to 0 °C and treated
dropwise with tert-butyl nitrite (10 mg, 11.5 µL, 0.092 mmol,
2.0 equiv), and the resulting reaction mixture was stirred at
0 °C for 1 h. The solvent was removed in vacuo at 0 °C, the
residue was immediately treated with 10 mL of an aqueous
solution containing Cu(NO3)2‚3H2O (1.11 g, 4.6 mmol, 100
equiv) and Cu2O (33 mg, 0.23 mmol, 5.0 equiv) at 0 °C under
Ar, and the mixture was warmed to 25 °C for 1 h. The reaction
mixture was filtered through Celite (H2O and CH2Cl2 wash),
and the filtrate was extracted with CH2Cl2 (5 × 10 mL). The
combined CH2Cl2 extracts were washed with saturated aque-
ous NH4Cl (5 mL), H2O (5 mL), and saturated aqueous NaCl
(5 mL), dried (MgSO4), and concentrated in vacuo. Flash
chromatography (SiO2, 1 × 8 cm, 10-30% EtOAc-hexane
gradient elution) afforded (9R,12S)-25 (11.4 mg, 22.3 mg
theoretical, 51%) and the corresponding reduced product (3.0
mg, 21.5 mg theoretical, 14%). For (9R,12S)-25: colorless oil,
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o ]-10-m e t h y l-4-n it r o -11-o x o -10-a za -2-o x a t r ic y c lo -
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(R)-ca r -
boxylate ((9R,12S)-23). A suspension of NaH (60% dispersion
in mineral oil, 6.9 mg, 0.173 mmol, 1.2 equiv) in anhydrous
THF (5 mL) was treated dropwise with a solution of (9R,12S)-
15 (72 mg, 0.144 mmol) in anhydrous THF (1 mL) at 0 °C
under Ar, and the resulting mixture was stirred for 10 min at
0 °C before being treated with CH3I (204 mg, 90 µL, 1.44 mmol,
10.0 equiv) and anhydrous DMF (0.3 mL). The reaction
mixture was stirred at 0 °C for 30 min before being warmed
to 25 °C for 3 h. The reaction was quenched by addition of
H2O (2 mL), and the aqueous solution was extracted with
EtOAc (4 × 5 mL). The combined EtOAc extracts were washed
with H2O (5 mL) and saturated aqueous NaCl (5 mL), dried
(MgSO4), and concentrated in vacuo. Flash chromatography
(SiO2, 1 × 8 cm, 20-40% EtOAc-hexane gradient elution)
afforded (9R,12S)-23 (67.8 mg, 73.8 mg theoretical, 92%) as a
which solidified upon standing; [R]25 -137 (c 0.5, CHCl3); 1H
D
NMR (CDCl3, 400 MHz) δ 7.48 (dd, 1H, J ) 2.0, 8.2 Hz, C18-
H), 7.31 (dd, 1H, J ) 2.0, 8.2 Hz, C15-H), 6.99 (dd, 2H, J )
2.0, 8.2 Hz, C16- and C17-H), 6.82 (d, 1H, J ) 8.2 Hz, C5-H),
6.58 (dd, 1H, J ) 1.6, 8.2 Hz, C6-H), 5.55 (s, 1H, C4-OH), 5.33
(dd, 1H, J ) 5.0, 11.6 Hz, C12-H), 4.81 (d, 1H, J ) 11.7 Hz,
C9-H), 4.71 (d, 1H, J ) 1.6 Hz, C19-H), 3.66 (s, 3H, CO2CH3),
3.24 (t, 1H, J ) 11.6 Hz, C13-HR), 3.07 (d, 1H, J ) 17.5 Hz,
C8-Hâ), 2.94 (dd, 1H, J ) 11.7, 17.5 Hz, C8-HR), 2.90-2.97
(m, 1H, C13-Hâ, partially obscured by C12-NCH3 and C8-HR),
2.90 (s, 3H, C12-NCH3), 2.77 (s, 3H, N10-CH3), 1.50 (s, 9H,
CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 171.8, 170.2, 155.8,
150.3, 142.9, 135.6, 133.6, 131.2, 130.6, 129.4, 124.5, 123.5,
121.7, 115.2, 112.6, 80.4, 56.9, 56.0, 52.3, 35.6, 30.6, 30.1, 29.8,
28.4 (3C); IR (neat) νmax 3374, 2964, 2923, 2851, 1743, 1682,
colorless oil, which solidified as a white solid upon standing:
1
[R]25 -99 (c 0.12, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.87
D
(d, 1H, J ) 8.3 Hz, C5-H), 7.51 (dd, 1H, J ) 2.2, 8.3 Hz, C18-
H), 7.33 (dd, 1H, J ) 2.2, 8.3 Hz, C15-H), 7.04 (dd, 1H, J )
2.2, 8.3 Hz, C17-H), 7.01 (dd, 1H, J ) 2.2, 8.3 Hz, C16-H),
6.76 (dd, 1H, J ) 2.2, 8.3 Hz, C6-H), 5.37 (dd, 1H, J ) 5.0,
12.0 Hz, C12-H), 5.01 (d, 1H, J ) 2.2 Hz, C19-H), 4.81 (d, 1H,
J ) 12.0 Hz, C9-H), 3.68 (s, 3H, CO2CH3), 3.26 (t, 1H, J )
12.0 Hz, C13-HR), 3.20 (d, 1H, J ) 18.6 Hz, C8-Hâ), 3.03 (dd,

2066 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
1652, 1595, 1518, 1441, 1364, 1333, 1282, 1213, 1180, 1139,
1108, 1021, 836, 805, 754 cm-1; FABHRMS (NBA-CsI) m/e
617.1277 (M+ + Cs, C26H32N2O7 requires 617.1264).
8.3 Hz, C6-H), 4.73 (d, 1H, J ) 2.2 Hz, C19-H), 4.64 (dd, 1H,
J ) 2.6, 12.6 Hz, C9-H), 4.06 (dd, 1H, J ) 5.5, 10.8 Hz, C12-
H), 3.94 (s, 3H, ArOCH3), 3.69 (s, 3H, CO2CH3), 3.47 (dd, 1H,
J ) 5.5, 12.5 Hz, C13-Hâ), 3.08 (dd, 1H, J ) 2.6, 18.1 Hz, C8-
Hâ), 2.94 (dd, 1H, J ) 12.6, 18.1 Hz, C8-HR), 2.78 (dd, 1H, J
) 10.8, 12.5 Hz, C13-HR), 2.77 (s, 3H, N10-CH3), 2.48 (s, 3H,
C12-NCH3); IR (KBr) νmax 3447, 2919, 2848, 1738, 1652, 1555,
1533, 1516, 1459, 1266, 1212, 1161, 1125, 1069, 1023, 875, 839,
808 cm-1; FABHRMS (NBA-CsI) m/e 531.0883 (M+ + Cs,
C22H26N2O5 requires 531.0896).
