An Approach to 2,3-Methanoamino Acids with Extended Side Chains: Syntheses of trans-BOC-cyclo-Lys(CBZ)-OH, trans-BOC-cyclo-Glu(OEt), and trans-BOC-cyclo-Arg(CBZ)-OH

Full text of DOI:10.1021/jo9717447

9382
J . Org. Chem. 1997, 62, 9382-9384
Sch em e 1. Syn th esis of
tr a n s-BOC-cyclo-Lys(CBZ)-OH
An Ap p r oa ch to 2,3-Meth a n oa m in o Acid s
w ith Exten d ed Sid e Ch a in s: Syn th eses of
tr a n s-BOC-cyclo-Lys(CBZ)-OH,
tr a n s-BOC-cyclo-Glu -OEt, a n d
tr a n s-BOC-cyclo-Ar g(CBZ)-OH
Dongyeol Lim and Kevin Burgess*
Department of Chemistry, Texas A & M University,
College Station, Texas 77843
Received September 16, 1997
Lactone 1, available as either antipode from D-mannitol
or L-gulono-1,4-lactone,1,2 is a valuable starting material
for syntheses of methanoamino acids3 with 3-substituents
that are functionalized methylene groups (CH2X, X )
heteroatom).4 For instance, it has been used to prepare
the 2,3-methanoamino acids 25 and 36 efficiently. Chiron
1 also has been used in syntheses of 2,3-methanoamino
acids with functionalized ethylene substituents (CH2-
CH2X, X ) heteroatom).7 These reaction sequences
involved SN2-displacements with cyanide as a nucleophile
to obtain intermediates such as 4. Unfortunately, these
displacements add steps to the route, and they are not
particularly efficient reactions since the leaving group
is proximal to the cyclopropane ring. Moreover, hydroly-
sis of the nitrile functionality in 4 was not straightfor-
ward, and attempts to circumvent this by using nucleo-
philes other than cyanide were unsuccessful.
thionyl chloride to give a cyclic sulfite,9 oxidized via
Sharpless conditions,10 and then reacted with diethyl
malonate to give chiron 5.11 None of the intermediates
in these three steps was purified. Selective hydrolysis
of the less hindered ester, Curtius rearrangement, and
hydrogenolysis gave the BOC-protected amino alcohol 7.
Mesylation of 7 and displacement with cyanide gave the
nitrile 8 in good yield. Hydrolysis of the ester functional-
ity in 8, catalytic reduction of the nitrile group, and
protection with a carboxybenzyl group gave the first
product in this series in a protected form suitable for
solid-phase syntheses, i.e., trans-BOC-cyclo-Lys(CBZ)-
OH. As far as we are aware, this is the first reported
synthesis of any optically pure 2,3-methanolysine deriva-
tive, although other interesting constrained Lys ana-
logues have been reported.12
Intermediates in the synthesis of BOC-cyclo-Lys(CBZ)-
OH were then used to prepare other 2,3-methanoamino
acid derivatives. A Sharpless oxidation of 7 at the
hydroxyethyl functionality converted it to BOC-cyclo-Glu-
OEt; overall, this route is much more efficient than the
one we originally developed for this same product.7
Similarly, a Mitsunobu reaction of alcohol 7 with a
guanidine nucleophile13 gave trans-BOC-cyclo-Arg(CBZ)-
OH after hydrolysis (Scheme 2). The yield of this product
was diminished due to cleavage of one of the guanidine-
This paper reports a synthesis of the cyclopropane
chiron 5 from L-malic acid and reaction sequences that
demonstrate that this chiron is well-suited to syntheses
of the hitherto less accessible cyclopropyl analogues of
amino acids. Specifically, this starting material is useful
for the preparation of 2,3-methanoamino acids with
extended side chains. Three products made to prove this
assertion were trans-BOC-cyclo-Lys(CBZ)-OH, trans-
BOC-cyclo-Glu-OEt, and trans-BOC-cyclo-Arg(CBZ)-OH.
The optically pure diol 6 was conveniently obtained on
a 50 g scale via published procedures that do not involve
chromatography (Scheme 1).8 Diol 6 was reacted with
(1) Burgess, K.; Ho, K.-K.; Ke, C.-Y. J . Org. Chem. 1993, 58,
3767-8.
