Stereoselective synthesis of meso-2,6-diaminopimelic acid and its selectively protected derivatives

Article abstract of DOI:10.1021/jo972133h

Four synthetic routes to selectively protected derivatives and isomers of meso-diaminopimelic acid (DAP) (1a), a key constituent of bacterial peptidoglycan, were investigated. N-(tert-butyloxycarbonyl)-D-allylglycine (2) and N-(benzyloxycarbonyl)-L-allylglycine (4) were esterified to ethylene glycol and cyclized via olefin metathesis to a protected derivative 7 of 2,7- diaminosuberic acid. Analogous linking of propane-1,3-diol with 2 and potential precursors of N-(benzyloxycarbonyl)-L-vinylglycine moieties, such as N-(benzyloxycarbonyl)-L-glutamate or N-(benzyloxycarbonyl)-L-methionine sulfoxide, gave 12 or 15, both of which produced the α,β-unsaturated ester 14 upon attempted generation of the vinylglycine precursor for olefin metathesis to DAP derivatives. An alternative route, based on SnCl₄- catalyzed ene reaction of methyl N-(benzyloxycarbonyl)-L-allylglycinate (18) with glyoxylate esters of phenylcyclohexanol isomers as chiral auxiliaries, gave ca. 85:15 ratios of diastereomeric alcohols (19 or 20). These could be transformed to DAP derivatives in a series of steps employing azide displacement of corresponding mesylates to introduce the second nitrogen. A third method, involving reduction of pure dimethyl (6S)-2-keto-6-[N- (benzyloxycarbonyl)amino]pimelate (32) to the corresponding alcohol 33 with (S)-binaphthol-ruthenium catalyst as the key step, gives a 79:21 isomeric ratio. The fourth route employs the bis(oxazoline)-copper complex 41 as a chiral catalyst for the ene reaction of methyl (S)-4- (phenylthio)allylglycinate (39) and methyl glyoxylate to afford 42 and 94:6 isometric ratio. Nickel boride removal of sulfur and the double bond in the presence of the Cbz group gives the desired alcohol, dimethyl (2S,6S)-6-[N- (benzyloxycarbonyl)amino]-2-hydroxyheptane-1,7-dioate (33). The required selectively protected second nitrogen is introduced using Mitsunobu inversion with N-tert-butyl [[2-(trimethylsilyl)-ethyl]sulfonyl]carbomate (34) as a key step.

Full text of DOI:10.1021/jo972133h

J . Org. Chem. 1998, 63, 2133-2143
2133
Ster eoselective Syn th esis of m eso-2,6-Dia m in op im elic Acid a n d Its
Selectively P r otected Der iva tives
Yong Gao, Patricia Lane-Bell, and J ohn C. Vederas*
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2
Received November 20, 1997
Four synthetic routes to selectively protected derivatives and isomers of meso-diaminopimelic acid
(DAP) (1a ), a key constituent of bacterial peptidoglycan, were investigated. N-(tert-butyloxycar-
bonyl)-D-allylglycine (2) and N-(benzyloxycarbonyl)-L-allylglycine (4) were esterified to ethylene
glycol and cyclized via olefin metathesis to a protected derivative 7 of 2,7-diaminosuberic acid.
Analogous linking of propane-1,3-diol with 2 and potential precursors of N-(benzyloxycarbonyl)-
L-vinylglycine moieties, such as N-(benzyloxycarbonyl)-L-glutamate or N-(benzyloxycarbonyl)-L-
methionine sulfoxide, gave 12 or 15, both of which produced the R,â-unsaturated ester 14 upon
attempted generation of the vinylglycine precursor for olefin metathesis to DAP derivatives. An
alternative route, based on SnCl4-catalyzed ene reaction of methyl N-(benzyloxycarbonyl)-L-
allylglycinate (18) with glyoxylate esters of phenylcyclohexanol isomers as chiral auxiliaries, gave
ca. 85:15 ratios of diastereomeric alcohols (19 or 20). These could be transformed to DAP derivatives
in a series of steps employing azide displacement of corresponding mesylates to introduce the second
nitrogen. A third method, involving reduction of pure dimethyl (6S)-2-keto-6-[N-(benzyloxycarbo-
nyl)amino]pimelate (32) to the corresponding alcohol 33 with (S)-binaphthol-ruthenium catalyst
as the key step, gives a 79:21 isomeric ratio. The fourth route employs the bis(oxazoline)-copper
complex 41 as a chiral catalyst for the ene reaction of methyl (S)-4-(phenylthio)allylglycinate (39)
and methyl glyoxylate to afford 42 in 94:6 isomeric ratio. Nickel boride removal of sulfur and the
double bond in the presence of the Cbz group gives the desired alcohol, dimethyl (2S,6S)-6-[N-
(benzyloxycarbonyl)amino]-2-hydroxyheptane-1,7-dioate (33). The required selectively protected
second nitrogen is introduced using Mitsunobu inversion with N-tert-butyl [[2-(trimethylsilyl)-
ethyl]sulfonyl]carbamate (34) as a key step.
The biosynthesis of the peptidoglycan cell wall layer
in bacterial cells provides numerous potential targets for
development of new antibiotics.1,2 Among these is meso-
diaminopimelic acid (DAP) (1a ), the key cross-linking
as on the mechanism and genetic organization of DAP-
related enzymes.3,7 However, improved methods are still
needed to provide facile access to stereochemically pure
(4) For leading references see: (a) Cox, R. J .; Sherwin, W. A.; Lam,
L. K. P.; Vederas, J . C. J . Am. Chem. Soc. 1996, 118, 7449-7460. (b)
Williams, R. M.; Fegley, G. J .; Gallegos, R.; Schaefer, F.; Pruess, D. L.
Tetrahedron 1996, 52, 1149-1164. (c) Auger, G.; van Heijenoort, J .;
Vederas, J . C.; Blanot, D. FEBS Lett. 1996, 391, 171-174. (d) Couper,
L.; McKendrick, J . E.; Robins, D. J .; Chrystal, E. J . T. Biorg. Med.
Chem. Lett. 1994, 4, 2267-2272. (e) Abbott, S. D.; Lane-Bell, P.; Sidhu,
K. P. S.; Vederas, J . C. J . Am. Chem. Soc. 1994, 116, 6513-6520. (f)
Song, Y. H.; Niederer, D.; Lane-Bell, P.; Lam, L. K. P.; Crawley, S.;
Palcic, M. M.; Pickard, M. A.; Pruess, D. L.; Vederas, J . C. J . Org.
Chem. 1994, 59, 5784-5793. (g) Roberts, J . L.; Borgese, J .; Chan, C.;
Keith, D. D.; Wei, C.-C. Heterocycles 1993, 35, 115-120.
(5) For leading references see: (a) J ohannsen, L.; Wecke, J .; Obal,
F.; Krueger, J . M. Am. J . Physiol. 1991, 260, R126-R133. (b)
J ohannsen, L. APMIS 1993, 101, 337-344. (c) Luker, K. E.; Tyler, A.
N.; Marshall, G. R.; Goldman, W. E. Molec. Microbiol. 1995, 16, 733-
743. (d) Takada, H.; Kawabata, Y.; Kawata, S.; Kusumoto, S. Infect.
Immun. 1996, 64, 657-659.
(6) For some examples see: (a) Gelb, M. H.; Lin, Y.; Pickard, M. A.;
Song, Y.; Vederas, J . C. J . Am. Chem. Soc. 1990, 112, 4932-4942. (b)
J urgens, J . Tetrahedron Lett. 1992, 33, 4727-4730. (c) Kolodziejczyk,
A. M.; Kolodziejczyk, A. S.; Stoev, S. Int. J . Peptide Protein Res. 1992,
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Holcomb, R. C.; Schow, S.; Ayral-Kaloustian, S.; Powell, D. Tetrahedron
Lett. 1994, 35, 7005-7008. (i) Arakawa, Y.; Goto, T.; Kawase, K.;
Yoshifuji. S. Chem. Pharm. Bull. 1995, 43, 535-536. (j) Nadin, A.;
Derrer, S.; McGeary, R. P.; Goodman, J . M.; Raithby, P. R.; Holmes,
A. B.; O’Hanlon, P. J .; Pearson, N. D. J . Am. Chem. Soc. 1995, 117,
9768-9769. (k) Williams, R. M.; Fegley, G. J .; Gallegos, R.; Schaefer,
F.; Pruess, D. L. Tetrahedron 1996, 52, 1149-1164. (l) J ackson, R. F.
W.; Turner, D.; Block, M. H. J . Chem. Soc., Perkin Trans. 1 1997, 865-
870.
amino acid in this essential structural polymer in Gram-
negative bacteria and a precursor to L-lysine, which is
used for this purpose by many Gram-positive organisms.3
Since mammals lack the DAP biosynthetic pathway,
require L-lysine in their diet, and usually excrete DAP
unchanged (except ruminants), there has been substan-
tial interest in the specific inhibition of enzymes involved
in its biosynthesis.3,4 DAP also occurs in physiologically
active peptidoglycan fragments that act as bacterial
toxins, sleep-inducing factors, or antitumor agents.5
Hence, considerable previous effort has focused on the
synthesis of DAP isomers and their analogues,6 as well
* To whom correspondence should be addressed. Tel.: (403) 492-
5475. Fax: (403) 492-8231. E-mail: J ohn.Vederas@Ualberta.ca.
(1) For reviews of peptidoglycan formation see: (a) Ghuysen, J .-M.
Int. J . Antimicrob. Agents 1997, 8, 45-60. (b) Ama´bile-Cuevas, C. F.;
Ca´rdenas-Garcia, M.; Ludgar, M. Am. Sci. 1995, 83, 320-329.
(2) (a) Ward, J . B. In Antibiotic Inhibitors of Bacterial Cell Wall
Biosynthesis; Tipper, D. J ., Ed.; Pergamon Press: New York, 1987; pp
1-43. (b) Bugg, T. D. H.; Walsh, C. T. Nat. Prod. Rep. 1992, 9, 199-
215.
(3) For a reviews of DAP metabolism see: (a) Cox, R. J . Nat. Prod.
Rep. 1996, 13, 29-43. (b) Scapin, G. S.; Blanchard, J . S. Adv. Enzymol.
1997, 72A, in press.
S0022-3263(97)02133-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/04/1998

2134 J . Org. Chem., Vol. 63, No. 7, 1998
Gao et al.
Sch em e 1
DAP derivatives with different protecting groups on the
two amino and/or carboxyl functions. Ideally, complete
orthogonal protection would permit individual manipula-
tion of each of these four functionalities for synthesis of
enzyme inhibitors or peptidoglycan-derived peptides. In
the present work, we examine several approaches to
selectively protected meso-DAP using optically pure
L-allylglycine as a starting material. One route, poten-
tially applicable to a variety of unusual molecules with
amino acid moieties at either end, employs a ring-closing
olefin metathesis reaction.8 Several alternative methods
reported herein are based on the ene reaction. In earlier
studies, we4a and others9,10 had employed nonstereose-
lective ene reactions to assemble the DAP skeleton. In
addition to other approaches, we now describe the use of
chiral auxiliaries and catalysts in such ene condensa-
tions.
Resu lts a n d Discu ssion
Olefin Meta th esis Ap p r oa ch to DAP a n d 2,7-
Dia m in osu ber ic Acid .11 The successful application of
olefin metathesis reactions to the synthesis of cyclic
peptide derivatives by Grubbs and co-workers8 suggested
this methodology as a possible avenue to selectively
protected DAP. Since 12-membered rings can often be
formed quite readily, it appeared that linking two dif-
ferentially N-protected amino acids bearing terminal
olefins as esters of the appropriate chosen diol would
permit metathesis cyclization with desired concomitant
carbon-carbon bond formation. To test this, N-(tert-
butyloxycarbonyl)-D-allylglycine (2) and N-(benzyloxy-
carbonyl)-L-allylglycine (4) were sequentially esterified
onto ethylene glycol to form diester 5 (Scheme 1).