For the reduced product, methyl 12(S)-[N-(tert-butyl-
oxycarbonyl)-N-methylamino]-10-methyl-11-oxo-10-aza-2-
oxatricyclo[12.2.2.13,7]nonadeca-3,5,7(19),14,16,17-hexaene-
9(R)-carboxylate: colorless oil, which solidified upon standing;
1H NMR (CDCl3, 400 MHz) δ 7.47 (dd, 1H, J ) 2.0, 8.2 Hz,
C18-H), 7.29 (dd, 1H, J ) 2.0, 8.2 Hz, C15-H), 7.15 (t, 1H, J )
8.0 Hz, C5-H), 6.98 (d, 3H, J ) 8.2 Hz, C6-, C16- and C17-H),
6.67 (dd, 1H, J ) 1.6, 8.0 Hz, C4-H), 5.35 (dd, 1H, J ) 5.0,
11.6 Hz, C12-H), 4.81 (d, 1H, J ) 12.0 Hz, C9-H), 4.73 (d, 1H,
J ) 1.6 Hz, C19-H), 3.66 (s, 3H, CO2CH3), 3.23 (t, 1H, J )
11.6 Hz, C13-HR), 3.14 (d, 1H, J ) 17.8 Hz, C8-Hâ), 3.01 (dd,
1H, J ) 12.0, 17.8 Hz, C8-HR), 2.95 (dd, 1H, J ) 5.0, 11.6 Hz,
C13-Hâ), 2.92 (s, 3H, C12-NCH3), 2.80 (s, 3H, N10-CH3), 1.50
(s, 9H, CO2C(CH3(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 171.7,
170.3, 163.5, 156.2, 155.8, 138.8, 135.1, 133.4, 131.1, 129.0,
124.6, 123.5, 121.2, 114.3, 112.4, 80.4, 56.7, 55.8, 52.3, 35.7,
31.2, 30.2, 29.8, 28.4 (3C); IR (KBr) νmax 2974, 2928, 1744, 1682,
1645, 1587, 1487, 1445, 1364, 1333, 1221, 1147, 1026, 862, 835,
Meth yl 4-Am in o-12(S)-[N-(ter t-bu tyloxyca r bon yl)-N-
m et h yla m in o]-11-oxo-10-a za -2-oxa t r icyclo[12.2.2.13,7]-
n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r b oxyla t e
((9S,12S)-28). Following the procedure detailed for 24, (9S,-
12S)-16 (43 mg, 0.086 mmol) afforded (9S,12S)-28 (38.3 mg,
40.3 mg theoretical, 95%) as a pink solid:
1H NMR (acetone-
d6, 400 MHz) mixture of two rotamers, δ 7.47-7.51 (m, 1H,
C15- or C18-H), 7.28-7.34 (m, 1H, C18- or C15-H), 7.12 and
7.10 (two dd, 1H, J ) 2.0, 8.4 Hz, C16- or C17-H), 6.81-6.93
(m, 2H, C17- or C16-H and C5-H), 6.31-6.59 (m, 2H, C6-H
and N10-H), 5.54 and 5.39 (two br s, 1H, C19-H), 4.57-4.62
(m, 1H, C9- or C12-H), 4.04-4.09 (m, 1H, C12- or C9-H), 3.42
and 3.40 (two s, 3H, CO2CH3), 3.05 and 3.04 (two s, 3H, NCH3),
2.79-3.17 (m, 4H, C8-H2 and C13-H2), 1.43 (s, 9H, CO2C-
(CH3)3); IR (neat) νmax 3358, 2931, 1761, 1726, 1676, 1627,
1587, 1519, 1502, 1440, 1366, 1202, 1147, 1097, 1054, 988, 859,
735 cm-1; FABHRMS (NBA-CsI) m/e 602.1252 (M+ + Cs,
C25H31N3O6 requires 602.1267).
780, 687 cm-1; FABHRMS (NBA-CsI) m/e 601.1337 (M+
Cs, C26H32N2O6 requires 601.1315).
+
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o]-4-m et h oxy-10-m et h yl-11-oxo-10-a za -2-oxa t r icyclo-
[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-9(R)-ca r -
boxylate ((9R,12S)-26). A suspension of NaH (60% dispersion
in mineral oil, 1.0 mg, 0.025 mmol, 1.2 equiv) in anhydrous
THF (0.5 mL) was treated dropwise with a solution of (9R,-
12S)-25 (10.0 mg, 0.021 mmol) in anhydrous THF (100 µL) at
0 °C under Ar, and the resulting mixture was stirred for 10
min at 0 °C before being treated with CH3I (28.4 mg, 13.0 µL,
0.21 mmol, 10.0 equiv). The reaction mixture was stirred at
0 °C for 10 min and at 25 °C for 1 h. The reaction was
quenched by addition of H2O (0.5 mL), and the aqueous
solution was extracted with EtOAc (4 × 4 mL). The combined
EtOAc extracts were washed with H2O (2 mL) and saturated
aqueous NaCl (2 mL), dried (MgSO4), and concentrated in
vacuo. Flash chromatography (SiO2, 1 × 6 cm, 20-30%
EtOAc-hexane gradient elution) afforded (9R,12S)-26 (9.7 mg,
10.5 mg theoretical, 92%) as a colorless oil, which solidified
Meth yl 12(S)-[N-(ter t-bu tyloxyca r bon yl)-N-m eth yla m i-
n o]-4-h yd r oxy-11-oxo-10-a za -2-oxa t r icyclo[12.2.2.13,7]-
n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r b oxyla t e
((9S,12S)-29). Following the procedure described for 25, (9S,-
12S)-28 (32 mg, 0.068 mmol) afforded (9S,12S)-29 (13.4 mg,
32 mg theoretical, 41%) and the corresponding reduced product
(5.2 mg, 30.9 mg theoretical, 17%). For (9S,12S)-29: white
solid; [R]25 -106 (c 0.55, CHCl3); 1H NMR (CDCl3, 400 MHz)
D
δ 7.45 (dd, 1H, J ) 2.0, 8.2 Hz, C15- or C18-H), 7.41 (dd, 1H,
J ) 2.0, 8.2 Hz, C18- or C15-H), 7.09 (dd, 1H, J ) 2.2, 8.4
Hz, C16- or C17-H), 7.00 (dd, 1H, J ) 2.4, 8.4 Hz, C17- or
C16-H), 6.72 (d, 1H, J ) 8.2 Hz, C5-H), 6.44 (dd, 1H, J ) 1.6,
8.2 Hz, C6-H), 5.94 (s, 1H, ArOH), 5.32 (br s, 1H, N10-H), 5.28
(d, 1H, J ) 1.6 Hz, C19-H), 4.56 (m, 1H, C12-H), 4.25 (m, 1H,
C9-H), 3.51 (s, 3H, CO2CH3), 3.19 (t, 1H, J ) 12.4 Hz, C13-
HR), 3.12 (dd, 1H, J ) 4.2, 12.4 Hz, C13-Hâ), 3.06 (s, 3H,
NCH3), 2.99 (dd, 1H, J ) 5.4, 16.2 Hz, C8-HR), 2.82 (dd, 1H,
J ) 2.8, 16.2 Hz, C8-Hâ), 1.46 (s, 9H, CO2C(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ 170.9, 169.1, 158.3, 156.0, 149.9, 143.5,
135.0, 133.7, 130.2, 127.4, 126.2, 124.6, 122.6, 117.7, 115.5,
80.5, 61.8, 57.7, 51.8, 36.7, 34.6, 31.0, 28.3 (3C); IR (neat) νmax
3316, 2961, 2927, 2862, 1761, 1725, 1677, 1442, 1366, 1259,
1195, 1146, 1082, 1025, 860, 803, 757 cm-1; FABHRMS (NBA-
CsI) m/e 603.1120 (M+ + Cs, C25H30N2O7 requires 603.1107).