(2) Burgess, K.; Ke, C.-Y. Synthesis 1996, 1463-7.
(3) Stammer, C. H. Tetrahedron 1990, 46, 2231-54.
(4) Burgess, K.; Ho, K.-K.; Moye-Sherman, D. Synlett 1994, 8,
575-83.
(9) Lohray, B. B. Synthesis 1992, 1035-52.
(10) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-8.
(5) Burgess, K.; Ho, K.-K. J . Org. Chem. 1992, 57, 5931-6.
(6) Burgess, K.; Lim, D.; Ho, K.-K.; Ke, C.-Y. J . Org. Chem. 1994,
59, 2179-85.
(11) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110,
7538-9.
(12) Murray, P. J .; Starkey, I. D. Tetrahedron Lett. 1996, 11,
1875-8.
(13) Dodd, D. S.; Kozikowski, A. P. Tetrahedron Lett. 1994, 35,
977-80.
(7) Burgess, K.; Lim, D. Y. Tetrahedron Lett. 1995, 36, 7815-8.
(8) Mori, K.; Takagawa, T.; Matsuo, T. Tetrahedron 1979, 35,
933-40.
S0022-3263(97)01744-1 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 26, 1997 9383
was allowed to warm to 25 °C and stirred for 16 h. The reaction
mixture was concentrated and extracted with ether (200 mL ×
3). The aqueous layer was acidified with concd HCl and
extracted with ether (300 mL × 2), and then the organic layer
was washed with water and brine and dried over MgSO4. After
evaporation of the solvent, 10.2 g of the crude product was
obtained and used for the next step without purification (63%
yield). A small sample was purified via column chromatography
for further characterization: Rf 0.56 (60% EtOAc/hexane with
trace AcOH); 1H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.50
(s, 2H), 4.23 (q, J ) 7.2 Hz, 2H), 4.6-4.45 (m, 2H), 2.25-2.15
(m, 1H), 1.97-1.85 (br, 2H), 1.75-1.67 (br, 1H), 1.29 (t, J ) 7.2
Hz, 3H); 13C NMR (75.4 MHz, CDCl3) δ 172.6, 137.9, 128.7,
128.4, 127.7, 126.8, 73.1, 69.0, 62.5, 34.2, 28.4, 23.8, 14.0; IR
Sch em e 2. Syn th esis of tr a n s-BOC-cyclo-Glu -OEt
a n d tr a n s-BOC-cyclo-Ar g(CBZ)-OH
(neat) 2982, 1735, 1453, 1375, 1320, 1206, 1147 cm-1; [R]25
D
+2.6° (c ) 1.7, CH2Cl2); +FAB/DP m/z calcd for C16H20O5; 292
found 315 for [M + Na]+.
The crude monocarboxylic acid derivative prepared above
(10.0 g, 37.9 mmol) and NEt3 (8.12 mL, 37.7 mmol) were mixed
with dry t-BuOH (100 mL) at 25 °C under N2. Diphenyl
phosphorazidate (4.16 g, 42.0 mmol) was added, and the reaction
mixture was refluxed with stirring for 12 h. The reaction
solution was concentrated, and the crude product was extracted
with ether. After being washed with 1 N HCl and saturated
NaHCO3(aq) and dried, 11.2 g of the crude product was obtained
(81% yield). A relatively pure sample was obtained via column
chromatography (33% Et2O/n-C6H14) for characterization pur-
CBZ protecting groups in competition with ester hydroly-
sis. This is, however, a relatively minor problem that
will be solved when these syntheses are optimized.
Exp er im en ta l Section
1
poses: Rf 0.53 (50% ether/hexane); H NMR (300 MHz, CDCl3)
δ 7.31 (s, 5H), 4.47 (s, 2H), 4.2-4.0 (m, 2H), 3.55-3.4 (m, 2H),
1.95-1.8 (m, 2H), 1.65-1.5 (m, 2H), 1.43 (s, 4H), 1.21 (t, 3H);
13C NMR (75.4 MHz, CDCl3) δ 170.4, 155.8, 138.4, 128.2, 127.5,
79.6, 72.7, 69.1, 61.0, 28.7, 27.1, 22.5, 14.1; [R]25D +0.8° (c ) 1.55,
CH2Cl2); +FAB/DP m/z calcd for C20H29NO5 363, found 386 for
[M + Na]+.