Reaction with the Grubbs catalyst 6 produces the cyclic
olefin 7, a protected derivative of 2,7-diaminosuberic acid
in modest (35%, not optimized) yield. Presumably, ester
hydrolysis and hydrogenation under standard conditions4a
would generate (2S,7R)-2-[N-(tert-butyloxycarbonyl)amino]-
7-aminooctanedioic acid, although this was not done for
this model system. LL-Diaminosuberic acid [(2S,7S)-2,7-
diaminooctanedioic acid] has been extensively employed
as a nonreducible isosteric replacement for cystine in
biologically active peptides.11,12
This encouraging result suggested that similar cycliza-
tion of the propanediol diester of N-(benzyloxycarbonyl)-
L-vinylglycine and N-(tert-butyloxycarbonyl)-D-allylgly-
cine could produce a differentially protected DAP deriv-
ative. Although N-protected vinylglycine esters are quite
sensitive to isomerization of the double bond from the
â,γ- to the R,â-position, they can be made by lead
tetraacetate decarboxylation of glutamate derivatives13
or by elimination of methionine sulfoxides.14 Both routes
were investigated with a strategy of generating the
vinylglycine moiety just before attempted metathesis
cyclization (Scheme 2). Conversion of the known glu-
tamate derivative 815 to its (trimethylsilyl)ethyl ester 9
followed by reaction with 1,3-propanediol affords 10,
which is readily linked to N-(tert-butyloxycarbonyl)-D-
allylglycine (2) to give 11. Deprotection quantitatively
generates the acid 12. Unfortunately, attempts to gener-
ate the vinylglycine moiety via lead tetraacetate decar-
boxylation13 of 12 produce only the conjugated compound
14 and none of the desired vinylglycine derivative 13.
An analogous approach provides the propanediol diester
15 of methionine sulfoxide and 2 (54% overall yield for
three steps from N-(benzyloxycarbonyl)-L-methionine).
However, attempted elimination under conditions known
to normally give vinylglycine esters14 again generates the
undesired conjugated 14 rather than 13. The reason for
the unexpectedly rapid isomerization of presumed inter-
mediate 13 is unknown but may involve deprotonation
(7) For leading references see: (a) Scapin, G.; Reddy, S. G.; Blan-
chard, J . S. Biochemistry 1996, 35, 13540-13551. (b) Blickling, S.;
Renner, C.; Laber, B.; Pohlenz, H. D.; Holak, T. A.; Huber, R.
Biochemistry 1997, 36, 24-33. (c) Beaman, T. W.; Binder, D. A.;
Blanchard, J . S.; Roderick, S. L. Biochemistry 1997, 36, 489-494. (d)
Karsten, W. F. Biochemistry 1997, 36, 1730-1739. (e) Pavelka, M. S.;
Weisbrod, T. R.; J acobs, W. R. J . Bacteriol. 1997, 179, 2777-2782. (f)
Karita, M.; Etterbeek, M. L.; Forsyth, M. H.; Tummuru, M. K. R.;
Blaser, M. J . Infect. Immun. 1997, 65, 4158-4164. (g) Hoang, T. T.;
Williams, S.; Schweizer, H. P. Microbiology 1997, 143, 899-907. (h)
Wang, F.; Blanchard, J . S.; Tang, X. Biochemistry 1997, 36, 3755-
3759.
(8) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1996, 118, 9606-9614.
(9) (a) Agouridas, K.; Girodeau, J . M.; Pineau, R. Tetrahedron Lett.
1985, 26, 3115-3118. (b) Girodeau, J .-M.; Agouridas, C.; Masson, M.;
Pineau, R.; Le Goffic, F. J . Med. Chem. 1986, 29, 1023-1030.
(10) For closely related syntheses of chiral 2-amino-6-hydroxypimelic
acid derivatives see: (a) Schneider, H.; Sigmund, G.; Schricker, B.;
Thirring, K.; Berner, H. J . Org. Chem. Soc. 1993, 58, 683-689. (b)
Mehlfu¨hrer, M.; Thirring, K.; Berner, H. J . Org. Chem. 1997, 62, 4078-
4081.
(11) After completion of this work, we became aware that Professor
Robert M. Williams (Colorado State University) has independently
developed an olefin metathesis procedure for generation of selectively
protected chiral 2,7-diaminosuberic acids in high yield: Williams, R.
M.; Liu, J . J . Org. Chem. 1998, 63, 2130.
(12) (a) Veber, D. F.; Strachan, R. G.; Bergstrand, S. J .; Holly, F.
W.; Homnick, C. F.; Hirschmann, R.; Torchiana, M. L.; Saperstein, R.
J . Am. Chem. Soc. 1976, 98, 2367-2369. (b) Veber, D. F.; Holly, F.
W.; Nutt, R. F.; Bergstrand, S. J .; Brady, R. F.; Hirschmann, R.; Glitzer,
M. S.; Saperstein, R. Nature (London) 1979, 280, 512-514. (c) Ueki,
M.; Oyamada, H.; Oka, T. Pept. Chem. 1986, 55-58. (d) Videnov, G.;
Buettner, K.; Casaretto, M.; Fohles, J .; Gattner, H. G.; Stoev, S.;
Brandenburg, D. Biol. Chem. Hoppe-Seyler 1990, 371, 1057-1066. (e)
Cuthbertson, A. S.; Husbyn, M.; Engebretsen, M.; Hartmann, M.;
Lange, M.; Sandosham, J .; Fischer, P. M.; Fjerdingstad, H.; Lovhaug,
D. J . Med. Chem. 1997, 40, 2876-2882.
(13) (a) Hanessian, S.; Sahoo, S. P. Tetrahedron Lett. 1984, 25,
1425-1428. (b) Krol, W. J .; Mao, S.; Steele, D. L.; Towensend, C. A. J .
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J . C. J . Am. Chem. Soc. 1992, 114, 2270-2272.
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(15) Itoh, M. Chem. Pharm. Bull. 1969, 17, 1679-1686.

Synthesis of meso-Diaminopimelic Acid
J . Org. Chem., Vol. 63, No. 7, 1998 2135
Sch em e 2
of achiral glyoxylate esters with optically pure dipeptides
having an L-allylglycine moiety reported relatively low
diastereomeric excess (25%) at the newly generated
hydroxyl-bearing carbon.10a Since elegant work by Whi-
tesell and co-workers had previously shown that pure
isomers of 2-phenylcyclohexyl glyoxylate undergo ene
reaction with high diastereoselection,16 we investigated
the use of such auxiliaries to form selectively protected
DAP isomers. Thus, optimized condensation of the
known esters 16 and 1716b (as their aldehyde hydrates)
with N-(benzyloxycarbonyl)-L-allylglycine methyl ester
(18)4a,e using tin tetrachloride at -23 °C affords the
corresponding functionalized alcohols 19 and 20, respec-
tively (Scheme 3). Initial NMR (1H and 13C) examination
suggested isomeric ratios of 84:16 and 86:14, respectively,
at the newly generated asymmetric center. However,
because of extensive spectral overlap and the possibility
that epimerization at the R-amino center could occur
during the ene reaction, each isomer mixture was further
transformed to DAP for additional stereochemical analy-
sis to confirm this.
Hydrogenation in the presence of tert-butoxypyrocar-
bonate (Boc anhydride) affords saturated alcohols 21 and
22, which upon mesylation, azide displacement, and a
second hydrogenation generate the selectively protected
DAP derivatives 27 and 28, respectively. Basic hydroly-
sis removes both ester functionalities to give 29 and 30.
Deprotection of 29 with trifluoroacetic acid provides a 84:
16 mixture of LL-DAP (1b) and meso-DAP (1a ), whereas
the same procedure with 30 gives a 86:14 mixture of 1a
and 1b. The stereochemistry was confirmed by conver-
sion of these DAP isomer mixtures to the corresponding
bis-N-(S)-camphanamide dimethyl esters 31a and 31b
(Scheme 4). 1H NMR comparison (particularly the meth-
yl ester region) with stereochemically pure samples
31a -c made from pure LL-, meso- and DD-DAP isomers,
obtained by literature separation-enzymatic resolution
procedures,17 verifies the initial stereochemical outcome
of the ene reactions and indicates that no significant
epimerization occurs in subsequent transformations. The
absence of DD-DAP derivative 31c from the camphana-
mides obtained via the ene condensation route confirms
that no epimerization occurs at the amino center derived
from L-allylglycine.
Although other auxiliaries could in principle provide
better diastereoselection in the ene reaction, this ap-
proach was not investigated further. Primary reasons
include the extra steps necessary for attachment and
disconnection of the chiral auxiliary, the lack of selectiv-
ity during removal of groups from the carboxyl moieties
of DAP, and the development of more expedient ap-
proaches involving chiral catalysis (see below).
Syn th esis of DAP Der iva tives Usin g Ch ir a l Ca ta -
lysts for Red u ction or for En e Rea ction . We had
previously prepared optically pure dimethyl (6S)-2-keto-
6-[N-(benzyloxycarbonyl)amino]pimelate (32) by a short
at the R-carbon by a remote functional group in the
allylglycine moiety. Nevertheless, the formation of 7
indicates that this approach could be a viable route to a
number of compounds bearing orthogonally protected
amino acid moieties at opposite ends of a central chain.11
Syn th esis of DAP Der iva tives Usin g Ch ir a l Au x-
ilia r ies for En e Rea ction . The ene reaction of pro-
tected allylglycines with esters of glyoxylic acid provides
rapid access to a variety of unusual amino acids and has
been successful for production of DAP derivatives as
isomeric mixtures9a,b as well as for generation of stereo-
chemically pure derivatives of substituted R-aminopimel-
ic acids.4a,10b An earlier investigation of ene condensation
(16) (a) Whitesell, J . K. Acc. Chem. Res. 1985, 18, 280-284. (b)
Whitesell, J . K.; Lawrence, R. M.; Chen, H. H. J . Org. Chem. 1986,
51, 4779-4784. (c) Whitesell, J . K.; Bhattacharya, A.; Buchanan, C.
M.; Chen, H. H.; Deyo, D.; J ames, D.; Liu, C. L.; Minton, M. A.
Tetrahedron 1986, 42, 2993-3001. (d) Whitesell, J . K.; Lawrence, R.
M. Chimia 1986, 40, 318-321.
(17) Pure DAP isomers were obtained by literature separation and
enzymatic resolution procedures; see ref 4e and: (a) Work, E.;
Birnbaum, S. M.; Winitz, M.; Greenstein, J . P. J . Am. Chem. Soc. 1955,
77, 1916-1918. (b) Wade, R.; Birnbaum, S. M.; Winitz, M.; Koegel, R.
J .; Greenstein, J . P. J . Am. Chem. Soc. 1957, 79, 648-652. (c) Van
Heijenoort, J .; Bricas, E. Bull. Chim. Soc. Fr. 1968, 2828-2831.

2136 J . Org. Chem., Vol. 63, No. 7, 1998
Gao et al.
Sch em e 3
Sch em e 4
Sch em e 5
with nitrogen to make DAP analogues (Scheme 5).
However, after considerable effort to obtain high selectiv-
ity, the best reduction conditions afford only a 79:21 ratio
of 6S:6R isomers of 33. Since the R-hydroxy esters are
prone to epimerization, the product mixture was directly
transformed to meso-DAP (1a ) using Mitsunobu substitu-
tion with N-tert-butyl [[2-(trimethylsilyl)ethyl]sulfonyl]-
carbamate (34)19 to give 35 followed by deprotection.
Conversion to the bis-Mosher amides and HPLC analysis
confirmed the isomeric ratio. Although fairly short, this
route lacks the desired level of stereoselection in the
hydrogenation of the oxo functionality. Attempts to
discover a better catalyst for this process or to accomplish
this reduction on the parent keto acid using various
dehydrogenases have not been successful thus far.
Numerous recent reports of ene reactions facilitated
by chiral catalysts20,21 suggest that such reagents could
(18) Noyori, R.; Ikeda, T.; Ohkuma, T.; Widhalm, M.; Kitamura, M.;
Takaya, H.; Akutagawa, S.; Sayo, N.; Saito, T.; Taketomi, T.; Kumoba-
yashi, H. J . Am. Chem. Soc. 1989, 111, 9134-9135.
(19) Campbell, J . A.; Hart, D. J . J . Org. Chem. 1993, 58, 2900-
2903.
(20) For reviews and some references to chiral Binap-titanium
complexes for ene reactions see: (a) Mikami, K. Pure Appl. Chem. 1996,
68, 639-644. (b) Mikami, K.; Shimizu, M. Chem. Rev. 1992, 92, 1021-
1050. (c) Mikami, K.; Terada, M.; Nakai, T. J . Am. Chem. Soc. 1990,
112, 3949-3954. (d) Mikami, K.; Yoshida, A. Tetrahedron Lett. 1994,
35, 7793-7796. (e) Terada, M.; Motoyama, Y.; Mikami, K. Tetrahedron
Lett. 1994, 35, 6693-6694.
(21) For some references to chiral bis(oxazoline)copper complexes
see: (a) Evans, D.; Woerpel, K. A.; Scott, M. S. Angew. Chem., Int. Ed.