For the reduced product, methyl 12(S)-[N-(tert-butyl-
oxycarbonyl)-N-methylamino]-11-oxo-10-aza-2-oxatricyclo-
[12.2.2.13,7]nonadeca-3,5,7(19),14,16,17-hexaene-9(S)-carboxy-
late: colorless oil; 1H NMR (CDCl3, 400 MHz) δ 7.47 (dd, 1H,
J ) 2.0, 8.2 Hz, C15- or C18-H), 7.42 (dd, 1H, J ) 2.0, 8.2 Hz,
C18- or C15-H), 7.12 (dd, 1H, J ) 2.2, 8.4 Hz, C16- or C17-H),
7.11 (t, 1H, J ) 8.0 Hz, C5-H), 7.03 (dd, 1H, J ) 2.4, 8.4 Hz,
C17- or C16-H), 6.99 (dd, 1H, J ) 2.2, 8.0 Hz, C4-H), 6.56 (dd,
1H, J ) 1.6, 8.0 Hz, C6-H), 5.28 (br s, 1H, N10-H), 5.22 (d,
1H, J ) 1.6 Hz, C19-H), 4.58 (dd, 1H, J ) 4.0, 11.0 Hz, C12-
H), 4.32 (m, 1H, C9-H), 3.52 (s, 3H, CO2CH3), 3.19 (t, 1H, J )
12.4 Hz, C13-HR), 3.14 (dd, 1H, J ) 4.0, 12.4 Hz, C13-Hâ),
3.10 (dd, 1H, J ) 5.4, 16.4 Hz, C8-HR), 3.07 (s, 3H, NCH3),
2.89 (dd, 1H, J ) 2.8, 16.4 Hz, C8-Hâ), 1.46 (s, 9H, CO2C-
(CH3)3); IR (neat) νmax 3314, 3055, 2976, 2930, 1761, 1727,
1678, 1586, 1500, 1444, 1366, 1230, 1201, 1164, 1098, 1055,
1000, 859, 777, 737 cm-1; FABHRMS (NBA-CsI) m/e 587.1145
(M+ + Cs, C25H30N2O6 requires 587.1158).
upon standing: [R]25 -127 (c 0.2, CHCl3), -162 (c 0.15, CH3-
D
1
OH); H NMR (CDCl3, 400 MHz) δ 7.47 (dd, 1H, J ) 2.0, 8.2
Hz, C18-H), 7.29 (dd, 1H, J ) 2.0, 8.2 Hz, C15-H), 7.03 (dd,
1H, J ) 2.0, 8.2 Hz, C16-H), 7.00 (dd, 1H, J ) 2.0, 8.2 Hz,
C17-H), 6.80 (d, 1H, J ) 8.3 Hz, C5-H), 6.63 (dd, 1H, J ) 1.6,
8.3 Hz, C6-H), 5.35 (dd, 1H, J ) 5.0, 11.6 Hz, C12-H), 4.76 (d,
1H, J ) 11.8 Hz, C9-H), 4.74 (d, 1H, J ) 1.6 Hz, C19-H), 3.93
(s, 3H, ArOCH3), 3.65 (s, 3H, CO2CH3), 3.23 (t, 1H, J ) 11.6
Hz, C13-HR), 3.07 (d, 1H, J ) 17.5 Hz, C8-Hâ), 2.96 (dd, 1H,
J ) 11.8, 17.5 Hz, C8-HR), 2.92-2.96 (m, 1H, C13-Hâ, partially
obscured by C12-NCH3 and C8-HR), 2.91 (s, 3H, C12-NCH3),
2.80 (s, 3H, N10-CH3), 1.49 (s, 9H, CO2C(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ 171.4, 170.3, 156.2, 154.4, 152.4, 146.5,
135.1, 133.5, 131.0, 130.1, 124.6, 123.6, 121.1, 113.2, 111.8,
80.6, 56.8, 56.2, 56.1, 52.3, 35.7, 30.6, 30.4, 29.7, 28.4 (3C); IR
(neat) νmax 2923, 2851, 1739, 1682, 1646, 1513, 1446, 1262,
1215, 1025, 795 cm-1; FABHRMS (NBA-CsI) m/e 631.1443
(M+ + Cs, C27H34N2O7 requires 631.1420).
Meth yl 4-Meth oxy-12(S)-(N-m eth yla m in o)-10-m eth yl-
11-oxo-10-aza-2-oxatr icyclo[12.2.2.13,7]n on adeca-3,5,7(19),-
14,16,17-h exa en e-9(R)-ca r boxyla te ((9R,12S)-27). A solu-
tion of (9R,12S)-26 (12 mg, 0.024 mmol) in 2.2 M HCl-EtOAc
(1.0 mL) was stirred at 25 °C for 30 min before the volatiles
were removed in vacuo. The residue was neutralized by
addition of saturated aqueous NaHCO3 (2.0 mL). The aqueous
solution was extracted with EtOAc (3 × 5 mL), and the
combined EtOAc extracts were washed with H2O (2.0 mL) and
saturated aqueous NaCl (2 mL), dried (MgSO4), and concen-
trated in vacuo. Flash chromatography (SiO2, 1 × 6 cm, 0-5%
CH3OH-CHCl3 gradient elution) afforded (9R,12S)-27 (8.9 mg,
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)-N-m eth ylam i-
n o]-4-m et h oxy-11-oxo-10-a za -2-oxa t r icyclo[12.2.2.13,7]-
n on a d eca -3,5,7(19),14,16,17-h exa en e-9(S)-ca r b oxyla t e
((9S,12S)-30). Following the procedure detailed for 26, selec-
tive O-methylation of (9S,12S)-29 (12.0 mg, 0.025 mmol) with
NaH (1.5 mg, 0.038 mmol, 1.5 equiv) afforded (9S,12S)-30 (10.8
9.6 mg theoretical, 93%) as a white solid: [R]25 +31 (c 0.1,
D
1
CHCl3); H NMR (CDCl3, 400 MHz) δ 7.40 (dd, 1H, J ) 2.2,
8.3 Hz, C18-H), 7.20 (dd, 1H, J ) 2.2, 8.3 Hz, C15-H), 7.05
(dd, 1H, J ) 2.2, 8.3 Hz, C17-H), 7.03 (dd, 1H, J ) 2.2, 8.3 Hz,
C16-H), 6.81 (d, 1H, J ) 8.3 Hz, C5-H), 6.63 (dd, 1H, J ) 2.2,

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2067
mg, 12.3 mg theoretical, 88%) as a white solid: [R]25 -90 (c
749 cm-1; FABHRMS (NBA-CsI) m/e 638.0938 (M+ + Cs,
C24H28N3O8F requires 638.0915).
D
1
0.45, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.47 (dd, 1H, J )
2.0, 8.2 Hz, C15- or C18-H), 7.42 (dd, 1H, J ) 2.0, 8.2 Hz, C18-
or C15-H), 7.16 (dd, 1H, J ) 2.1, 8.2 Hz, C16- or C17-H), 7.06
(dd, 1H, J ) 2.1, 8.2 Hz, C17- or C16-H), 6.72 (d, 1H, J ) 8.2
Hz, C5-H), 6.51 (dd, 1H, J ) 1.6, 8.2 Hz, C6-H), 5.27 (br s,
1H, N10-H), 5.23 (d, 1H, J ) 1.6 Hz, C19-H), 4.56 (m, 1H,
C12-H), 4.28 (m, 1H, C9-H), 3.92 (s, 3H, ArOCH3), 3.51 (s, 3H,
CO2CH3), 3.20 (t, 1H, J ) 12.4 Hz, C13-HR), 3.13 (dd, 1H, J )
4.4, 12.4 Hz, C13-Hâ), 3.07 (s, 3H, NCH3), 3.00 (dd, 1H, J )
5.5, 16.4 Hz, C8-HR), 2.85 (dd, 1H, J ) 2.4, 16.4 Hz, C8-Hâ),
1.45 (s, 9H, CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 171.0,
169.1, 158.4, 151.8, 147.0, 142.7, 134.6, 133.5, 130.1, 127.8,
126.3, 124.7, 122.0, 117.8, 111.9, 80.4, 61.9, 56.0, 53.7, 51.8,
36.7, 34.5, 31.1, 28.4 (3C); IR (neat) νmax 3356, 2974, 2932,
2841, 1733, 1681, 1516, 1441, 1366, 1260, 1200, 1148, 1098,
1029, 858, 832, 800, 756, 735 cm-1; FABHRMS (NBA-CsI)
m/e 617.1248 (M+ + Cs, C26H32N2O7 requires 617.1264).