A mixture of the BOC-protected ester formed as described
above (11.2 g, 30.8 mmol) and 10% Pd/C (1.0 g) in MeOH (100
mL) was stirred for 12 h at 25 °C under a hydrogen balloon.
The reaction solution was filtered through a silica gel pad and
washed with MeOH (ca. 200 mL). The filtrate was evaporated
to give 8.05 g of the crude product 7 (96% yield). A pure sample
Gen er a l P r oced u r es. Melting points were uncorrected.
Proton NMR spectra were recorded at 200 or 300 MHz and 13C
spectra at 50 or 75.4 (δ ppm). Where necessary, the carbon
multiplicities were determined via APT experiments. Thin-layer
chromatography was performed on silica gel 60 F254 plates.
Flash chromatography was performed on silica gel (230-600
mesh). DMF was stored over 4 Å molecular sieves for 1 week
before use, and CH2Cl2 and t-BuOH were distilled from ap-
propriate drying agents. Other chemicals were purchased from
commercial suppliers and used as received.
(S)-Dieth yl 2-[(Ben zyloxy)eth yl]cyclop r op a n e-1,1-d ica r -
boxyla te (5). Thionyl chloride (10.9 mL, 150 mmol) was added
to the solution of the benzyl protected diol 6 (24.5 g, 125 mmol)
in CCl4 (100 mL), and the mixture was heated to reflux for 1 h.
The reaction mixture was cooled to 0 °C and diluted with 100
mL of CH3CN. Sodium periodate (40.1 g, 188 mmol) and RuCl3‚
3H2O (ca. 20 mg) were added to the above solution, followed by
H2O (150 mL). The resulting orange mixture was stirred
vigorously for 2 h at 25 °C and then extracted with ether (300
mL). The organic layer was washed with water, saturated
NaHCO3 solution, and brine and then dried over Na2SO4. After
filtration through a pad of silica gel, the organic layer was
concentrated to yield 26.3 g of the crude cyclic sulfate. This
cyclic sulfate was slowly added to a solution of sodium diethyl
malonate prepared by addition of sodium hydride (5.18 g, 95%,
214 mmol) to the solution of diethyl malonate (15.5 mL, 102
mmol) in 500 mL of dimethoxyethane. The reaction mixture was
heated to reflux for 20 h and then cooled to 25 °C. After
evaporation of the organic solvent, the residue was extracted
with EtOAc (200 mL × 2), and the extract was washed with
saturated NaHCO3 solution, H2O, and brine and then dried over
Na2SO4. After evaporation of the solvent, 26 g of the crude
product 5 was obtained as an oil and used in the next step
without further purification. A relatively pure sample of 5 was
obtained via column chromatography (50% Et2O/n-C6H14) for
characterization purposes: Rf 0.57 (67% ether/hexane); 1H NMR
(300 MHz, CDCl3) δ 7.40-7.15 (m, 5H), 4.50 (s, 2H), 4.25-4.05
(m, 4H), 3.54 (t, J ) 6.6 Hz, 2H), 2.10-1.95 (m, 1H), 1.85-1.70
(m, 1H), 1.6-1.45 (m, 1H), 1.42-1.35 (m, 2H), 1.30-1.20 (m,
6H); 13C NMR (75.4 MHz, CDCl3) δ 170.1, 168.0, 138.3, 128.7,
128.2, 127.4, 72.8, 69.0, 61.23, 61.18, 29.0, 25.1, 20.5, 14.0, 13.9;
IR (CDCl3) 2982, 2938, 2863, 1728, 1369, 1320 cm-1; [R]25D -0.6°
(c ) 1.45, CH2Cl2); HRMS (FAB/DP) m/z calcd for C18H24O5
343.1522, found 343.1519 for [M + Na]+.