Engl. 1992, 31, 430-432. (b) Corey, E. J .; Ishihara, K. Tetrahedron
Lett. 1992, 33, 6807-6810. (c) Evans, D.; Miller, S. J .; Lectka, T. J .
Am. Chem. Soc. 1993, 115, 6460-6461. (d) J ohannsen M.; J o¨rgensen,
K. A. J . Org. Chem. 1995, 60, 5757-5762.
sequence using nonselective ene reaction of methyl
N-(benzyloxycarbonyl)-L-allylglycinate (18) and methyl
glyoxylate.4a It seemed that enantioselective hydrogena-
tion of the keto group of 32 with the (S)-binaphtholru-
thenium (Binap-Ru) catalyst developed by Noyori et al.18
would provide an attractive alternative entry to stereo-
chemically pure 2-amino-6-hydroxypimelic acid deriva-
tives,10 whose hydroxyl group could then be substituted

Synthesis of meso-Diaminopimelic Acid
J . Org. Chem., Vol. 63, No. 7, 1998 2137
Sch em e 6
accomplish stereoselective condensation of N-(benzyloxy-
carbonyl)-L-allylglycine methyl ester (18) with simple
glyoxylate esters. However, a large variety of chiral
catalysts fail because their activation of the aldehyde
carbonyl is insufficient to promote bond formation with
the unreactive terminal olefin of 18. To circumvent this
difficulty, a sulfur substituent was temporarily intro-
duced at the terminus of the allylglycine residue (Scheme
6). Thus, alkylation of the anion of commercially avail-
able Scho¨llkopf bis-lactim ether (36)22 with the known
2-(phenylthio)-3-chloropropene (37)23 affords 38, which
hydrolyzes to L-valine methyl ester and (S)-4-(phenylth-
io)allylglycine methyl ester (39) (g98% ee by NMR
analysis of the corresponding camphanamides). This is
then protected as the N-Cbz derivative 40 prior to ene
condensation with methyl glyoxylate.
Attempted conversion of 40 using chiral binaphthol-
titanium complexes20 as Lewis acids fails and leads only
to recovery of starting material. However, the bis-
(oxazoline)-copper complex 41,21 which was initially used
for asymmetric Diels-Alder reactions and was reported
to produce undesired ene side products,21d catalyzes the
desired reaction between 40 and methyl glyoxylate to give
alcohol 42 in modest (42%) yield. The diastereomeric
excess on the newly generated center could not be easily
determined at this stage because this product is some-
what unstable. The olefinic bond and the phenylthio
group of 42 are simultaneously removed by NiCl2-
sodium borohydride (nickel boride)24 to generate satu-
rated alcohol 33 in good yield. Other desulfurization
reagents such as Raney-Ni, tributyltin hydride, and
lithium in ammonia give primarily undesired over-
reduction. Mitsunobu substitution of the hydroxy group
of 33 using 3419 as before inverts the chiral center to give
a protected DAP derivative 35 with the desired meso
stereochemistry. Removal of the silyl-containing group
proceeds quantitatively with tetrabutylammonium fluo-
ride to form 43. Saponification of the diester generates
a selectively N-protected analogue 44 in high yield. The
Boc and Cbz protecting groups can then be selectively
removed as desired. Hydrogenation (1 atm) with 10%
Pd/C catalyst followed by acidic cleavage of the Boc group
affords meso-DAP (1a ). 1H NMR analysis of the corre-
sponding Mosher’s diamide derivative as above shows the
stereochemistry to be 94% (2R,6S) (1a ) and 6% (2S,6S)
(1b). Since earlier studies show that there is usually no
isomerization under the deprotection conditions, and the
Mitsunobu process usually occurs with clean inversion,25
this suggests that the key ene reaction proceeds with ca.
88% diastereomeric excess.
aminopimelic derivatives (obtained via nonselective ene
processes4a) with Binap-ruthenium catalyst, and ene
reaction using chiral copper oxazoline catalysts. Al-
though the metathesis cyclization is useful for generation
of diaminosuberic acid derivatives,11 problems with isomer-
ization of vinylglycine moieties blocked this route to DAP.
Both the chiral phenylcyclohexyl auxiliary ene route and
the stereospecific reduction successfully lead to the
desired DAP derivatives, but the best isomer ratio (94:
6) and the most facile method employ chiral copper
catalyst for ene condensation of methyl glyoxylate with
methyl N-(benzyloxycarbonyl)-L-allylglycinate (18). Mit-
sunobu insertion of the nitrogen functionality then af-
fords the target protected DAP derivatives. This syn-
thetic approach can be used not only to produce these
compounds, but also other DAP analogues useful for
enzyme mechanism and inhibition studies. Additional
studies on DAP enzymes and their inhibitors as potential
antibiotic drug candidates are in progress.
Su m m a r y. The stereoselective synthesis of selectively
protected derivatives of meso-DAP (1a ) has been inves-
tigated using four approaches: olefin metathesis skeleton
assembly, ene reaction employing chiral 2-phenylcyclo-
hexyl auxiliaries, stereospecific reduction of 2-keto-6-
(22) (a) Scho¨llkopf, U.; Groth, U.; Deng, C. Angew. Chem., Int. Ed.
Engl. 1981, 20, 798-799. (b) Scho¨llkopf, U.; Hartwig, W.; Groth, U.
Angew. Chem., Int. Ed. Engl. 1979, 18, 863.
(23) Mueller, W. H.; Butler, P. E. J . Org. Chem. 1968, 33, 1533-
1537.
(24) (a) Back, T. G.; Baron, D. L.; Yang, K. J . Org. Chem. 1993, 58,
2407-2413. (b) Luh, T.-Y.; Hsieh, Y.-T. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, U.K.,
1995; Vol. 6, pp 3706-3707.
(25) (a) Mitsunobu, O. Synthesis 1981, 1-28. (b) Hughes, D. L. Org.
React. 1992, 42, 335-656. (c) Hughes, D. L.; Reamer, R. A. J . Org.
Chem. 1996, 61, 2967-2971.

2138 J . Org. Chem., Vol. 63, No. 7, 1998
Gao et al.
4.22-4.59 (m, 6 H), 5.12 (s, 2 H), 5.42-5.50 (m, 2 H), 7.30-
7.42 (m, 5 H); MS CI m/z (NH3) 480 (33, [M + 18]+), 463 (41,
[M + 1]+).
Exp er im en ta l Section
Gen er a l Meth od s. Common experimental procedures and
instrumentation have been described previously.4a,e The pro-
cedure of Whitesell and co-workers16b was used to prepare
(1R,2S)-trans-2-phenylcyclohexyl oxoacetate (16). The optical
purity of this starting material was determined to g98% ee
by conversion to its (R)-(+)-R-methoxy-R-(trifluoromethyl)-
phenylacetic acid ester (Mosher ester) using the corresponding
acid chloride, followed by comparison to the diastereomeric
product derived from the (1S,2R) -trans-2-phenylcyclohexyl
oxoacetate (17) by 1H NMR spectrometry. The bis-lactim ether
3622 was purchased from Merck Schuchardt (Hohenbrunn,
Germany).
2-(Tr im eth ylsilyl)eth yl (4S)-3-[3-N-(Ben zyloxyca r bo-
n yl)-5-oxa zolid in on -4-yl]p r op a n oa te (9). To a stirred solu-
tion of compound 815 (233 mg, 0.789 mmol), 2-(trimethylsilyl)-
ethanol (113 µL, 0.789 mmol), and N,N-bis(2-oxo-3-oxa-
zolidinyl)phosphinic chloride (201 mg, 0.789 mmol) in CH2Cl2
(30 mL) was added Et3N (220 µL, 1.58 mmol). After 10 h, the
solvent was evaporated in vacuo to give a residue that was
purified by flash chromatography (30% EtOAc in hexane) to
afford 9 as an oil (158 mg, 51%): Rf 0.92 (60% EtOAc in
hexane); IR (CHCl3 cast) 1802, 1724, 1453 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ -0.03 (s, 9 H), 0.91 (t, 2 H, J ) 8.6 Hz),
2.01-2.38 (m, 4 H), 4.07 (t, 2 H, J ) 8.6 Hz), 4.29 (t, 1 H, J )
5.8 Hz), 5.16 (s, 2 H), 5.21 (m, 1 H), 5.40 (m, 1 H), 7.19-7.28
(m, 5 H); 13C NMR (CD2Cl2, 75.5 MHz) δ -1.92, 16.88, 25.55,
29.08, 53.63, 62.39, 67.44, 77.42, 127.82, 128.08, 128.23,
135.15, 152.60, 171.37, 171.70; CI MS m/z (NH3) 411 (35, [M
+ 18]+). Anal. Calcd for C19H27NO6Si: C, 57.99; H, 6.92; N,
3.56. Found: C, 58.10; H, 7.21; N, 3.26.
N-(ter t-Bu toxyca r bon yl)-D-a llyglycin e (2). To a solution
of D-allylglycine26 (0.61 g, 5.3 mmol) in saturated aqueous
NaHCO3 (60 mL) and 1,4-dioxane (10 mL) was added Boc2O
(1.4 g, 6.4 mmol). After being stirred for 5 h, the solution was
washed with EtOAc (20 mL), acidified to pH 1 with 2 M HCl,
and extracted with EtOAc (3 × 30 mL). The organic extracts
were dried and evaporated to give 2 as an oil (0.68 g, 61%):
Rf 0.67 (70% EtOAc in hexane); [R]D -13.33° (c 1.08 CHCl3);
N-(Ben zyloxyca r bon yl)-L-glu ta m ic Acid , r-(3-Hyd r oxy-
p r op yl) γ-(2-Tr im eth ylsilyl)eth yl Ester (10). Propane-1,3-
diol (34 µL, 0.47 mmol) in THF (10 mL) was treated with 2.5
M n-BuLi in hexane (188 µL, 0.47 mmol). After being stirred
at room temperature for 10 min, this solution was transferred
to a solution of 9 (154 mg, 0.392 mmol) in THF (20 mL) via
cannula. The resulting mixture was stirred for 12 h, and the
solvent was removed in vacuo. The residue was redissolved
in EtOAc (40 mL), washed with water (10 mL), dried, and
evaporated in vacuo to give an oil. Purification by flash
chromatography (60% EtOAc in hexane) afforded 10 as a
yellow oil (80 mg, 47%): Rf 0.43 (60% EtOAc in hexane); [R]D
) +6.7° (c 7.2 CHCl3); IR (Nujol) 3079-2853, 1642, 1611, 1586,
IR (CHCl3 cast) 3340-3000, 1736, 1712, 1620, 1592 cm-1; H
1
NMR (CDCl3, 400 MHz) δ 1.42 (s, 9 H), 2.42-2.62 (m, 2 H),
4.32-4.44 (m, 1 H), 5.02-5.21 (m, 2 H), 5.65-5.80 (m, 1 H);
13C NMR (CDCl3, 100 MHz) δ 28.27, 36.40, 52.76, 80.30,
119.36, 132.14, 155.53, 176.61; CI MS m/z (NH3) 233 (80, [M
+ 18]+). Anal. Calcd for C10H17NO4: C, 55.80; H, 7.96; N,
6.51. Found: C, 56.36; H, 8.17; N, 6.42.
N-(ter t-Bu toxyca r bon yl)-D-a llylglycin e, 2-Hyd r oxyeth -
yl Ester (3). Condensation of 2 and ethylene glycol analogous
to preparation of 9 below gave 3 in 82% yield: Rf 0.28 (40%
EtOAc in hexane); IR (CHCl3 cast) 3428, 3215, 1770, 1729,
1
1620, 1587 cm-1; H NMR (CDCl3, 400 MHz) δ 1.40 (s, 9 H),
1
1559, 1512 cm-1; H NMR (CDCl3, 360 MHz) δ 0.01 (s, 9 H),
2.41-2.59 (m, 2 H), 3.79 (t, 2 H, J ) 4.5 Hz), 4.20-4.32 (m, 3
H), 5.08-5.21 (m, 4 H), 5.63-5.74 (m, 1 H); 13C NMR (CDCl3,
100 MHz) δ 28.26, 36.40, 53.13, 60.60, 66.73, 80.26, 119.21,
132.37, 155.64, 172.26; CI MS m/z (NH3) 277 (62, [M + 18]+).
Anal. Calcd for C12H21NO5: C, 55.58; H, 8.16; N, 5.40.
Found: C, 55.81; H, 8.36; N, 5.14.