On occasions, a small amount of the C9 epimer (32) was
3-F lu or o-4-n it r o-N -[N -(t er t -b u t yloxyca r b on yl)-L-t y-
r osyl]-D-p h en yla la n in e Meth yl Ester ((R,S)-34). Following
the procedure detailed for (S,S)-13, D-6 (5.0 mg, 0.021 mmol)
and L-12 (11.1 mg, 0.025 mmol, 1.2 equiv) afforded (R,S)-34
(9.6 mg, 10.6 mg theoretical, 91%) as a pale-yellow oil, which
solidified upon standing: [R]25 -38 (c 0.18, CHCl3); 1H NMR
D
(CDCl3, 400 MHz) δ 7.91 (t, 1H, J ) 8.0 Hz, C5-H), 7.00 (d,
2H, J ) 8.3 Hz, C2′- and C6′-H), 6.88 (d, 1H, J ) 11.6 Hz,
C2-H), 6.84 (d, 1H, J ) 8.5 Hz, C6-H), 6.71 (d, 2H, J ) 8.3
Hz, C3′- and C5′-H), 6.70 (br s, 1H, NH), 5.84 (br s, 1H, ArOH),
4.94 (d, 1H, J ) 6.5 Hz, NHBOC), 4.84 (dd, 1H, J ) 6.0, 13.0
Hz, ArCH2CH), 4.29 (m, 1H, ArCH2CH), 3.70 (s, 3H, CO2CH3),
3.10 (dd, 1H, J ) 5.8, 14.0 Hz, ArCHH), 3.05 (dd, 1H, J ) 6.4,
14.0 Hz, ArCHH), 2.98 (dd, 1H, J ) 7.6, 14.0 Hz, ArCHH),
2.91 (dd, 1H, J ) 6.6, 14.0 Hz, ArCHH), 1.38 (s, 9H, CO2C-
(CH3)3); IR (neat) νmax 3327, 2976, 2931, 1744, 1695, 1667,
1612, 1518, 1441, 1349, 1250, 1167, 1101, 1048, 1022, 910, 840,
732 cm-1; FABHRMS (NBA-CsI) m/e 638.0931 (M+ + Cs,
C24H28N3O8F requires 638.0915).
generated (0-7%): white solid; [R]25 -131 (c 0.04, CHCl3);
D
1H NMR (CDCl3, 400 MHz) δ 7.44 (dd, 1H, J ) 2.0, 8.3 Hz,
C15-H), 7.28 (dd, 1H, J ) 2.0, 8.3 Hz, C18-H), 7.10 (dd, 1H, J
) 2.0, 8.3 Hz, C16-H), 6.98 (dd, 1H, J ) 2.0, 8.3 Hz, C17-H),
6.77 (d, 1H, J ) 8.2 Hz, C5-H), 6.59 (dd, 1H, J ) 1.8, 8.2 Hz,
C6-H), 5.83 (d, 1H, J ) 7.5 Hz, N10-H), 5.12 (d, 1H, J ) 1.8
Hz, C19-H), 4.56 (m, 1H, C12-H), 4.19 (t, 1H, J ) 9.8 Hz, C9-
H), 3.93 (s, 3H, ArOCH3), 3.65 (s, 3H, CO2CH3), 3.26 (t, 1H, J
) 12.0 Hz, C13-HR), 2.98 (s, 3H, NCH3), 2.96 (m, 1H, C13-
Hâ, partially obscured by NCH3), 2.87 (d, 1H, J ) 16.3 Hz,
C8-HR), 2.69 (dd, 1H, J ) 11.0, 16.3 Hz, C8-Hâ), 1.49 (s, 9H,
CO2C(CH3)3); IR (neat) νmax 3360, 2931, 2841, 1747, 1678, 1585,
Meth yl 12(S)-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-n i-
tr o-11-oxo-10-a za -2-oxa tr icyclo[12.2.2.13,7]n on a d eca -3,5,7-
(19),14,16,17-h exa en e-9(R)-ca r b oxyla t e ((9R,12S)-35). A
solution of (R,S)-34 (8.0 mg, 0.016 mmol) in anhydrous DMF
(4 mL, 0.004 M) was treated with K2CO3 (11 mg, 0.08 mmol,
5.0 equiv) at 25 °C under Ar. The resulting reaction mixture
was warmed at 70 °C for 10 h before the solvent was removed
in vacuo. Flash chromatography (SiO2, 1 × 5 cm, 20-40%
EtOAc-hexane gradient elution) afforded (9R,12S)-35 (4.9 mg,
7.7 mg theoretical, 63%) as a white solid: mp > 230 °C; [R]25
D
1516, 1441, 1367, 1262, 1210, 1146, 1027, 980, 838, 755 cm-1
;
-32 (c 0.17, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 1H,
J ) 8.4 Hz, C5-H), 7.45 (dd, 1H, J ) 2.0, 8.4 Hz, C18-H), 7.26
(dd, 1H, J ) 2.0, 8.4 Hz, C15-H), 7.09 (dd, 1H, J ) 2.0, 8.4 Hz,
C17-H), 7.03 (dd, 1H, J ) 2.0, 8.4 Hz, C16-H), 6.73 (dd, 1H, J
) 1.7, 8.4 Hz, C6-H), 6.04 (d, 1H, J ) 7.7 Hz, N10-H), 5.35 (d,
1H, J ) 1.7 Hz, C19-H), 5.16 (d, 1H, J ) 9.2 Hz, NHBOC),
4.08-4.17 (m, 2H, C9- and C12-H), 3.68 (s, 3H, CO2CH3), 3.27
(dd, 1H, J ) 5.1, 12.0 Hz, C13-Hâ), 2.99 (d, 1H, J ) 17.4 Hz,
C8-Hâ), 2.89 (t, 1H, J ) 12.0 Hz, C13-HR), 2.77 (dd, 1H, J )
11.3, 17.4 Hz, C8-HR), 1.45 (s, 9H, CO2C(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ 171.9, 171.0, 156.5, 155.9, 155.2, 144.7,
136.6, 135.5, 133.0, 131.0, 125.7, 124.5, 124.0, 121.4, 116.6,
80.5, 58.2, 52.9, 52.7, 38.7, 34.7, 28.3 (3C); IR (neat) νmax 3299,
2976, 2933, 1749, 1703, 1676, 1589, 1520, 1500, 1435, 1349,
FABHRMS (NBA-CsI) m/e 617.1247 (M+ + Cs, C26H32N2O7
requires 617.1264).
Met h yl 4-Met h oxy-12(S)-(N-m et h yla m in o)-11-oxo-10-
a za -2-oxa tr icyclo[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-
h exa en e-9(S)-ca r boxyla te ((9S,12S)-31). Following the
procedure detailed for 27, (9S,12S)-30 (10.0 mg, 0.021 mmol)
afforded (9S,12S)-31 (7.6 mg, 8.1 mg theoretical, 94%) as a
1
yellow solid: [R]25 -5 (c 0.38, CHCl3); H NMR (CDCl3, 400
D
MHz) δ 7.21 (dd, 2H, J ) 2.4, 8.4 Hz, C15- and C18-H), 7.08
(dd, 1H, J ) 2.4, 8.4 Hz, C16- or C17-H), 6.96-7.02 (m, 2H,
C17- or C16-H and N10-H), 6.75 (d, 1H, J ) 8.2 Hz, C5-H),
6.59 (dd, 1H, J ) 1.6, 8.2 Hz, C6-H), 5.01 (d, 1H, J ) 1.6 Hz,
C19-H), 4.12 (dd, 1H, J ) 8.1, 9.5 Hz, C9-H), 3.93 (s, 3H,
ArOCH3), 3.69 (s, 3H, CO2CH3), 3.38-3.41 (m, 1H, C12-H),
3.36 (dd, 1H, J ) 4.9, 12.0 Hz, C13-HR), 2.95 (dd, 1H, J ) 2.0,
12.0 Hz, C13-Hâ), 2.83 (d, 1H, J ) 16.4 Hz, C8-Hâ), 2.70 (dd,
1H, J ) 14.8, 16.4 Hz, C8-HR), 2.55 (s, 3H, NHCH3); 13C NMR
(CDCl3, 100 MHz) δ 172.4 (2C), 157.7, 152.5, 146.7, 134.1,
132.8, 130.3, 130.1, 125.1, 123.4, 121.2, 115.1, 111.5, 65.7, 56.1,
53.8, 52.4, 37.5, 35.3, 34.8; IR (neat) νmax 3337, 2921, 2850,
1745, 1658, 1582, 1496, 1435, 1262, 1201, 1125, 1024, 912, 861,
1287, 1233, 1195, 1171, 1097, 1052, 1015, 987, 841, 732 cm-1
;
FABHRMS (NBA-CsI) m/e 618.0872 (M+ + Cs, C24H27N3O8
requires 618.0852).