was obtained via column chromatography (50% Et2O/n-C6H14
)
for characterization purposes: Rf 0.46 (67% ether/hexane); 1H
NMR (200 MHz, CDCl3) δ 5.42 (bs, 1H), 4.2-3.97 (m, 2H), 3.74-
3.45 (m, 2H), 1.98-1.8 (m, 1H), 1.80-1.45 (m, 2H), 1.38 (s, 9H),
1.4-1.28 (m, 1H), 1.18 (t, J ) 7.1 Hz, 1H), 1.2-1.06 (m, 1H);
13C NMR (50 MHz, CDCl3) δ 171.5, 157.3, 80.3, 61.6, 61.3, 37.6,
30.3, 29.4, 28.2, 21.3, 14.1; IR (CDCl3) 3360, 2980, 1698, 1506,
1393, 1369, 1280, 1185 cm-1; [R]25 +3.4° (c ) 1.5, CH2Cl2);
D
HRMS (+FAB/DP) m/z calcd for C13H23NO5 296.1474, found
296.1493 for [M + Na]+.
(1R,2R)-Eth yl 1-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-(cya -
n oeth yl)cyclop r op a n e-1-ca r boxyla te (8). A solution of the
hydroxyethyl derivative 7 (1.6 g, 5.86 mmol) in CH2Cl2 (20 mL)
was cooled to 0 °C, NEt3 (0.548 mL, 7.03 mmol, 1.2 equiv) and
then methanesulfonyl chloride (0.978 mL, 7.03 mmol) were
added, and the solution was stirred for 5 h at 25 °C under N2.
The reaction solution was concentrated, and the residue was
extracted with ether. After being washed with water and brine,
the organic layer was concentrated to yield the crude mesylate.
The crude mesylate formed above was treated with KCN (954
mg, 14.7 mmol) and 18-crown-6 (310 mg, 1.17 mmol) in DMF
(20 mL) and then stirred for 4 h at 70 °C and for 12 h at 40 °C.
The reaction solution was concentrated and extracted with ether
(100 mL). The organic layer was washed with water, saturated
NaHCO3, and brine and then concentrated to give a 1.66 g of
the crude nitrile. The crude material (1.31 g) was partially
purified via silica gel column chromatography (Et2O/Hex, 1:1)
to yield 1.05 g of the product 8 as an oil (80% yield). A pure
sample was obtained via column chromatography (50% Et2O/n-
C6H14) for characterization purposes: Rf 0.32 (50% ether/
hexane); 1H NMR (200 MHz, CDCl3) δ 5.13 (br, 1H), 4.25-4.13
(m, 2H), 2.5-2.37 (brt, J ) 6.8 Hz, 2H), 2.1-1.9 (brq, J ) 7 Hz,
2H), 1.67-1.56 (m, 1H), 1.54-1.46 (m, 1H), 1.44 (s, 9H), 1.4-
1.32 (m, 1H), 1.26 (t, J ) 7.1 Hz, 3H); 13C NMR (50 MHz, CDCl3)
δ 171.4, 155.8, 119.4, 80.1, 61.6, 38.2, 30.4, 28.3, 23.0, 22.9, 16.9,
14.2; IR (neat) 3362, 2979, 2247, 1718, 1701, 1507, 1369, 1251,
(1R,2S)-Eth yl 1-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-(h y-
d r oxyeth yl)cyclop r op a n e-1-ca r boxyla te (7). The crude di-
ethyl dicarboxylate derivative 6 (18.0 g, 61.6 mmol) was dis-
solved in 67.8 mL of EtOH. An aqueous KOH solution (1 M,
67.8 mL, 1.1 equiv) was added at 0 °C, and then the solution

9384 J . Org. Chem., Vol. 62, No. 26, 1997
Notes
1184 cm-1; [R]25 -0.1° (c ) 1.35, CH2Cl2); HRMS (+FAB/DP)
for 2.5 h at 25 °C and then extracted with EtOAc (10 mL × 2).