0.97 (t, 2 H, J ) 8.4 Hz), 1.85 (t, 2 H, J ) 5.9 Hz), 2.05 (m, 1
H), 2.17 (m, 1 H), 2.38 (m, 2 H), 3.67 (t, 2 H, J ) 5.9 Hz), 4.16
(t, 2 H, J ) 8.4 Hz), 4.27 (t, 2 H, J ) 5.9 Hz), 4.37 (m, 1 H),
5.15 (s, 2 H), 5.42 (d, 1 H, J ) 7.7 Hz); 13C NMR (CDCl3, 75.5
MHz) δ -1.58, 17.24, 27.35, 30.21, 31.34, 53.47, 58.76, 62.51,
63.02, 67.03, 128.04, 128.15, 128.49, 136.12, 155.96, 172.14,
172.89; FAB MS m/z (Cleland) 440 (2.6, [M + 1]+). Anal.
Calcd for C21H33NO7Si: C, 57.38; H, 7.57; N, 3.19. Found: C,
57.29; H, 7.62; N, 3.15.
2-[(2R )-2-[[(t er t -Bu t oxyca r b on yl)a m in o]-4-p e n t e n -
oyl]oxy]eth yl N-(Ben zyloxycar bon yl)-L-allylglycin ate (5).
Condensation of 3 and methyl N-(benzyloxycarbonyl)-L-allyl-
glycinate (4) analogous to preparation of 9 below gave 5 in
83% yield: Rf 0.60 (30% EtOAc in hexane); [R]D -3° (c 0.5
N-(Ben zyloxyca r bon yl)-L-glu ta m ic Acid , r-3-[[(2R)-2-
[N-t er t -Bu t oxyca r b on yl)a m in o]-4-p en t en oyl]oxy]p r o-
p yl γ-2-(Tr im eth ylsilyl)eth yl Ester (11). A flask was
charged with dicyclohexylcarbodiimide (DCC) (60 mg, 0.32
mmol), 4-(dimethylamino)pyridine (DMAP) (59 mg, 0.48 mmol),
and DMAP‚HCl (51 mg, 0.32 mmol) in CH2Cl2 (20 mL). The
resulting solution was brought to reflux, and a solution of 10
(70 mg, 0.16 mmol) and (R)-N-(tert-butoxycarbonyl)allylglycine
(2) (34 mg, 0.16 mmol) in CH2Cl2 (10 mL) was added. After
16 h, the solution was cooled to room temperature and washed
with 1 M HCl (10 mL) and saturated aqueous NaHCO3
solution. Hexane (10 mL) was added, and the resulting
suspension was filtered, the filtrate being evaporated in vacuo
to give an oily residue that was purified by flash chromatog-
raphy (30% EtOAc in hexane) to afford 11 (90 mg, 88%): Rf
0.28 (20% EtOAc in hexane); [R]D ) +0.33 (c 0.3 CHCl3); IR
CHCl3); IR (CHCl3 cast) 3347, 1747, 1716, 1642, 1518 cm-1
;
1H NMR (CDCl3, 360 MHz) δ 1.41 (s, 9 H), 2.39-2.62 (m, 4
H), 4.21-4.38 (m, 5 H), 4.40-4.44 (m, 1 H), 4.97-5.08 (m, 1
H), 5.08-5.14 (m, 4 H), 5.35 (d, 1 H, J ) 7.5 Hz), 5.59-5.72
(m, 2 H), 7.27-7.38 (m, 5 H); 13C NMR (CDCl3, 100 MHz) δ
28.29, 36.54, 52.86, 53.27, 61.87, 62.58, 62.83, 67.04, 80.00,
119.27, 119.53, 128.11, 128.21, 128.53, 131.91, 132.18, 136.23,
155.10, 155.76, 171.48, 171.84; CI MS m/z (NH3) 492 (27, [M
+ 1]+). Anal. Calcd for C25H34N2O8: C, 61.21; H, 6.99; N, 5.71.
Found: C, 61.39; H, 7.06; N, 5.47.
(6R,11S)-11-[N-(Ben zyloxyca r bon yl)a m in o]-6-[N-(ter t-
bu toxyca r bon yl)a m in o]-5,12-d ioxo-1,4-d ioxa cyclod od ec-
8-en e (7). All reagents and solvents were dried and degassed.
A round-bottomed flask charged with catalyst bis(tricyclo-
hexylphosphine)benzylidineruthenium dichloride (6) (17 mg,
0.021 mmol) (Strem Chemicals, Newburyport, MA) was evacu-
ated and filled with Ar three times before the addition of 5
(50.8 mg, 0.104 mmol) in degassed CH2Cl2 (15 mL) by an
airtight syringe. The resulting orange solution was stirred
under Ar for 1.5 h and then stirred for 2 h exposed to the air.
The solution color changed from orange to dark black. Re-
moval of the solvent in vacuo gave an oily residue that was
purified by flash chromatography (25% EtOAc in hexane) to
afford 7 as an equal mixture of double bond isomers (17 mg,
(CHCl3 cast) 3353, 1724, 1520 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 0.05 (s, 9 H), 0.95 (t, 2 H J ) 8.5 Hz), 1.42 (s, 9 H),
1.98 (m, 3 H), 2.40 (m, 1 H), 2.31-2.60 (m, 4 H), 4.15 (t, 2 H,
J ) 8.5 Hz), 4.18-4.26 (m, 4 H), 5.07 (d, 1 H, J ) 7.8 Hz),
5.10 (s, 2 H), 5.13-5.17 (m, 2 H), 5.48 (d, 1 H, J ) 7.8 Hz),
5.48-5.73 (m, 1 H), 7.27-7.40 (m, 5 H); 13C NMR (CDCl3, 75.5
MHz) δ -1.52, 17.30, 27.47, 27.88, 28.30, 30.36, 36.69, 52.91,
53.48, 61.61, 62.05, 63.01, 67.07, 79.96, 119.18, 128.11, 128.20,
128.54, 132.27, 136.20, 155.23, 155.98, 171.80, 172.00, 172.77;
FAB MS m/z (Cleland) 637 (2, [M + 1]+). Anal. Calcd for
1
35%): Rf 0.09 (20% EtOAc in hexane); H NMR (CDCl3, 300
C
31H48N2O10Si: C, 58.47; H, 7.60; N, 4.40. Found: C, 58.78;
MHz) δ 1.45 (s, 9 H), 2.27-2.48 (m, 2 H), 2.48-2.68 (m, 2 H),
H, 7.54; N, 4.21.
N-(Ben zyloxyca r bon yl)-L-glu ta m ic Acid , r-3-[[(2R)-2-
[N-(ter t-Bu t oxyca r b on yl)a m in o]-4-p en t en oyl]oxy]p r o-
p yl Ester (12). To a solution of 11 (83 mg, 0.13 mmol) in
(26) D-Allylglycine was obtained by resolution of the racemate as
previously reported in ref 4a.

Synthesis of meso-Diaminopimelic Acid
J . Org. Chem., Vol. 63, No. 7, 1998 2139
1
THF (10 mL) was added a 1 M solution of TBAF in THF (400
µL, 0.4 mmol). The resulting red solution was stirred for 45
min and then evaporated in vacuo. The residue was dissolved
in Et2O (45 mL), and the ethereal solution was washed with
1 M HCl (20 mL), dried, and evaporated in vacuo to give 12
as a gray oil (70 mg, quantitative): Rf 0.62 (EtOAc); IR (CHCl3
cast) 3200-2800, 1773, 1760, 1596 cm-1; 1H NMR (CDCl3, 360
MHz) 1.42 (s, 9 H), 1.96-2.15 (m, 3 H), 2.15-2.22 (m, 1 H),
2.40-2.48 (m, 4 H), 4.16-4.30 (m, 4 H), 4.30-4.45 (m, 2 H),
5.07-5.18 (m, 5 H), 5.56 (d, 1 H, J ) 7.8 Hz), 5.61-5.78 (m, 1
H), 7.26-7.40 (m, 5 H); CI MS m/z (NH3) 537 (42, [M + 1]+).
Lea d Tetr a a ceta te Oxid a tion of 12 To Gen er a te 14. To
a solution of 12 (70 mg, 0.13 mmol) in benzene (20 mL) was
added cupric acetate monohydrate (8 mg, 0.0373 mmol), and
the suspension was stirred under Ar for 1 h. Freshly prepared
lead tetraacetate (132 mg, 0.299 mmol) was added, and the
resulting suspension was stirred for 1 h at room temperature
then 15 h at reflux. The suspension was then cooled and
diluted with EtOAc (20 mL). The mixture was washed with
water (3 × 20 mL) and brine (15 mL), dried, and evaporated
in vacuo. The resulting syrup was purified by flash chroma-
tography (30% EtOAc in hexane) to give 14 (28 mg, 43%): 1H
NMR (CDCl3, 400 MHz) δ 1.45 (s, 9 H), 1.80 (d, 3 H, J ) 7.2
Hz), 1.94-2.11 (m, 2 H), 2.41-2.59 (m, 2 H), 4.12-4.27 (m, 5
H), 5.03 (d, 1 H, J ) 7.8 Hz), 5.09-5.18 (m, 5 H), 5.65-5.76
(m, 1 H), 6.74 (q, 1 H, J ) 7.2 Hz), 7.26-7.40 (m, 5 H).
N-(Ben zyloxyca r b on yl)-L-m et h ion in e Su lfoxid e, 3-
[[(2R)-2-[N-(ter t-Bu t oxyca r b on yl)a m in o]-4-p en t en oyl]-
oxy]p r op yl Ester (15). To a solution of L-methionine (1.0 g,
6.7 mmol) in saturated aqueous NaHCO3 (20 mL) solution was
added benzyl chloroformate (1.11 mL, 7.4 mmol) dropwise over
2 min. After being stirred at room temperature for 2 h, the
solution was washed with EtOAc (20 mL), acidified to pH 2
with 2 M HCl, and extracted with EtOAc (3 × 20 mL). The
combined organic extracts were dried and evaporated in vacuo
to give N-(benzyloxycarbonyl)-L-methionine as an oil (1.2 g,
63%). A solution of this oil (721 mg) and propane-1,3-diol (968
mg, 12.74 mmol) in CH2Cl2 (10 mL) was transferred to a
solution of DCC (524 mg, 2.55 mmol), DMAP (310 mg, 2.55
mmol), and DMAP‚HCl (405 mg, 2.55 mmol) in CH2Cl2 (20
mL) at reflux. After 6 h at reflux, the solution was cooled and
washed with 1 M HCl (2 × 20 mL). The organic layer was
dried and evaporated in vacuo to give a residue that was
purified by flash chromatography (40% EtOAc in hexane) to
afford N-(benzyloxycarbonyl)-L-methionine 3-hydroxypropyl
ester (685 mg, 79%): Rf 0.14 (40% EtOAc in hexane); IR
1770, 1720, 1580 cm-1; H NMR (CDCl3, 300 MHz) δ 1.41 (s,
9 H), 1.97 (m, 2 H), 2.15 (m, 1 H), 1.93-2.50 (m, 3 H), 2.54 (s,
3 H), 2.77 (t, 2 H, J ) 7.6 Hz), 4.10-4.26 (m, 4 H), 4.33 (m, 1
H), 4.46 (m, 1 H), 5.08 (s, 2 H), 5.11-5.19 (m, 2 H), 5.60-5.78
(m, 1 H), 5.83 (d, 1 H, J ) 8.0 Hz), 5.89 (d, 1 H, J ) 7.8 Hz),
7.37-7.41 (m, 5 H); 13C NMR (CDCl3, 75.5 MHz) δ 27.87, 28.33,
32.27, 36.63, 38.54, 50.07, 52.95, 53.21, 61.52, 62.32, 67.20,
80.01, 119.20, 128.19, 128.29, 128.57, 132.31, 136.14, 155.30,
156.13, 171.19, 172.06; CI MS m/z (NH3) 572 (23, [M + 18]+),
555 (17, [M + 1]+). Anal. Calcd for C26H38N2O9S: C, 56.30;
H, 6.91; N, 5.05. Found: C, 56.71; H, 6.77; N, 5.17.