Meth yl 12(S)-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-n i-
tr o-11-oxo-10-a za -2-oxa tr icyclo[12.2.2.13,7]n on a d eca -3,5,7-
(19),14,16,17-h exa en e-9(S)-ca r boxyla te ((9S,12S)-36).
A
solution of (S,S)-33 (200 mg, 0.4 mmol) in anhydrous THF (2
mL) was added dropwise to a suspension of NaH (60%
dispersion in mineral oil, 53 mg, 1.32 mmol, 3.3 equiv) in
anhydrous THF (98 mL) at 0 °C under Ar, and the resulting
reaction mixture was stirred at 0 °C for 30 min and 25 °C for
12 h. The reaction was quenched by addition of H2O (10 mL)
and EtOAc (50 mL), and the aqueous phase was extracted with
EtOAc (3 × 20 mL). The combined organic extracts were
washed with H2O (20 mL) and saturated aqueous NaCl (15
mL), dried (MgSO4), and concentrated in vacuo. Flash chro-
matography (SiO2, 2 × 15 cm, 20-40% EtOAc-hexane gradi-
ent elution) afforded (9S,12S)-36 (111 mg, 194 mg theoretical,
57%) and (9R,12S)-35 (35 mg, 194 mg theoretical, 18%). For
795, 729 cm-1; FABHRMS (NBA-CsI) m/e 517.0724 (M+
Cs, C21H24N2O5 requires 517.0740).
+
3-F lu or o-4-n it r o-N -[N -(t er t -b u t yloxyca r b on yl)-L-t y-
r osyl]-L-p h en yla la n in e Meth yl Ester ((S,S)-33). Following
the procedure detailed for (S,S)-13, L-6 (48 mg, 0.2 mmol) and
L-12 (98 mg, 0.22 mmol, 1.1 equiv) afforded (S,S)-33 (95 mg,
101 mg theoretical, 94%) as a pale-yellow solid: [R]25 -34 (c
D
1
0.1, acetone), +18 (c 0.16, CHCl3); H NMR (acetone-d6, 400
MHz) δ 8.14 (s, 1H, OH), 8.03 (t, 1H, J ) 8.0 Hz, C5-H), 7.56
(d, 1H, J ) 6.8 Hz, NH), 7.40 (d, 1H, J ) 12.3 Hz, C2-H), 7.30
(d, 1H, J ) 8.3 Hz, C6-H), 7.04 (d, 2H, J ) 8.4 Hz, C2′- and
C6′-H), 6.72 (d, 2H, J ) 8.4 Hz, C3′- and C5′-H), 5.97 (d, 1H,
J ) 7.6 Hz, NHBOC), 4.80 (m, 1H, ArCH2CH), 4.25 (m, 1H,
ArCH2CH), 3.69 (s, 3H, CO2CH3), 3.33 (dd, 1H, J ) 5.0, 14.0
Hz, ArCHH), 3.15 (dd, 1H, J ) 8.2, 13.7 Hz, ArCHH), 2.97
(dd, 1H, J ) 5.2, 14.0 Hz, ArCHH), 2.76 (dd, 1H, J ) 9.0, 13.7
Hz, ArCHH), 1.32 (s, 9H, CO2C(CH3)3); 13C NMR (acetone-d6,
100 MHz) δ 172.6, 171.7, 157.1, 156.9, 155.3 (d, J ) 271 Hz,
C3), 147.9 (d, J ) 7.0 Hz, C1), 136.9 (d, J ) 20 Hz, C4), 131.1
(2C), 129.0, 127.0 (d, J ) 4.0 Hz, C6), 126.7 (C5), 120.0 (d, J
) 21 Hz, C2), 115.9 (2C), 79.3, 57.0, 53.5, 52.6, 37.7 (2C), 28.4
(3C); IR (KBr) νmax 3333, 2968, 2860, 1737, 1664, 1612, 1519,
1442, 1349, 1295, 1246, 1162, 1093, 1049, 1015, 965, 892, 839,
(9S,12S)-36: white solid; mp > 230 °C; [R]25 +48 (c 2.0,
D
CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.88 (d, 1H, J ) 8.4 Hz,
C5-H), 7.34 (dd, 2H, J ) 2.2, 8.4 Hz, C15- and C18-H), 7.15
(dd, 1H, J ) 2.2, 8.4 Hz, C16- or C17-H), 7.06 (dd, 1H, J )
2.2, 8.4 Hz, C17- or C16-H), 6.73 (dd, 1H, J ) 1.5, 8.4 Hz, C6-
H), 5.84 (br s, 1H, N10-H), 5.31 (d, 1H, J ) 1.5 Hz, C19-H),
4.97 (br s, 1H, NHBOC), 4.56 (m, 1H, C12-H), 4.24 (m, 1H,
C9-H), 3.68 (s, 3H, CO2CH3), 3.51 (dd, 1H, J ) 5.2, 13.4 Hz,
C13-Hâ), 2.98 (dd, 1H, J ) 2.0, 17.4 Hz, C8-Hâ), 2.87-2.93
(m, 2H, C8-HR and C13-HR), 1.50 (s, 9H, CO2C(CH3)3); 13C
NMR (CDCl3, 100 MHz) δ 171.0 (2C), 156.5, 156.3, 154.7,
144.5, 136.7, 134.8, 133.0, 130.1, 125.8, 124.8, 123.5, 121.6,

2068 J . Org. Chem., Vol. 62, No. 7, 1997
Boger et al.
117.0, 80.5, 56.8, 52.7, 52.6, 38.6, 35.0, 28.2 (3C); IR (KBr) νmax
3374, 3303, 2974, 2933, 1754, 1703, 1667, 1605, 1585, 1519,
1497, 1431, 1344, 1226, 1195, 1164, 1092, 1046, 1015, 985, 841
cm-1; FABHRMS (NBA-CsI) m/e 618.0838 (M+ + Cs,
C24H27N3O8 requires 618.0852).
Following the procedure detailed for (R,S)-34, (S,S)-33 (25.3
mg, 0.05 mmol) afforded (9S,12S)-36 (7.0 mg, 24.3 mg theo-
retical, 29%) and (9R,12S)-35 (6.4 mg, 24.3 mg theoretical,
26%).
νmax 3313, 2976, 2924, 1675, 1582, 1562, 1423, 1367, 1321,
1252, 1164, 1065, 1025 cm-1; FABHRMS (NBA-CsI) m/e
573.1026 (M+ + Cs, C24H28N2O6 requires 573.1002).