The combined organic layers were passed through a pad of silica
gel and concentrated to yield 100 mg of trans-BOC-cyclo-Glu-
OEt (95% yield): Rf 0.45 (60% EtOAc/hexane with trace AcOH);
mp 115-115.5 °C; 1H NMR (200 MHz, CDCl3) δ 6.26 (br s, 1H),
5.46 (br s, 1H), 4.14 (q, J ) 7.2 Hz, 2H), 2.92-2.55 (br m, 2H),
1.81-1.63 (m, 1H), 1.58-1.25 (overlapping, 2H), 1.43 (s, 9H),
1.23 (t, J ) 7.2 Hz, 3H); 13C NMR (50 MHz, CDCl3) δ 176.6,
171.7, 157.2, 81.2, 62.1, 38.7, 32.9, 28.7, 26.4, 23.2, 14.6; IR
(CHBr3) 1707, 1490, 1392, 1369, 1324, 1247 cm-1; +FAB/DP m/z
calcd for C13H21NO6 287, found 288 for [M + H]+; [R]20D +6.0° (c
) 1.14, CH2Cl2). Anal. Calcd for C13H21N1O6: C, 54.34; H, 7.37;
N, 4.88 Found: C, 53.84; H, 7.24; N, 4.83.
(1R,2R)-2-[[(Ben zyloxyca r bon yl)gu a n id in yl]eth yl]-1-[N-
(ter t-b u t oxyca r b on yl)a m in o]cyclop r op a n e-1-ca r b oxylic
Acid . Triphenylphosphine (1.24 g, 4.71 mmol, 1.25 equiv) and
bis(benzyloxycarbonyl)guanidine (1.70 g, 5.20 mmol, 1.38 equiv)
were added to a solution of the hydroxyethyl derivative 7 (1.03
g, 3.77 mmol) in THF (50 mL) under N2. This solution was
cooled to 0 °C, diethyl azodicarboxylate (0.742 mL, 4.71 mmol,
1.25 equiv) was slowly added over 30 min, and the reaction
mixture was then stirred for 20 h at 25 °C under N2. The
reaction solution was concentrated, and the residue was ex-
tracted with EtOAc. The organic layer was washed with water
and brine and then concentrated to yield 3.0 g of the crude
protected guanidine product with two CBZ groups, i.e., trans-
BOC-cyclo-Arg(CBZ)2-OH: +FAB/DP m/z calcd for C30H38N4O8
582, found 583 for [M + H]+.
A sample of the material synthesized above (2.32 g) was
dissolved in THF (30 mL) and reacted with 1 M LiOH (20 mL)
for 10 d at 25 °C. A white solid formed and was removed by
filtration, and the filtrate was extracted with ether (20 mL ×
3). The aqueous layer was acidified with 2 M HCl and extracted
with a 1:1 EtOAc-ether mixture (40 mL). The organic layer
was washed with H2O, dried over MgSO4, and concentrated to
yield 520 mg of trans-BOC-cyclo-Arg(CBZ)-OH as an amorphous
solid (42% yield overall from 7): mp 125-140 °C; 1H NMR (300
MHz, acetone-d6) δ 7.47-7.20 (m, 5H), 6.30 (br s, 1H), 5.15 (br
s, 2H), 3.58-3.30 (br, 2H), 2.18-1.85 (br, 2H), 1.40-1.22
(overlapping, 2H), 1.34 (s, 9H), 1.04-1.14 (br s, 1H); 13C NMR
(75.4 MHz, acetone-d6) δ 174.0, 151.8, 151.2, 150.9, 131.5, 123.9,
123.4, 123.3, 73.2, 62.5, 36.9, 33.9, 23.5, 22.3, 21.9, 16.8; IR
(CHBr3) 1718, 1612, 1497, 1400, 1366 cm-1; HRMS (+FAB/DP)
m/z calcd for C20H28N4O6 421.2087, found 421.2085 for [M + H]+.
D
m/z calcd for C14H22N2O4 305.1477, found 305.1494 for [M +
Na]+.
(1R,2R)-2-[[[(Ben zyloxycar bon yl)]am in o]eth yl]-1-[N-(ter t-
b u t oxyca r b on yl)a m in o]cyclop r op a n e-1-ca r b oxylic Acid .