1-Meth yl 7-[(1R,2S)-tr a n s-2-P h en ylcycloh exyl] (2S,6R)-
2-[N-(Ben zyloxyca r bon yl)a m in o]-6-h yd r oxy-3-h ep ten e-
d ioa te (19). SnCl4 (10.0 mL, 86.7 mmol) was added over 2
min to a stirred solution of 1616b (5.01 g, 20.0 mmol) in dry
CH2Cl2 (125 mL) at approximately -55 °C. The solution was
cooled to -78 °C and stirred for 5 min, and 18 (5.86 g, 22.3
mmol) in dry CH2Cl2 (40 mL) was added over 15 min. The
solution was warmed to -23 °C and was stirred for 3 h. The
mixture was quenched with ether (500 mL) and washed with
saturated NaHCO3 (2 × 250 mL) and water (250 mL). The
organic layer was dried over Na2SO4 and concentrated in vacuo
to give a pale yellow oil. Purification by flash chromatography
(EtOAc 40%/hexane 60%) gave 8.20 g (83%) of 19 as a clear
oil: [R]D +28.1° (c ) 1.88, CHCl3); IR (CHCl3 cast) 3420, 3360,
2936, 1726, 1271, 1208 cm-1 1H NMR (360 MHz, CDCl3) δ
;
7.44-7.10 (m, 10H), 5.55 (d, 1H, J ) 7.9 Hz), 5.25-4.92 (m,
5H), 4.75-4.64 (m, 1H), 3.96 (dd, 1H, J ) 11.0, 6.0 Hz), 3.68
(s, 3H) 2.90 (br s, 1H), 2.65 (m, 1H), 2.18-2.00 (m, 1H) 2.00-
1.18 (m, 9H); 13C NMR (75.5 MHz, CDCl3) δ 173.3, 171.0, 155.4,
142.8, 136.2, 128.5, 128.3, 127.55, 127.5, 126.8, 78.0, 69.3, 67.0,
55.3, 52.5, 49.8, 36.5, 33.7, 32.1, 25.6, 24.6; exact mass
495.2259 (495.2257 calcd for C28H33NO7). Anal. Calcd for
C
28H33NO7: C, 67.86; H, 6.71; N, 2.83. Found: C, 67.55; H,
6.88; N, 2.90.
1-Meth yl 7-[(1S,2R)-tr a n s-2-P h en ylcycloh exyl] (2S,6S)-
2-[N-(Ben zyloxyca r bon yl)a m in o]-6-h yd r oxy-3-h ep ten e-
d ioa te (20). The previous procedure was adapted to condense
1716b (1.05 g, 4.20 mmol) and 18 (1.01 g, 3.84 mmol) to give an
81% yield of 20: [R]D +24.4° (c ) 0.85, CHCl3); IR (CHCl3 cast)
3420, 3360, 2936, 1726, 1265, 1209 cm-1; 1H NMR (360 MHz,
CDCl3) δ 7.34-7.06 (m, 10H), 5.54 (d, 1H, J ) 8.3 Hz), 5.25-
4.90 (m, 5H), 4.72-4.64 (m, 1H), 4.04-3.96 (m, 1H), 3.68 (s,
3H) 2.90 (d, 1H, J ) 6.0 Hz), 2.65 (ddd, 1H, J ) 12.2, 11.0, 3.7
Hz), 2.18-2.00 (m, 1H) 2.05-1.22 (m, 9H); 13C NMR (90.5
MHz, CDCl3) δ 173.4, 171.1, 155.4, 142.8, 136.2, 128.5, 128.3,
127.8, 127.52, 127.48, 127.4, 127.3, 126.8, 78.1, 69.4, 67.0, 55.4,
52.5, 49.8, 36.5, 33.8, 32.2, 25.6, 24.6; exact mass 495.2256
(495.2257 calcd for C28H33NO7). Anal. Calcd for C28H33NO7:
C, 67.86; H, 6.71; N, 2.83. Found: C, 68.02; H, 6.93; N, 2.96.
1-Meth yl 7-[(1R,2S)-tr a n s-2-P h en ylcycloh exyl] (2S,6R)-
2-[N-(ter t-Bu toxyca r bon yl)a m in o]-6-h yd r oxyh ep ta n ed io-
a te (21). The procedure of Sakaitani et al.27 was adapted. To
a solution of 19 (2.68 g, 5.41 mmol) and di-tert-butyl pyrocar-
bonate (1.56 g, 7.06 mmol) in MeOH (20 mL) was added 5%
Pd on carbon (0.0479 g) in MeOH (5 mL). The suspension was
stirred under H2 (1 atm) for 20 h and then filtered through
Celite. The Celite was washed with MeOH, and the combined
filtrates were concentrated in vacuo to give a colorless oil.
Purification by flash chromatography (CHCl3 followed by 3%
MeOH/CHCl3 97%) afforded 2.10 g (84% yield) of 21 as a
colorless oil: [R]D -8.3° (c ) 0.579, CHCl3); IR (CH3OH cast)
3480 br, 3410 br, 2935, 2865, 2858, 1742, 1716 cm-1; 1H NMR
(360 MHz, CDCl3) δ 7.36-7.12 (m, 5H), 5.03 (ddd, 1H, J )
11.0, 10.4, 4.3 Hz), 4.87 (br d, 1H, J ) 7.9 Hz), 4.12 (m, 1H),
3.94 (m, 1H), 3.73 (s, 3H), 2.74-2.60 (m, 2H), 2.24-2.18 (m,
1H), 2.01-1.70 (m, 3H), 1.66-1.05 (m, 8H), 1.46 (s, 9H), 1.00-
0.78 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ 174.3, 173.1, 155.2,
142.8, 128.2, 127.4, 127.3, 126.6, 126.5, 79.4, 77.7, 69.8, 53.1,
52.0, 49.8, 33.8, 33.3, 32.1, 32.0, 28.2, 25.5, 24.5, 20.3; exact
mass 463.2547 (463.2570 calcd for C25H37NO7). Anal. Calcd
1
(CHCl3 cast) 3400-2900, 1721, 1523 cm-1; H NMR (CDCl3,
300 MHz) δ 1.58-1.98 (m, 4 H), 2.09 (s, 3 H), 2.55 (t, 2 H, J )
7.6 Hz), 3.69 (t, 2 H, J ) 5.9 Hz), 4.34 (m, 2 H), 4.45 (m, 1 H),
5.12 (s, 2 H), 5.41 (d, 1 H, J ) 7.8 Hz), 7.26-7.38 (m, 5 H); CI
MS m/z (NH3) 359 (25, [M + 18]+). Anal. Calcd for C16H23
-
NO5S: C, 56.29; H, 6.79; N, 4.10. Found: C, 56.64; H, 6.97;
N, 3.98.
The method used above to make 11 transformed N-(benzyl-
oxycarbonyl)-L-methionine 3-hydroxypropyl ester and 2 to
N-(benzyloxycarbonyl)-L-methionine, 3-[[(2R)-2-[N-(tert-buty-
loxycarbonyl)amino]-4-pentenoyl]oxy]propyl ester in 84%
1
yield: Rf 0.63 (40% EtOAc in hexane); H NMR (CDCl3, 400
MHz) δ 1.40 (s, 9 H), 1.86-2.41 (m, 7 H), 2.37-2.60 (m, 4 H),
4.04-4.26 (m, 4 H), 4.35 (m, 1 H), 4.48 (m, 1 H), 5.00-5.18
(m, 4 H), 5.42 (d, 1 H, J ) 7.8 Hz), 5.54 (d, 1 H, J ) 7.8 Hz),
5.60-5.71 (m, 1 H), 7.26-7.40 (m, 5 H); CI MS m/z (NH3) 556
(34, [M + 18]+), 539 (20, [M + 1]+).
To a cooled solution (0 °C) of N-(benzyloxycarbonyl)-L-
methionine, 3-[[(2R)-2-[N-(tert-butyloxycarbonyl)amino]-4-pen-
tenoyl]oxy]propyl ester (150 mg, 0.28 mmol) in methanol (10
mL) was added a solution of NaIO4 (63 mg, 0.29 mmol) in
water (10 mL) dropwise over a period of 2 h through an
addition funnel. The mixture was then stirred at 4 °C for 12
h. The product was filtered through a bed of Celite, and the
filtrate was extracted with chloroform (6 × 50 mL). The
combined organic layers were washed with water (20 mL) and
brine (20 mL), dried, and evaporated in vacuo. The residue
was purified by flash chromatography (EtOAc) to give 15 (127
mg, 82%) as an oil: Rf 0.12 (EtOAc); IR (CHCl3 cast) 3340,
(27) Sakaitani, M.; Hori, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29,
2983-2984.

2140 J . Org. Chem., Vol. 63, No. 7, 1998
Gao et al.
for C25H37NO7: C, 64.78; H, 8.05; N, 3.02. Found C, 64.55; H,
7.69; N, 2.94.
11.0, 3.7 Hz), 2.16-2.10 (m, 1H), 2.02-1.73 (m, 3H), 1.72-
1.02 (m, 10H), 1.45 (s, 9H); 13C NMR (MHz, CDCl3) δ 172.9,
169.3, 155.2, 142.5, 128.4, 127.5, 126.7, 79.8, 77.7, 61.7, 52.9,
52.2, 49.9, 33.8, 32.1, 31.8, 30.5, 28.2, 25.6, 24.7, 21.3; MS (Pos
FAB glycerol) 463.36 (463.27 calcd for MH+). Anal. Calcd for
1-Meth yl 7-[(1S,2R)-tr a n s-2-P h en ylcycloh exyl] (2S,6S)-
2-[N-(ter t-Bu toxyca r bon yl)a m in o]-6-h yd r oxyh epta n edio-
a te (22). Alcohol 22 was prepared in 80% yield from 20 (0.512
g, 1.03 mmol) by the same procedure used for the synthesis of
21, employing Boc anhydride (99%, 0.291 g, 1.32 mmol) and
5% Pd on carbon (0.109 g) in 11 mL of MeOH: [R]D +17.7 (c )
1.30, CHCl3); IR (CHCl3 cast) 3380, 2936, 1737, 1719, 1253,
C
25H36N4O6: C, 61.46; H, 7.43; N, 11.47. Found: C, 61.65; H,
7.70; N, 11.40.
1-Meth yl 7-[(1S,2R)-tr a n s-2-P h en ylcycloh exyl] (2S,6R)-
2-[N-(ter t-Bu t oxyca r b on yl)a m in o]-6-a zid oh ep t a n ed io-
a te (26). Azide 26 was prepared from 24 (1.12 g, 2.06 mmol)
in 77% yield by the same method as employed for the
preparation of 25 from 23, using NaN3 (0.552 g, 8.49 mmol)
in dry DMF (20 mL): [R]D +25.3° (c ) 1.44, CHCl3); IR (CHCl3
1
1210, 1165, 1113 cm-1; H NMR (360 MHz, CDCl3) δ 7.34-
7.16 (m, 5H), 5.10 (ddd, 1H, J ) 11.0, 10.4, 4.3 Hz), 4.85 (d,
1H, J ) 8.6 Hz), 4.18-4.08 (m, 1H), 3.99-3.90 (m, 1H), 3.74
(s, 3H), 2.74-2.64 (m, 1H), 2.62 (d, 1H, J ) 5.5 Hz), 2.22-
2.10 (m, 1H), 2.00-1.87 (m, 3H), 1.66-0.70 (m, 10H), 1.45 (s,
9H); 13C NMR δ 174.2, 173.0, 155.2, 142.6, 128.2, 128.1, 127.2,
126.64, 126.58, 79.5, 77.6, 69.6, 53.0, 51.9, 49.7, 33.6, 33.1, 32.0,
1
cast) 3375, 2936, 2861, 2107, 1739, 1717 cm-1; H NMR (360
MHz, CDCl3) δ 7.38-7.16 (m, 5H), 5.06 (ddd, 1H, J ) 11.0,
10.4, 4.3 Hz), 4.94 (br d, 1H, J ) 8.6 Hz), 3.74 (s, 3H), 3.45
(dd, 1H, J ) 7.9, 6.7 Hz), 2.72 (ddd, 1H, J ) 11.0, 11.0, 3.7
Hz), 2.22-2.12 (m, 1H), 2.04-1.78 (m, 3H), 1.78-1.06 (m,
10H), 1.45 (s, 9H); 13C NMR (MHz, CDCl3) δ 172.9, 169.3,
155.2, 142.5, 128.3, 127.5, 126.7, 79.9, 77.7, 61.7, 53.0, 52.2,
49.8, 33.7, 32.1, 31.9, 30.5, 28.2, 25.6, 24.7, 21.3; MS (Pos FAB
glycerol) 463.36 (463.27 calcd for MH+). Anal. Calcd for
31.8, 28.1, 25.5, 24.5, 19.7; exact mass 404.2426 (M+
C2H3O2). Anal. Calcd for C25H37NO7: C,64.78; H, 8.05; N,
3.02. Found: C, 64.83; H, 7.75; N, 2.83.
-
1-Meth yl 7-(1R,2S)-tr a n s-2-P h en ylcycloh exyl (2S,6R)-
2-(N-(ter t-Bu t oxyca r b on yl)a m in o]-6-[(m et h ylsu lfon yl)-
oxy]h ep ta n ed ioa te (23). Methanesulfonyl chloride (98%,
0.220 mL, 2.75 mmol) was added to a stirred solution of 21
(0.965 g, 2.08 mmol) in dry pyridine (20 mL) under argon. The
mixture was stirred for 1.75 h and was then quenched by the
addition of 20% CuSO4‚5H2O solution (30 mL). The solution
was extracted with CH2Cl2 (3 × 50 mL), and the combined
organic phases were washed with 2 M HCl (3 × 30 mL), dried
over Na2SO4, and then concentrated in vacuo to yield 1.05 g
C
25H36N4O6: C, 61.46; H, 7.43; N, 11.47. Found: C, 61.28; H,
7.62; N, 11.50.