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)am in o]-4-m eth -
oxy-11-oxo-10-aza-2-oxo-tr icyclo[12.2.2.13,7]n on adeca-3,5,7-
(19),14,16,17-h exa en e-9(S)-ca r boxyla te ((9S,12S)-39). Fol-
lowing the procedure detailed for 26, O-methylation of (9S,12S)-
38 (13.7 mg, 0.03 mmol) with NaH (1.8 mg, 0.045 mmol, 1.5
equiv) afforded (9S,12S)-39 (12.7 mg, 14.1 mg theoretical, 90%)
1
as a white solid: [R]25 +57 (c 0.6, CHCl3); H NMR (CDCl3,
Equ ilibr a tion Ep im er iza tion of (9S,12S)-36. Following
the procedure described for 16, (9S,12S)-36 (9.7 mg, 0.02 mmol,
D
400 MHz) δ 7.27 (dd, 2H, J ) 2.2, 8.2 Hz, C15- and C18-H),
7.10 (dd, 1H, J ) 2.2, 8.2 Hz, C16- or C17-H), 7.04 (dd, 1H, J
) 2.2, 8.2 Hz, C17- or C16-H), 6.77 (d, 1H, J ) 8.2 Hz, C5-H),
6.59 (dd, 1H, J ) 1.7, 8.2 Hz, C6-H), 5.88 (br s, 1H, N10-H),
5.00 (d, 1H, J ) 1.7 Hz, C19-H), 4.98 (br s, 1H, NHBOC), 4.57
(m, 1H, C12-H), 4.19 (m, 1H, C9-H), 3.93 (s, 3H, ArOCH3),
3.65 (s, 3H, CO2CH3), 3.49 (dd, 1H, J ) 4.9, 13.4 Hz, C13-Hâ),
2.74-2.89 (m, 3H, C13-HR and C8-H2), 1.49 (s, 9H, CO2C-
(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 171.2, 170.7, 157.9,
154.7, 152.3, 146.9, 133.8, 132.9, 129.4, 125.6, 123.8, 121.6,
116.8, 114.9, 111.7, 81.1, 56.5, 56.1, 53.7, 52.4, 38.4, 34.7, 28.2
(3C); IR (neat) νmax 3356, 3058, 2931, 2852, 1752, 1719, 1672,
1586, 1517, 1499, 1439, 1367, 1263, 1222, 1203, 1162, 1129,
1025, 870, 803, 735 cm-1; FABHRMS (NBA-CsI) m/e 603.1125
(M+ + Cs, C25H30N2O7 requires 603.1107).
[R]25 +48 (c 2.0, CHCl3)) after 72 h afforded (9R,12S)-35 (5.0
D
mg, 9.7 mg theoretical, 52%), which was identical in all
respects with an authentic sample, as a white solid ([R]25D -31
(c 0.25, CHCl3)) and recovered (9S,12S)-36 (2.5 mg, 26%).
Meth yl 4-Am in o-12(S)-[N-(ter t-bu tyloxyca r bon yl)a m i-
n o]-11-oxo-10-aza-2-oxatr icyclo[12.2.2.13,7]n on adeca-3,5,7-
(19),14,16,17-h exa en e-9(S)-ca r boxyla te ((9S,12S)-37). Fol-
lowing the procedure detailed for 24, (9S,12S)-36 (123 mg, 0.25
mmol) afforded (9S,12S)-37 (113 mg, 116 mg theoretical, 98%)
as a pink solid: 1H NMR (acetone-d6, 400 MHz) mixture of
two rotamers, δ (for major rotamer) 7.36 (dd, 1H, J ) 2.2, 8.4
Hz, C15- or C18-H), 7.17 (dd, 1H, J ) 2.2, 8.4 Hz, C18- or
C15-H), 7.03 (dd, 1H, J ) 2.3, 8.2 Hz, C16- or C17-H), 6.92
(dd, 1H, J ) 2.3, 8.4 Hz, C17- or C16-H), 6.57 (d, 1H, J ) 8.0
Hz, C5-H), 6.40 (dd, 1H, J ) 2.0, 8.0 Hz, C6-H), 6.19 (br s,
1H, N10-H), 5.05 (d, 1H, J ) 2.0 Hz, C19-H), 4.56 (br s, 1H,
NHBOC), 4.52 (m, 1H, C12-H), 3.96 (ddd, 1H, J ) 1.6, 6.4,
9.3 Hz, C9-H), 3.57 (s, 3H, CO2CH3), 3.22 (dd, 1H, J ) 5.0,
13.2 Hz, C13-Hâ), 2.90 (dd, 1H, J ) 8.1, 13.2 Hz, C13-HR),
2.78 (dd, 1H, J ) 9.1, 16.4 Hz, C8-HR), 2.67 (dd, 1H, J ) 1.6,
16.4 Hz, C8-Hâ), 1.46 (s, 9H, CO2C(CH3)3); 13C NMR (acetone-
d6, 100 MHz) mixture of two rotamers, δ (for major rotamer)
172.3, 170.9, 159.3, 155.5, 152.7, 151.8, 136.0, 135.0, 133.4,
130.7, 125.7, 124.7, 122.3, 116.3, 115.2, 79.9, 57.6, 55.7, 52.1,
39.4, 35.3, 34.9 (3C); IR (neat) νmax 3351, 2978, 2932, 1709,
1663, 1588, 1516, 1500, 1438, 1368, 1204, 1164, 1098, 1050,
1017, 984, 870, 736 cm-1; FABHRMS (NBA-CsI) m/e 588.1124
(M+ + Cs, C24H29N3O6 requires 588.1111).
Met h yl 12(S)-Am in o-4-m et h oxy-11-oxo-10-a za -2-oxa -
tr icyclo[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-
9(S)-ca r boxyla te ((9S,12S)-40). Following the procedure
detailed for 27, (9S,12S)-39 (12.5 mg, 0.0266 mmol) afforded
(9S,12S)-40 (8.9 mg, 9.8 mg, 91%) as a white solid: [R]25D -16
(c 0.4, CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.31 (dd, 1H, J )
1.9, 8.2 Hz, C15- or C18-H), 7.23 (dd, 1H, J ) 1.9, 8.2 Hz,
C18- or C15-H), 7.12 (d, 1H, J ) 8.6 Hz, N10-H), 7.10 (dd, 1H,
J ) 2.0, 8.3 Hz, C16- or C17-H), 6.99 (dd, 1H, J ) 2.0, 8.3 Hz,
C17- or C16-H), 6.75 (d, 1H, J ) 8.2 Hz, C5-H), 6.59 (dd, 1H,
J ) 1.6, 8.2 Hz, C6-H), 5.02 (d, 1H, J ) 1.6 Hz, C19-H), 4.13
(t, 1H, J ) 8.8 Hz, C9-H), 3.93 (s, 3H, ArOCH3), 3.90 (m, 1H,
C12-H), 3.69 (s, 3H, CO2CH3), 3.49 (dd, 1H, J ) 4.0, 13.3 Hz,
C13-Hâ), 2.81 (t, 1H, J ) 13.3 Hz, C13-HR), 2.80 (dd, 1H, J )
2.1, 16.5 Hz, C8-Hâ), 2.71 (dd, 1H, J ) 10.6, 16.5 Hz, C8-HR),
1.70 (br s, 2H, C12-NH2); 13C NMR (CDCl3, 100 MHz) δ 173.2,
172.4, 157.8, 152.5, 146.7, 133.7, 133.0, 130.3, 130.0, 125.2,
123.0, 121.3, 114.8, 111.4, 56.1, 55.7, 53.7, 52.4, 40.4, 34.8; IR
(neat) νmax 3384, 2924, 2853, 1744, 1687, 1605, 1502, 1442,
1261, 1200, 1155, 1099, 1035, 843 cm-1; MS (ion spray) m/e
371 (M+ + H, C20H22N2O5).
Meth yl 4-Am in o-12(S)-[N-(ter t-bu tyloxyca r bon yl)a m i-
n o]-11-oxo-10-aza-2-oxatr icyclo[12.2.2.13,7]n on adeca-3,5,7-
(19),14,16,17-h exa en e-9(R)-ca r boxyla te ((9R,12S)-41). Fol-
lowing the procedure detailed for 24, (9R,12S)-35 (26 mg, 0.054
mmol) afforded (9R,12S)-41 (23.8 mg, 24.6 mg theoretical,
97%): 1H NMR (CDCl3, 400 MHz) δ 7.39 (dd, 1H, J ) 2.0, 8.2
Hz, C15- or C18-H), 7.19 (dd, 1H, J ) 2.0, 8.2 Hz, C18- or
C15-H), 7.04 (dd, 1H, J ) 2.0, 8.2 Hz, C16- or C17-H), 6.97
(dd, 1H, J ) 2.0, 8.2 Hz, C17- or C16-H), 6.74 (d, 1H, J ) 8.2
Hz, C5-H), 6.62 (dd, 1H, J ) 1.8, 8.2 Hz, C6-H), 6.46 (d, 1H,
J ) 8.0 Hz, N10-H), 5.17 (d, 1H, J ) 9.1 Hz, NHBOC), 4.86
(d, 1H, J ) 1.8 Hz, C19-H), 4.06-4.14 (m, 2H, C9- and C12-
H), 3.68 (s, 3H, CO2CH3), 3.24 (dd, 1H, J ) 4.7, 12.0 Hz, C13-
Hâ), 2.88 (t, 1H, J ) 12.0 Hz, C13-HR), 2.79 (d, 1H, J ) 16.0
Hz, C8-HR), 2.65 (dd, 1H, J ) 11.0, 16.0 Hz, C8-Hâ), 1.45 (s,
9H, CO2C(CH3)3); IR (neat) νmax 3322, 2976, 2933, 1739, 1692,
1660, 1516, 1439, 1367, 1282, 1208, 1163, 1016, 908, 837, 732
cm-1; FABHRMS (NBA-NaI) m/e 455.2051 (M+, C24H29N3O6
requires 455.2056).