A solution of the nitrile ester 8 (585 mg, 2.06 mmol) in MeOH
(3 mL) was cooled to 0 °C, and a 2 N NaOH solution (3.6 mL,
7.21 mmol, 3.5 equiv) was added with stirring. After 10 h of
stirring at 25 °C, the reaction mixture was concentrated to
remove the organic solvent and washed with ether (20 mL × 2)
to remove nonacidic byproducts. The aqueous solution was
acidified with 2 N HCl and then extracted with ether (20 mL ×
2) and EtOAc (20 mL × 2). After evaporation of the solvent,
522 mg of the crude acid was obtained (99% yield). A pure
sample was obtained via column chromatography (50% Et2O/n-
C6H14) for characterization purposes: Rf 0.38 (60% ether/hexane
1
with trace AcOH); H NMR (300 MHz, CDCl3) δ 5.32 (bs, 1H),
2.57-2.44 (bm, 2H), 2.13-2.02 (bm, 2H), 1.78-1.64 (m, 1H),
1.62-1.54 (m, 1H), 1.54-1.4 (overlapping, 1H), 1.44 (s, 9H); 13
C
NMR (75.4 MHz, CDCl3) δ 176.9, 156.1, 119.4, 80.5, 37.8, 31.2,
28.2, 23.6, 23.1, 16.7; IR (CDCl3) 2979, 2252, 1707, 1507, 1393,
1368, 1164 cm-1; [R]25 -0.1° (c)1.6, CH2Cl2).
D
A mixture of the cyano acid derivative (138 mg, 0.543 mmol),
NH4OH (0.367 mL, 5.43 mmol), and a catalytic amount of Raney-
Ni in MeOH (6 mL) was stirred for 6 h in a Parr reactor under
H2 (300 psi). The reaction solution was filtered through a cotton
plug and washed with MeOH/H2O. After evaporation of the
solvent, the crude amino acid was obtained (136 mg): 1H NMR
(300 MHz, D2O) δ 2.87 (bs, 2H), 1.58 (br, 2H), 1.29 (s, 9H), 1.5-
1.15 (overlapping, 4H), 0.95 (br, 1H); 13C NMR (75.4 MHz, D2O)
δ 166.7, 161, 89.6, 55.9, 47.8, 36.3, 35.1, 32.7, 29.8. This material
was used for the next step without purification.
The crude amino acid (96 mg, 0.372 mmol) was dissolved in
50% concentrated Na2CO3 (1 mL), stirred for 10 min at 25 °C,
and then cooled to 0 °C. Carbobenzyloxy chloride (64 µL, 1.2
equiv) was added dropwise with vigorous stirring, and then the
mixture was stirred for 2 h at 0 °C. The reaction solution was
acidified with 2 M HCl and extracted with EtOAc. The organic
layer was washed with water and brine and then dried over
MgSO4. After evaporation of the solvent, 138 mg of trans-BOC-
cyclo-Lys(CBZ)-OH was obtained. A pure sample was obtained
via column chromatography (50% Et2O/n-C6H14) for character-
ization purposes: Rf 0.47 (60% ether/hexane with trace AcOH);
1H NMR (300 MHz, CD3OD) δ 7.41-7.22 (m, 5H), 5.05 (s, 2H),
3.2-3.05 (bs, 2H), 1.7-1.5 (bs, 4H), 1.5-1.3 (br, 2H), 1.42 (s,
9H), 1.2-1.1 (br, 1H); 13C NMR (75.4 MHz, CDCl3) δ 176.3,
156.6, 152.2, 136.6, 128.5, 128.1, 80.5, 66.6, 40.1, 32.0, 29.2, 28.3,
24.5, 23.6; IR (neat) 3337, 2975, 2929, 1701, 1522, 1368, 1255,
1165 cm-1; [R]25D +0.7° (c ) 1.3, CH2Cl2); HRMS(+FAB/DP) m/z
calcd for C20H28N2O6 393.2025, found 393.2040 for [M + H]+.
(1R,2S)-Eth yl 1-[N-(ter t-Bu toxyca r bon yl)a m in o]-2-(ca r -
b oxym et h yl)cyclop r op a n e-1-ca r b oxyla t e. The alcohol 7
(0.10 g, 0.366 mmol) was dissolved in 3.5 mL of CCl4-CH3CN-
H2O (2:2:3). Sodium periodate (235 mg, 1.10 mmol) was added,
followed by RuCl3‚H2O (3 mg). The reaction mixture was stirred
Ack n ow led gm en t. We thank The National Insti-
tutes of Health (GM 50772 and DA 06554) and The
Robert A. Welch Foundation for support for this re-
search, and K.B. thanks the NIH for a Research Career
Development Award and the Alfred P. Sloan Foundation
for a fellowship. NMR facilities were provided by the
NSF via the chemical instrumentation program.
J O9717447