1-Meth yl 7-[(1R,2S)-tr a n s-2-P h en ylcycloh exyl] (2S,6S)-
2-[N-(ter t-Bu t oxyca r b on yl)a m in o]-6-a m in oh ep t a n ed io-
a te (27). Azide 25 (0.645 g, 1.32 mmol) in MeOH (10.0 mL)
was added to 5% Pd on carbon (0.0805 g) moistened with
MeOH. The mixture was then stirred under H2 (1 atm) for
1.5 h. It was filtered through Celite, and the Celite was
washed with MeOH. The combined filtrates were concentrated
in vacuo to give 0.485 g (80% yield) of 27 as an oil: [R]D -4.7°
(c ) 0.867, CHCl3); IR (CHCl3 cast) 3370, 2934, 1743, 1716,
(94%) of 23 as an oil: [R]D +14.00° (c ) 1.35, CHCl3); IR (CHCl3
-1
cast) 3380, 2935, 2860, 1746, 1714, 1365, 1208, 1176 cm
;
1H NMR (360 MHz, CDCl3) δ 7.36-7.17 (m, 5H), 5.06 (ddd,
1H, J ) 11.0, 10.4, 4.3 Hz), 4.90 (br d, 1H, J ) 8.6 Hz), 4.76
(dd, 1H, J ) 6.1, 5.5 Hz), 4.22-4.12 (m, 1H), 3.75 (s, 3H), 2.95
(s, 3H), 2.77-2.66 (m, 1H), 2.23-2.15 (m, 1H), 2.03-1.78 (m,
3H), 1.70-0.90 (m, 10H), 1.48 (s, 9H); 13C NMR (90.5 MHz,
CDCl3) δ 172.9, 168.1, 155.2, 142.8, 128.5, 128.4, 127.6, 127.4,
126.7, 79.8, 78.1, 77.3, 52.9, 52.2, 49.8, 38.7, 34.1, 32.1, 31.8,
31.0, 28.2, 25.5, 24.6, 20.3; exact mass 482.2206 (482.2206
calcd for M+ - C2H3O2), MS (Pos FAB, Cleland) 542.53 (542.23
calcd for MH+). Anal. Calcd for C26H39NO9S: C, 57.65; H,
7.26; N, 2.58; S, 5.92. Found: C, 57.53; H, 7.15; N, 2.70; S,
5.66.
1
1166 cm-1; H NMR (360 MHz CDCl3) δ 7.38-7.12 (m, 5H),
5.16-4.89 (m, 2H), 4.25-4.08 (m, 1H), 3.73 (s, 3H), 2.73-2.59
(m, 1H), 2.18-0.80 (m, 16H), 1.43 (s, 9H); 13C NMR (75.5 MHz,
CDCl3) δ 174.2, 172.8, 155.0, 142.5, 127.9, 127.1, 126.1, 76.0,
53.7, 52.8, 51.6, 49.4, 33.2, 31.8, 31.6, 27.9, 25.3, 24.3, 20.9;
exact mass 462.2734 (462.2730 calcd for C25H38N2O6).
1-Meth yl 7-[(1S,2R)-tr a n s-2-P h en ylcycloh exyl] (2S,6R)-
2-[N-(ter t-Bu t oxyca r b on yl)a m in o]-6-a m in oh ep t a n ed io-
a te (28). Amine 28 was prepared from 26 (0.775 g, 1.59) in
93% yield in a manner analogous to the synthesis of 27 from
25, using 5% Pd on carbon (0.489 g) in MeOH (15 mL): [R]D
+23.1° (c ) 1.21, CHCl3); IR (CHCl3 cast) 3370, 2973, 2931,
1-Meth yl 7-(1S,2R)-tr a n s-2-P h en ylcycloh exyl (2S,6S)-
2-[N-(ter t-Bu t oxyca r b on yl)a m in o]-6-[(m et h ylsu lfon yl)-
oxy]h ep ta n ed ioa te (24). Mesylate 24 was prepared from 22
(1.47 g, 3.23 mmol) in 94% yield in the same manner as 23
was prepared from 21, using methanesulfonyl chloride (98%,
0.330 mL, 4.18 mmol), in dry pyridine (20 mL): [R]D +2.9° (c
) 1.0, CHCl3); IR (CHCl3 cast) 3380, 2936, 1749, 1715, 1365,
1210, 1176 cm -1; 1H NMR (360 MHz, CDCl3) δ 7.36-7.18 (m,
5H), 5.06 (ddd, 1H, J ) 11.0, 10.4, 4.3 Hz), 4.90 (br d, 1H, J )
8.0 Hz), 4.82-4.76 (m, 1H), 4.22-4.14 (m, 1H), 3.74 (s, 3H),
2.95 (s, 3H), 2.77-2.66 (m, 1H), 2.23-2.15 (m, 1H), 2.03-1.78
(m, 3H), 1.70-0.90 (m, 10H), 1.47 (s, 9H); 13C NMR (90.5 MHz,
CDCl3) δ 172.9, 168.1, 155.2, 142.8, 128.4, 127.3, 126.7, 79.7,
78.1, 77.8, 52.9, 52.1, 49.7, 38.6, 34.0, 32.0, 31.4, 30.8, 28.1,
25.5, 24.5, 19.9; exact mass 482.2206 (482.2206 calcd for M+
- C2H3O2), MS (Pos FAB, Cleland) 542.27 (542.23 calcd for
MH+). Anal. Calcd for C26H39NO9S: C, 57.65; H, 7.26; N, 2.58;
S, 5.92. Found: C, 57.82; H, 7.25; N, 2.48; S, 5.67.
2858,1741, 1714, 1165 cm-1 1H NMR (360 MHz CDCl3) δ
;
7.36-7.18 (m, 5H), 5.20-5.00 (m, 2H), 4.45-4.10 (m, 3H), 3.76
(s, 3H), 2.76-2.66 (m, 1H), 2.23-1.00 (m, 14H), 1.46 (s, 9H);
13C NMR (75.5 MHz, CDCl3) δ 174.3, 172.8, 155.0, 142.5, 127.9,
127.2, 126.2, 79.2, 76.0, 53.7, 52.8, 51.6, 49.5, 33.2, 31.8, 31.6,
27.9, 25.3, 24.3, 20.9; exact mass 462.2731 (462.2730 calcd for
C
25H38N2O6).
(2S,6S)-2-[N-(ter t-Bu toxycar bon yl)am in o]-6-am in oh ep-
ta n ed ioic Acid (29). LiOH‚H2O (0.0999 g, 2.38 mmol) was
added to a stirred solution of 27 (0.275 g, 0.595 mmol) in 3:1
THF/H2O (20.0 mL), and the solution was stirred at room
temperature for 4.5 h. The THF was removed in vacuo, and
the aqueous solution was washed with CH2Cl2 (3 × 10 mL). It
was then acidified to pH 4 with 5.7 M HCl. Lyophilization
yielded 29 as its lithium salt in the form of a hygroscopic white
foam (0.259 g): IR (CH3OH cast) 3360, 3040, 1687, 1601 cm-1
;
1-Meth yl 7-(1R,2S)-tr a n s-2-P h en ylcycloh exyl (2S,6S)-
2-[N-(Bu toxycar bon yl)am in o]-6-azidoh eptan edioate (25).
Mesylate 23 (0.819 g, 1.51 mmol) and NaN3 (0.400 g, 6.16
mmol) were dissolved in dry DMF (15 mL) and stirred under
Ar for 28 h. The DMF was removed in vacuo, and the residue
was taken up in CH2Cl2 (75 mL) and washed with brine (2 ×
30 mL). The organic layer was dried over Na2SO4 and then
concentrated in vacuo to give a red oil that was purified by
flash chromatography (EtOAc 25%/hexane 75%) to afford 0.647
g (88% yield) of 25 as a colorless oil: [R]D -4.1° (c ) 2.18,
CHCl3); IR (CHCl3 cast) 3375, 2936, 2861, 2107, 1739, 1717
1H NMR (360 MHz, CD3OD) δ 4.08-3.83 (m, 1H), 3.78-3.55
(m, 1H), 2.10-1.12 (m, 6H) 1.47 (s, 9H); 13C NMR (75.5 MHz,
CD3OD) δ 179.4, 174.8, 157.8, 80.4, 56.7, 55.9, 33.6, 31.9, 28.8,
22.4; MS (Pos FAB glycerol/HCl) 291.02 (291.16 calcd for
C11H20N2O6Li2), 297.03 (297.18 calcd for C11H20N2O6Li3). Acidic
deprotection with trifluoroacetic acid and standard cation-
exchange chromatography (AG50) gave LL-DAP (1b) and meso-
DAP (1a ) in a ratio of 84:16. The ratio was determined by
conversion to corresponding camphanamide derivatives 31a ,b
(see below).
(2S,6S)-2-[N-(ter t-Bu toxycar bon yl)am in o]-6-am in oh ep-
ta n ed ioic Acid (30). The procedure used for the conversion
of 27 to 29 was utilized to prepare 30 as its lithium salt (0.216
g) from 28 (0.209 g, 0.452 mmol), employing LiOH‚H2O (0.0765
1
cm-1; H NMR (360 MHz, CDCl3) δ 7.33-7.16 (m, 5H), 5.06
(ddd, 1H, J ) 11.0, 10.4, 4.3 Hz), 4.94 (br d, 1H, J ) 8.6), 3.73
(s, 3H), 3.47 (dd, 1H, J ) 7.3, 6.7 Hz), 2.72 (ddd, 1H, J ) 12.2,

Synthesis of meso-Diaminopimelic Acid
J . Org. Chem., Vol. 63, No. 7, 1998 2141
g, 1.82 mmol) in 3:1 THF/H2O (20.0 mL) over 5 h: IR (CH3-
Dim eth yl (2S,6S)-6-[N-(Ben zyloxyca r bon yl)a m in o]-2-
h yd r oxyh ep ta n e-1,7-d ioa te (33) fr om 32. The procedure
of Noyori and co-workers18 was adapted. All the reagents and
solvents were predried and degassed. To a dry Schlenk tube
charged with dimethyl (6S)-6-[N-(benzyloxycarbonyl)amino]-
2-oxoheptane-1,7-dioate (32)4a (180 mg, 0.513 mmol) and
methanol (5 mL) was added the in situ prepared (S)-Binap-
Ru(II) complex (2 mg)18 under a stream of Ar. The resulting
yellow-orange solution was further degassed by two freeze-
thaw cycles and transferred to a dry, argon-filled autoclave
that was evacuated by vacuum and refilled with hydrogen five
times. Finally, the system was kept at 4 atm hydrogen, 100
°C for 4 h. After the autoclave was cooled to room temperature
and excess hydrogen was allowed to bleed off, the solution was
evaporated in vacuo. The residue was separated by flash
chromatography (40% EtOAc in hexane) to give 33 as an oil
(163 mg, 90%). Conversion to DAP and NMR analysis of the
corresponding Mosher amides (see Scheme 6 and below)
showed an isomeric ratio 6S:6R of 79:21 (58% de): Rf 0.79
OH cast) 3400, 3040, 1686, 1602 cm-1 1H NMR (360 MHz,
;
CD3OD) δ 4.08-3.83 (m, 1H), 3.78-3.55 (m, 1H), 2.10-1.12
(m, 6H) 1.47 (s, 9H); 13C NMR (75.5 MHz, CD3OD) δ 179.3,
174.6, 157.8, 80.2, 56.8, 56.0, 33.9, 32.0, 28.8, 22.7; MS (Pos
FAB glycerol/HCl) 297.03 (297.18 calcd for C11H20N2O6Li3).
Acidic deprotection with trifluoroacetic acid and standard
cation-exchange chromatography (AG50) gave meso-DAP (1a )
and LL-DAP (1b) in a ratio of 86:13. The ratio was determined
by conversion to corresponding camphanamide derivatives
31a ,b.