Meth yl 12(S)-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-h y-
d r oxy-11-oxo-10-a za -2-oxa t r icyclo[12.2.2.13,7]n on a d eca -
3,5,7(19),14,16,17-h exa en e-9(S)-ca r boxyla te ((9S,12S)-38).
Following the procedure detailed for 25, (9S,12S)-37 (36.4 mg,
0.08 mmol) afforded (9S,12S)-38 (17.6 mg, 36.4 mg theoretical,
48%) and the corresponding reduced product (4.2 mg, 35.2 mg
theoretical, 12%). For (9S,12S)-38: white solid; [R]25 +54 (c
D
1
0.85, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.28 (dd, 2H, J )
2.0, 8.2 Hz, C15- and C18-H), 7.09 (dd, 1H, J ) 2.3, 8.4 Hz,
C16- or C17-H), 7.02 (dd, 1H, J ) 2.3, 8.4 Hz, C17- or C16-H),
6.79 (d, 1H, J ) 8.2 Hz, C5-H), 6.52 (dd, 1H, J ) 2.1, 8.2 Hz,
C6-H), 5.85 (br s, 1H, N10-H), 5.78 (s, 1H, ArOH), 4.99 (br s,
2H, C19-H and NHBOC), 4.56 (m, 1H, C12-H), 4.20 (m, 1H,
C9-H), 3.65 (s, 3H, CO2CH3), 3.50 (dd, 1H, J ) 4.9, 13.5 Hz,
C13-Hâ), 2.70-2.90 (m, 3H, C13-HR and C8-H2), 1.50 (s, 9H,
CO2C(CH3)3); 13C NMR (CDCl3, 100 MHz) δ 171.2, 170.7, 157.7,
154.8, 150.3, 143.3, 134.1, 132.8, 129.7, 129.0, 125.5, 123.8,
122.2, 115.4, 114.7, 81.2, 56.6, 53.6, 52.4, 38.5, 34.6, 28.2 (3C);
IR (neat) νmax 3345, 2958, 2854, 1724, 1664, 1595, 1496, 1441,
1367, 1256, 1205, 1162, 1113, 1051, 1021, 869, 736 cm-1
;
FABHRMS (NBA-CsI) m/e 589.0968 (M+ + Cs, C24H28N2O7
requires 589.0951).
For the reduced product, methyl 12(S)-[N-(tert-butyl-
oxycarbonyl)amino]-11-oxo-10-aza-2-oxatricyclo[12.2.2.13,7]-
nonadeca-3,5,7(19),14,16,17-hexaene-9(S)-carboxylate: pale yel-
1
low oil; H NMR (CDCl3, 400 MHz) δ 7.28 (dd, 2H, J ) 2.2,
8.4 Hz, C15- and C18-H), 7.13 (t, 1H, J ) 8.0 Hz, C5-H), 7.05
(dd, 1H, J ) 2.2, 8.4 Hz, C16- or C17-H), 7.01 (dd, 1H, J )
2.2, 8.4 Hz, C17- or C16-H), 6.99 (dd, 1H, J ) 2.3, 8.4 Hz,
C4-H), 6.61 (dd, 1H, J ) 2.3, 8.4 Hz, C6-H), 5.99 (br s, 1H,
N10-H), 5.08 (d, 1H, J ) 9.1 Hz, NHBOC), 5.03 (d, 1H, J )
2.3 Hz, C19-H), 4.54 (m, 1H, C12-H), 4.22 (m, 1H, C9-H), 3.63
(s, 3H, CO2CH3), 3.47 (dd, 1H, J ) 4.9, 13.4 Hz, C13-Hâ), 2.80-
2.89 (m, 3H, C13-HR and C8-H2), 1.48 (s, 9H, CO2C(CH3)3);
13C NMR (CDCl3, 100 MHz) δ 171.2, 170.7, 163.2, 157.9, 154.8,
138.3, 133.8, 132.6, 129.7, 129.3, 125.5, 123.8, 121.6, 114.8,
114.3, 81.1, 56.7, 53.3, 52.4, 38.5, 35.0, 28.2 (3C); IR (neat)
Meth yl 12(S)-[N-(ter t-Bu tyloxyca r bon yl)a m in o]-4-h y-
d r oxy-11-oxo-10-a za -2-oxa t r icyclo[12.2.2.13,7]n on a d eca -
3,5,7(19),14,16,17-h exa en e-9(R)-ca r boxyla te ((9R,12S)-42).
Following the procedure detailed for 25, (9R,12S)-41 (21 mg,
0.046 mmol) afforded (9R,12S)-42 (9.0 mg, 21 mg theoretical,
43%) and the corresponding reduced product (3.8 mg, 19%).
For (9R,12S)-42: white solid; [R]25 -38 (c 0.2, CHCl3); 1H
D
NMR (CDCl3, 400 MHz) δ 7.41 (dd, 1H, J ) 2.4, 8.4 Hz, C15-
or C18-H), 7.22 (dd, 1H, J ) 2.4, 8.4 Hz, C18- or C15-H), 7.06
(dd, 1H, J ) 2.4, 8.4 Hz, C16- or C17-H), 6.96 (dd, 1H, J )
2.4, 8.4 Hz, C17- or C16-H), 6.79 (d, 1H, J ) 8.2 Hz, C5-H),

Synthesis of (9R,12S)- and (9S,12S)-Cycloisodityrosine
J . Org. Chem., Vol. 62, No. 7, 1997 2069
6.53 (dd, 1H, J ) 1.6, 8.2 Hz, C6-H), 5.78 (d, 1H, J ) 7.6 Hz,
N10-H), 5.59 (br s, 1H, C4-OH), 5.15 (d, 1H, J ) 9.2 Hz,
NHBOC), 5.04 (d, 1H, J ) 1.6 Hz, C19-H), 4.08-4.14 (m, 2H,
C9- and C12-H), 3.66 (s, 3H, CO2CH3), 3.25 (dd, 1H, J ) 5.0,
12.1 Hz, C13-Hâ), 2.88 (t, 1H, J ) 12.1 Hz, C13-HR), 2.85 (d,
1H, J ) 16.7 Hz, C8-HR), 2.65 (dd, 1H, J ) 11.2, 16.7 Hz, C8-
Hâ), 1.45 (s, 9H, CO2C(CH3)3); IR (neat) νmax 3317, 2974, 2933,
1723, 1659, 1595, 1497, 1435, 1364, 1282, 1162, 1108, 1051,
1010, 836, 728 cm-1; FABHRMS (NBA-CsI) m/e 589.0933 (M+
+ Cs, C24H28N2O6 requires 589.0951).
For the reduced product, methyl 12(S)-[N-(tert-butyl-
oxycarbonyl)amino]-11-oxo-10-aza-2-oxatricyclo[12.2.2.13,7]-
nonadeca-3,5,7(19),14,16,17-hexaene-9(R)-carboxylate: pale-
yellow oil; 1H NMR (CDCl3, 400 MHz) δ 7.39 (dd, 1H, J ) 2.2,
8.4 Hz, C15- or C18-H), 7.21 (dd, 1H, J ) 2.2, 8.4 Hz, C18- or
C15-H), 7.13 (t, 1H, J ) 8.0 Hz, C5-H), 7.05 (dd, 1H, J ) 2.2,
8.4 Hz, C16- or C17-H), 7.01 (dd, 1H, J ) 2.2, 8.4 Hz, C17- or
C16-H), 6.98 (dd, 1H, J ) 2.0, 8.0 Hz, C4-H), 6.61 (dd, 1H, J
) 2.0, 8.0 Hz, C6-H), 6.00 (d, 1H, J ) 7.6 Hz, N10-H), 5.17 (d,
1H, J ) 9.2 Hz, NHBOC), 5.06 (d, 1H, J ) 2.0 Hz, C19-H),
4.07-4.15 (m, 2H, C9- and C12-H), 3.65 (s, 3H, CO2CH3), 3.26
(dd, 1H, J ) 5.0, 12.0 Hz, C13-Hâ), 2.88 (t, 1H, J ) 12.0 Hz,
C13-HR), 2.86 (d, 1H, J ) 16.6 Hz, C8-HR), 2.73 (dd, 1H, J )
11.2, 16.6 Hz, C8-Hâ), 1.43 (s, 9H, CO2C(CH3)3); IR (neat) νmax
3301, 2974, 2933, 1733, 1661, 1587, 1533, 1500, 1444, 1368,
1206, 1165, 1017, 836, 757 cm-1; FABHRMS (NBA-NaI) m/e
463.1838 (M+ + Na, C24H28N2O6 requires 463.1845).
Met h yl 12(S)-Am in o-4-m et h oxy-11-oxo-10-a za -2-oxa -
tr icyclo[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-
9(R)-ca r boxyla te ((9R,12S)-44). Following the procedure for
27, (9R,12S)-43 (4.6 mg, 0.01 mmol) afforded (9R,12S)-44 (3.4
1
mg, 3.6 mg theoretical, 94%): [R]25 -18 (c 0.15, CHCl3); H
D
NMR (CDCl3, 400 MHz) δ 7.34 (dd, 1H, J ) 2.1, 8.3 Hz, C18-
H), 7.19 (dd, 1H, J ) 2.1, 8.3 Hz, C15-H), 7.10 (dd, 1H, J )
2.1, 8.3 Hz, C17-H), 6.99 (dd, 1H, J ) 2.1, 8.3 Hz, C16-H),
6.77 (d, 1H, J ) 8.3 Hz, C5-H), 6.58 (dd, 1H, J ) 2.1, 8.3 Hz,
C6-H), 6.26 (br s, 1H, N10-H), 5.07 (d, 1H, J ) 2.1 Hz, C19-
H), 4.09 (ddd, 1H, J ) 1.4, 7.0, 11.4 Hz, C9-H), 3.93 (s, 3H,
ArOCH3), 3.73 (s, 3H, CO2CH3), 3.54 (m, 1H, C12-H), 3.22 (dd,
1H, J ) 4.7, 12.4 Hz, C13-Hâ), 2.74-2.88 (m, 3H, C8-H2 and
C13-HR); IR (KBr) νmax 3436, 3046, 2954, 1718, 1667, 1590,
1513, 1436, 1415, 1267, 1225, 1205, 1128, 1021, 980, 882, 836,
805, 765 cm-1; FABHRMS (NBA-CsI) m/e 503.0598 ((M+
Cs, C20H22N2O5 requires 503.0583).
+
Meth yl (9S,12S)-12-Am in o-4-n itr o-11-oxo-10-a za -2-oxa -
tr icyclo[12.2.2.13,7]n on a d eca -3,5,7(19),14,16,17-h exa en e-
9-ca r boxyla te Hyd r och lor id e ((9S,12S)-45). A solution of
(9S,12S)-36 (6.4 mg, 13 µmol) in 3.3 N HCl-THF (0.5 mL)
was stirred at 25 °C for 3 h before the volatiles were removed
in vacuo. The residue was then thoroughly dried under
vacuum to afford the crude HCl salt (5.5 mg, 5.5 mg theoreti-
cal, 100%) as a white solid, which afforded colorless parallel
piped shaped crystals after recrystallization from CH3OH-
Et2O. A single crystal X-ray structure determination of 45
confirmed the structure and relative stereochemistry of 45.17
Meth yl 12(S)-[N-(ter t-Bu tyloxycar bon yl)am in o]-4-m eth -
oxy-11-oxo-10-aza-2-oxatr icyclo[12.2.2.13,7]n on adeca-3,5,7-
(19),14,16,17-h exa en e-9(R)-ca r boxyla te ((9R,12S)-43). Fol-
lowing the procedure detailed for 26, (9R,12S)-42 (6.4 mg,
0.014 mmol) and NaH (0.9 mg, 0.021 mmol, 1.5 equiv) provided
Ack n ow led gm en t. We gratefully acknowledge the
financial support of the National Institutes of Health
(CA41101), The Skaggs Institute for Chemical Biology,
and the award of predoctoral (SLC, NSF GER-9253922)
and postdoctoral fellowships (RMB, NIH GM17548; SN,
Pfizer, J apan).
(9R,12S)-43 (6.0 mg, 6.6 mg theoretical, 91%): white solid;
1
[R]25 -42 (c 0.13, CHCl3); H NMR (CDCl3, 400 MHz) δ 7.40
D
(dd, 1H, J ) 2.1, 8.4 Hz, C15- or C18-H), 7.21 (dd, 1H, J )
2.1, 8.4 Hz, C18- or C15-H), 7.10 (dd, 1H, J ) 2.2, 8.4 Hz, C16-
or C17-H), 6.99 (dd, 1H, J ) 2.2, 8.4 Hz, C17- or C16-H), 6.76
(d, 1H, J ) 8.2 Hz, C5-H), 6.58 (dd, 1H, J ) 2.2, 8.2 Hz, C6-
H), 5.76 (d, 1H, J ) 7.4 Hz, N10-H), 5.15 (d, 1H, J ) 9.2 Hz,
NHBOC), 5.05 (d, 1H, J ) 2.2 Hz, C19-H), 4.07-4.13 (m, 2H,
C9- and C12-H), 3.93 (s, 3H, ArOCH3), 3.67 (s, 3H, CO2CH3),
3.25 (dd, 1H, J ) 5.1, 12.1 Hz, C13-Hâ), 2.87 (t, 1H, J ) 12.2
Hz, C13-HR), 2.84 (d, 1H, J ) 16.6 Hz, C8-HR), 2.68 (dd, 1H,
J ) 11.0, 16.6 Hz, C8-Hâ), 1.45 (s, 9H, CO2C(CH3)3); 13C NMR
(CDCl3, 100 MHz) δ 171.8, 171.5, 157.2, 155.2, 152.3, 146.0,
134.5, 132.5, 130.5, 129.8, 125.0, 124.7, 121.2, 115.0, 111.5,
80.3, 58.2, 56.1, 54.0, 52.5, 38.9, 34.3, 28.3 (3C); IR (KBr) νmax
3347, 3300, 2954, 2853, 1748, 1718, 1664, 1587, 1517, 1436,
1367, 1264, 1205, 1162, 1130, 1015, 978, 891, 869, 838, 797,
762, 729 cm-1; FABHRMS (NBA) m/e 471.2125 (M+ + H,
C25H30N2O7 requires 471.2131).
1
Su p p or tin g In for m a tion Ava ila ble: 2D H-1H ROESY
NMR and/or 1D decoupling NMR experimental results for 15,
16, 25, 26, 35, and 36, experimental procedures and charac-
terization for 3, 5, 6, 8-12, 47-69, 73-79, and 1H NMR
spectra of 3, (2S,5R)- and (2R,5S)-5, L- and D-6, 9-53, and
the corresponding reduced products of 20, 25, 29, and 38 (83
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O961346O