Ster eoch em ica l An a lysis of DAP Isom er s: Dim eth yl
(2S,6S)-2,6-Bis([(1S,4R)-4,7,7-tr im eth yl-3-oxo-2-oxabicyclo-
[2.2.1]h ep ta n e(ca r bon yla m in o)h ep ta n ed ioa te (31b), Its
(2R,6R)-Isom er 31c, a n d Its (2S,6R)-Isom er 31a . NMR
spectral comparison, particularly of the methyl ester region
(δ 3.7-3.8), of DAP derivatives 31 allows determination of
stereochemical purity to (2%. LL-DAP (1b) (1.93 mg, 0.0102
mmol) was dissolved in 1 M NaHCO3/Na2CO3 buffer, pH 10.4
(2 mL). Toluene (1 mL) was added followed by (1S,4R)-(-)-
camphanic chloride (10.2 mg, 0.0469 mmol), and the mixture
was stirred vigorously at room temperature for 2.5 h. The
solution was acidified to pH 1 with 5.7 M HCl. It was then
diluted to 5 mL with water and extracted with dichlo-
romethane (3 × 10 mL). The combined organic fractions were
dried over Na2SO4 and were concentrated in vacuo. The
residue was taken up in ether (2 mL). This was treated with
a solution of CH2N2 in ether until a yellow color persisted. The
ether was evaporated to give 17.1 mg of a waxy solid, which
was heated at 65-70 °C for 5 h at 0.4 mmHg to remove methyl
camphanoate and give 5.16 mg (88%) of a colorless oil: [R]D
-4.7° (c ) 1.25, CHCl3); IR (CHCl3 cast) 3416, 3365, 2965,
(EtOAc); IR (CH2Cl2 cast) 3356, 1790-1760, 1735, 1527 cm-1
;
1H NMR (CDCl3, 360 MHz) δ 1.40-1.95 (m, 6 H), 3.70 (s, 3
H), 3.78 (s, 3 H), 4.08-4.20 (m, 1 H), 4.31-4.41 (m, 1 H), 5.17
(s, 2 H), 5.20-5.31 (br s, 1 H), 7.29-7.40 (m, 5 H); 13C NMR
(CDCl3, 100 MHz) δ 20.73, 32.36, 33.70, 52.43, 52.61, 53.68,
67.07, 70.13, 128.15, 128.23, 128.57, 136.24, 156.20, 172.81,
175.43; exact mass 353.1468 (7.3, M+) (353.1474 calcd for
C
17H23NO7). Anal. Calcd for C17H23NO7: C, 57.78; H, 6.56;
N, 3.96. Found: C, 57.42; H, 6.65; N, 3.87.
Dim eth yl (2S,6R)-2-[N-(Ben zyloxyca r bon yl)a m in o]-6-
[N-(ter t-bu toxyca r bon yl)-N-[[2-(tr im eth ylsilyl)eth yl]su l-
fon yl]a m in o]h ep ta n e-1,7-d ioa te (35). To a solution of Ph3P
(115 mg, 0.442 mmol), carbamate 3419 (116 mg, 0.414 mmol),
and 33 (96 mg, 0.27 mmol) in 20 mL of THF at 0 °C was added
dropwise diethyl azodicarboxylate (65 µL, 0.414 mmol) over a
5 min period. The solution was stirred for 5 h at room
temperature, concentrated in vacuo, and purified by flash
chromatography (25% EtOAc in hexane) to give 35 as an oil
(132 mg, 79%): Rf 0.32 (30% EtOAc in hexane); IR (CHCl3 cast)
1793, 1745, 1674, 1527 cm-1 1H NMR (400 MHz, CDCl3) δ
;
6.87 (br d, J ) 8.2 Hz, 2H, 2 NH), 4.63-4.57 (m, 2H, 2 CHNH),
3.75 (s, 6H, OCH3), 2.53-2.42 (m, 2H, 2 CHaHCR2CON), 1.99-
1.82 (m, 6H, 2 CHaHCR2CON, 2 CHaHCR2CO2, 2 CHaHCHN),
1.78-1.47 (m, 4H, 2 CHHbCR2CO2, 2 CHHbCHN), 1.46-1.32
(m, 2H, CH2), 1.12 (s, 6H, 2 CH3), 1.11 (s, 6H, 2 CH3), 0.92 (s,
6H, 2 CH3); 13C NMR (75.5 MHz, CDCl3) δ 177.9 (CO2R), 171.6
(CO2R), 167.1 (CONH), 92.2 (NCO), 77.2 (CHNH), 55.3 (OCH3),
53.9 (CR4), 52.6 (CR4), 51.6 (CH3), 32.0 (CH2), 31.8 (CH2), 30.4
(CH2), 29.1 (CH2), 21.5 (CH2), 16.7 (CH3), 16.6 (CH3), 9.7 (CH2);
exact mass 578.2824 (578.2839 calcd for C29H42N2O10).
1
3376, 1729, 1520 cm-1; H NMR (CDCl3, 400 MHz) δ 0.06 (s,
9 H), 1.02-2.22 (m, 17 H), 1.47 (s, 9 H), 3.40-3.60 (m, 2 H),
3.71 (s, 6 H), 4.30-4.40 (m, 1 H), 4.68-4.75 (m, 1 H), 5.09 (s,
2 H), 5.30-5.37 (m, 1 H), 7.26-7.38 (m, 5 H); CI MS m/z (NH3)
634 (19, [M + 18]+), 617 (1, [M + 1]+). Anal. Calcd for
C
27H44N2O10SSi: C, 52.58; H, 7.19, N, 4.54. Found: C, 52.36;
Employing the same procedure, 31a was prepared from
meso-DAP (1a ): IR (CHCl3 cast) 3360, 2966, 1792, 1746, 1674,
H, 7.02; N, 4.68.
(3R,6S)-3-Isop r op yl-2,5-d im eth oxy-6-[2-(p h en ylth io)-2-
p r op en yl]-3,6-d ih yd r op yr a zin e (38). The alkylating agent
3-chloro-2-thiophenylpropene (37) was prepared by a modifica-
tion of the literature method23 and was used without purifica-
tion. Thus, allene (0.61 g, 15.2 mmol) was bubbled into a
solution of dry THF (25 mL) at -30 °C at a constant flow rate.
Sulfenyl chloride (1.871 g, 12.9 mmol) in THF (5 mL) was then
added dropwise (10 min). The resulting solution was stirred
at -30 to -20 °C for about 30 min to give a solution of 37 in
THF. A cooled solution (-78 °C) of (R)-Scho¨llkopf bis-lactim
ether 36 (2.32 mL, 12.9 mmol) in THF (20 mL) under Ar was
treated with a 2.5 M solution of n-BuLi in hexane (5.2 mL,
12.9 mmol). After being stirred for an additional 10 min at
-78 °C, the THF solution of 37 was added via cannula over
15 min and the resulting orange-black solution was stirred at
-60 °C for 4 h. After another 12 h, while the temperature
was gradually raised to room temperature, the solvent was
removed in vacuo and the black residue was partitioned
between Et2O (20 mL) and water (20 mL). The aqueous layer
was extracted with Et2O (3 × 20 mL), and the combined
organic extracts were dried and evaporated. The dark oily
residue was purified by flash chromatography (5% EtOAc in
hexane) to give 38 as an unstable oil (3.86 g, 90%): Rf 0.22
(10% EtOAc in hexane); IR (CHCl3 cast) 1779, 1721, 1635, 1578
cm-1; 1H NMR (CD2Cl2, 300 MHz) δ 0.68 (d, 3 H, J ) 6.9 Hz),
1.07 (d, 3 H, J ) 6.9 Hz), 2.20-2.32 (m, 1 H), 2.52-2.81 (m, 2
H), 3.18 (s, 3 H), 3.21 (s, 3 H), 3.92-3.95 (t, 1 H, J ) 3.5 Hz),
4.19-4.29 (m, 1 H), 4.92 (s, 1 H), 5.20 (s, 1 H), 7.20-7.47 (m,
5 H); 13C NMR (CD2Cl2, 75.5 MHz) δ 16.66, 19.36, 31.99, 41.37,
61.17, 61.27, 116.46, 128.07, 129.55, 132.89, 133.22, 134.17,
1
1528 cm-1 ; H NMR (360 MHz, CDCl3) δ 6.92 (br d, J ) 8.3
Hz, 1H, NH), 6.80 (br d, J ) 8.0 Hz, 1H, NH), 4.65-4.51 (m,
2H, 2 CHNH), 3.77 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 2.58-
2.40 (m, 2H, 2 CHaHCR2CON), 2.05-1.82 (m, 6H, 2 CHaHCR2-
CON, 2 CHaHCR2CO2, 2 CHaHCHN), 1.80-1.62 (m, 4H, 2
CHHbCR2CO2, 2 CHHbCHN), 1.45-1.30 (m, 2H, CH2), 1.08 (m,
9H, 3 CH3), 1.03 (s, 3H, CH3) 0.93 (s, 3H, 2CH3), 0.90 (s, 3H,
2CH3); 13C NMR (75.5 MHz, CDCl3) δ 178.0 (CO2R), 177.8
(CO2R), 171.62 (CO2R), 171.55 (CO2R), 167.0 (CONH), 92.21
(NCO), 92.15 (NCO), 55.3 (CHNH), 55.2 (OCH3), 54.1 (CR4),
53.9 (CR4), 52.5 (CR4), 52.4 (CR4), 51.53 (CH3), 51.47 (CH3),
51.4 (CH3), 51.3 (CH3), 31.9 (CH2), 31.8 (CH2), 31.4 (CH2), 30.3
(CH2), 29.0 (CH2), 21.5 (CH2), 16.6 (CH3), 16.5 (CH3), 16.4
(CH3), 9.6 (CH2); exact mass 578.2832 (578.2839 calcd for
C
29H42N2O10). Anal. Calcd for C29H42N2O10: C, 60.19; H, 7.32;
N, 4.84. Found: C, 60.03; H, 7.59; N, 4.56.
Employing the same procedure, 31c was prepared from DD-
DAP (1c): [R]D -13.5° (c ) 0.11, CHCl3); IR (CHCl3 cast) 3365,
2965, 1790, 1745, 1672, 1528 cm-1; 1H NMR (300 MHz, CDCl3)
δ 6.80 (br d, J ) 8.3 Hz, 2H, 2 NH), 4.63-4.57 (m, 2H, 2
CHNH), 3.75 (s, 6H, OCH3), 2.64-2.50 (m, 2H, 2 CHaHCR2-
CON), 2.02-1.85 (m, 6H, 2 CHaHCR2CON, 2 CHaHCR2CO2,
2 CHaHCHN), 1.85-1.62 (m, 4H, 2 CHHbCR2CO2, 2 CHHb-
CHN), 1.50-1.38 (m, 2H, CH2), 1.12 (s, 6H, 2 CH3), 1.08 (s,
6H, 2 CH3), 0.96 (s, 6H, 2 CH3); 13C NMR (75.5 MHz, CDCl3)
δ 178.1 (CO2R), 171.8 (CO2R), 167.2 (CONH), 92.3 (NCO), 55.4
(OCH3, CHNH)), 54.2 (CR4), 52.5 (CR4), 51.4 (CH3), 31.5 (CH2),
30.4 (CH2), 29.1 (CH2), 21.7 (CH2), 16.7 (CH3), 16.6 (CH3), 9.7
(CH2); exact mass 578.2836 (578.2839 calcd for C29H42N2O10).

2142 J . Org. Chem., Vol. 63, No. 7, 1998
Gao et al.
142.11, 163.08, 164.13; CI MS m/z (NH3) 333 (100, [M + 1]+).
Anal. Calcd for C18H24N2O2S: C, 65.03; H, 7.28; N, 8.43; S,
9.64. Found: C, 65.04; H, 7.24; N, 8.41; S, 9.97.
Dim eth yl (2S,6S)-6-[N-(Ben zyloxyca r bon yl)a m in o]-2-
h yd r oxyh ep ta n e-1,7-d ioa te (33) fr om 42. Compound 42
(150 mg, 0.327 mmol) and NiCl2‚6H2O (0.53 g, 2.28 mmol) were
dissolved in 9 mL of methanol and 3 mL of THF in a flask
cooled in an ice bath with stirring. NaBH4 (254 mg, 6.8 mmol)
was added in portions over 15 min. The immediate formation
of a black precipitate was observed, and the mixture was
stirred for an additional 15 min. The precipitate was filtered
through a bed of Celite, and the filtrate was evaporated to
dryness in vacuo. Purification of the residue by flash chro-
matography (20% EtOAc in hexane) gave 33 as an oil (97 mg,
85%) with spectral and chromatographic properties in agree-
ment with those for 33 prepared above from 32. Conversion
to DAP and NMR analysis of the corresponding Mosher amides
(see Scheme 6 and below) showed an isomeric ratio 6S:6R of
94:6: [R]D +37.23 (c ) 0.5, CHCl3).
Meth yl (2S)-4-(P h en ylth io)a llylglycin a te (39). A solu-
tion of 38 (3.0 g, 9.3 mmol) in 0.4 N CF3CO2H (70 mL, 28
mmol) and THF (10 mL) was stirred at room temperature for
4 h. The THF was removed in vacuo, and the aqueous residue
was washed with EtOAc (15 mL) before it was concentrated
to a volume of 15-20 mL. The pH was adjusted to 8-9 by
adding saturated aqueous Na2CO3 solution. The mixture was
extracted with EtOAc (3 × 25 mL), and the combined organic
extracts were washed with brine (15 mL). The organic solution
was dried and evaporated in vacuo. The resulting oil was bulb-
to-bulb distilled, and (R)-valine methyl ester was the forerun
separated from the residue that yielded relatively unstable 39
(1.73 g, 79%): Rf 0.19 (EtOAc); [R]D +21.31° (c ) 1.60, CHCl3);
1
IR (CHCl3 cast) 3379, 3316, 1739, 1607 cm-1; H NMR (CD2-
Dim eth yl (6R,2S)-2-[N-(Ben zyloxyca r bon yl)a m in o]-6-
[N-(ter t-bu toxyca r bon yl)a m in o]h ep ta n e-1,7-d ioa te (43).
To a solution of 35 (110 mg, 0.176 mmol) in 10 mL of THF
was added a 1 M solution of n-Bu4NF (TBAF) in THF (537
µL, 0.54 mmol). The resulting solution was stirred for 15 min
and then diluted with 45 mL of Et2O. The organic layer was
washed with water (4 × 20 mL) followed by 15 mL of saturated
aqueous NaHCO3, dried, and concentrated in vacuo. The
residue was purified by flash chromatography (50% EtOAc in
hexane) to give 43 (78 mg, quantitative) as an oil: Rf 0.55 (50%
EtOAc in hexane); [R]D +5.45 (c ) 0.5, CHCl3); IR (CHCl3 cast)
Cl2, 300 MHz) 2.40-2.70 (m, 2 H), 3.65 (s, 3 H), 3.72-3.80
(m, 1 H), 5.02 (s, 1 H), 5.26 (s, 1 H), 7.30-7.49 (m, 5 H); 13C
NMR (CD2Cl2, 75.5 MHz) δ 42.45, 52.21, 54.58, 110.79, 128.46,
129.69, 133.12, 133.51, 142.05, 175.53; exact mass 237.0823
(11, M+) (237.0823 calcd for C12H15NO2S).
To determine the enantiomeric excess, a stirred solution of
39 (11.1 mg, 0.047 mmol) and (1S)-camphanic acid chloride
(15.5 mg, 0.071 mmol) in CH2Cl2 (10 mL) was treated with
Et3N (10 µL, 0.071 mmol). After 1 h, the solution was washed
with 1 M HCl (10 mL), dried, and evaporated in vacuo to give
a residue. 1H NMR (CDCl3, 360 MHz) analysis showed an ee
g98%.
3348, 1741, 1716, 1521 cm-1 1H NMR (CDCl3, 400 MHz) δ
;
0.70-2.15 (m, 15 H), 1.41 (s, 9 H), 3.70 (s, 3 H), 3.72 (s, 3 H),
4.22-4.42 (m, 2 H), 5.09 (s, 2 H), 5.35 (m, 1 H), 7.27-7.38 (m,
5 H); 13C NMR (CDCl3, 75.5 MHz) δ 21.17, 28.28, 31.90, 32.31,
52.27, 53.55, 67.06, 67.51, 79.99, 127.75, 128.16, 128.51,
136.21, 155.10, 172.79, 173.03; CI MS m/z (NH3) 470 (51, [M
+ 18]+), 453 (17, [M + 1]+). Anal. Calcd for C22H32N2O8: C,
58.40; H, 7.13; N, 6.19. Found C, 58.00; H, 7.15; N, 6.13.
(2S,6R)-2-[N-(Ben zyloxyca r bon yl)a m in o]-6-[N-(ter t-bu -
toxyca r bon yl)a m in o]-h ep ta n e-1,7-d ioic Acid (44). A mix-
ture of 43 (70 mg, 0.153 mmol) and 10% aqueous NaOH (340
µL, 0.82 mmol) was stirred vigorously for 4 h and then diluted
with water (2 mL) and CH3CN (3 mL). After an additional 14
h of stirring, the mixture was diluted with water (4 mL),
washed with EtOAc (4 mL), acidified to pH 1 with 2 M HCl,
and extracted with EtOAc (3 × 20 mL). The combined extracts
were dried and evaporated in vacuo to give 44 (60 mg, 94%):
IR (CHCl3 cast) 3348, 1747, 1716, 1528 cm-1; 1H NMR (CDCl3,
360 MHz) δ 1.15-1.57 (m, 11 H), 1.41 (s, 9 H), 1.62-1.87 (m,
4 H), 4.21-4.44 (m, 4 H), 5.11 (s, 2 H), 7.28-7.40 (m, 5 H);
13C NMR (CDCl3, 75.5 MHz) δ 21.17, 28.29, 31.90, 32.31, 52.85,
53.55, 57.06, 79.99, 127.76, 128.17, 128.51, 136.22, 153.50,
153.92, 172.79, 173.04; CI MS m/z (NH3) 442 (92, [M + 18]+),
425 (30, [M + 1]+).
m eso-Dia m in op im elic Acid (1a ) fr om 44. To a solution
of 44 (14 mg, 0.033 mmol) in methanol (15 mL) and glacial
AcOH (1 mL) was added 10% Pd/C (10 mg). The suspension
was stirred under 1 atm of H2 for 14 h and then filtered
through cotton wool. The filtrate was evaporated in vacuo to
give a powder, to which was added a mixture of CF3CO2H (15
mL) and CH2Cl2 (15 mL). The resulting solution was stirred
at room temperature for 15 min and then evaporated in vacuo.
The residue was purified by ion-exchange chromatography
(AG50W × 8, H+ form, 5 mL), eluting with H2O and 2% to
10% aqueous NH4OH to give pure 1a (3.9 mg, 64%) with
chromatographic and spectral properties in agreement with
those of a reference sample of meso-DAP obtained by classical
resolution-separation procedures.17
Meth yl (2S)-N-(Ben zyloxyca r bon yl)-4-(p h en ylth io)a l-
lylglycin a te (40). To a solution of 39 (1.72 g, 7.3 mmol) and
benzyl chloroformate (Cbz-Cl) (1.25 mL, 8.76 mmol) in CH2-
Cl2 (40 mL) was added freshly distilled pyridine (0.71 mL, 8.76
mmol) over 5 min, and the mixture was stirred at room
temperature for 4 h. The mixture was then washed with 1 M
HCl (10 mL) and brine (10 mL). The organic layer was dried
and evaporated in vacuo to afford an oil that was purified by
flash chromatography (30% EtOAc in hexane) to obtain 40 as
an oil (2.69 g, 98%): Rf 0.48 (30% EtOAc in hexane); [R]D
+16.22° (c 1.0 CHCl3); IR (CHCl3 cast) 3345, 1721, 1583 cm-1
;
1H NMR (CDCl3, 360 MHz) δ 2.58-2.81 (m, 2 H), 3.72 (s, 3
H), 4.62 (m, 1 H), 4.95 (s, 1 H), 5.08-5.17 (m, 3 H), 5.48 (d, 1
H, J ) 7.8 Hz), 7.25-7.45 (m, 10 H); 13C NMR (CDCl3, 75.5
MHz) δ 52.32, 52.96, 66.95, 38.69, 116.80, 128.03, 128.11,
128.18, 128.47, 129.26, 132.22, 133.24, 136.27, 140.33, 155.61,
171.75; CI MS m/z (NH3) 372 (80, [M + 1]+). Anal. Calcd for
C
20H21NO4S: C, 64.67; H, 5.70; N, 3.77; S, 8.63. Found: C,
64.60; H, 5.49; N, 3.67; S, 8.90.
Dim eth yl (2S,6S)-6-[N-(Ben zyloxyca r bon yl)a m in o]-2-
h yd r oxy-4-(p h en ylth io)-4-h ep ten e-1,7-d ioa te (42). To a
dry flask under Ar containing copper trifluoromethane-
sulfonate (60 mg, 0.084 mmol) and (R)-2,2′-isopropylidenebis-
(4-phenyl-2-oxazoline) (41) (61 mg, 0.084 mmol) was added dry
CH2Cl2 (3 mL) under Ar, and the mixture was stirred for 2 h.
The resulting green homogeneous solution was then treated
with methyl gloxylate28 (70 mg, 0.8 mmol) and 40 (315 mg,
0.84 mmol) in CH2Cl2 (1 mL) at room temperature. After 12
h, the solution was diluted by adding CH2Cl2 (20 mL), washed
with brine (20 mL), dried, and evaporated in vacuo to give a
yellow oil that was purified by flash chromatography (20%
EtOAc in hexane) to give 42 as an oil (154 mg, 42%): Rf 0.22
(40% EtOAc in hexane); [R]D ) +82.91 (c 2.0 CHCl3); IR (CHCl3
cast) 3366, 1790, 1743, 1514 cm-1; 1H NMR (CDCl3, 360 MHz)
δ 2.80-2.88 (m, 2 H), 3.78 (s, 6 H), 4.09 (d, 1 H, J ) 6.8 Hz),
4.59 (m, 1 H), 5.11 (s, 2 H), 5.21 (dd, 1 H, J ) 9.0, 6.2 Hz),
5.42 (d, 1 H, J ) 9.0 Hz), 5.76 (d, 1 H, J ) 6.2 Hz), 7.20-7.51
(m, 10 H); 13C NMR (CDCl3, 75.5 MHz) δ 36.63, 52.40, 52.94,
53.10, 67.31, 69.22, 127.55, 128.07, 128.20, 128.30, 128.58,
129.37, 132.54, 135.98, 138.64, 155.62, 170.42, 173.89; FAB
MS m/z (Cleland) 481 (26, [M + Na]+), 460 (1, [M + H]+). Anal.
Calcd for C23H25NO7S: C, 60.12; H, 5.48; N, 3.05. Found: C,
59.60; H, 5.23; N, 2.98.
An a lysis of Dia ster eom er ic Excess of DAP Isom er s 1a ,
1b, a n d 1c. In a typical procedure, to a saturated aqueous
NaHCO3 (2 mL) solution of 1a (2.8 mg, 0.015 mmol) was added
(R)-(-)-R-methoxy-R-(trifluoromethyl)phenylacetyl chloride (11
mg, 0.033 mmol). After being stirred at room temperature for
1 h, the aqueous solution was washed with EtOAc (1 mL),
acidified to pH 2 by adding 2 M HCl, and extracted with EtOAc
(5 × 10 mL). The extracts were dried and evaporated in vacuo
to give a residue that was purified by HPLC (the Mosher
amides of different DAP isomers do not separate under these
(28) (a) Hook, J . M. Synth. Commun. 1984, 14, 83-87. (b) Kelly, T.
R.; Schmidt, T. E.; Haggerty, J . G. Synthesis 1972, 544.

Synthesis of meso-Diaminopimelic Acid
J . Org. Chem., Vol. 63, No. 7, 1998 2143
conditions): (BioRad Model 400 system; solid phase-C18
Resolve 10 µm, two 8 mm × 10 cm columns in tandem; solvent
A: 0.1% CF3CO2H in H2O; solvent B: CH3CN; method:
gradient 5%-70% in 35 min, at 1 mL/min, detection at 254 nM;
retention time: 27.71 min). 1H NMR (CDCl3, 500 MHz)
analysis of the methoxy region allowed discrimination between
all DAP isomers and provided the isomeric ratios of DAP
synthesized by the various procedures.
ences and Engineering Research Council of Canada. We
thank Drs. Mark D. Andrews, J oanna M. Harris, and
Lister Lam for helpful discussions and assistance.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of compounds 1a , 7, 12, 14, 27-29, 39, and 44 (13
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.
Ack n ow led gm en t. The authors are grateful to
Professor Robert M. Williams for sharing the results of
his studies11 prior to publication. This work was sup-
ported by Merck Frosst Canada and the Natural Sci-
J O972133H