Synthesis of conformationally constrained arginine and ornithine analogues based on the 3-substituted pyrrolidine framework

Full text of DOI:10.1021/jo010242x

J . Org. Chem. 2001, 66, 6483-6486
6483
Syn th esis of Con for m a tion a lly Con str a in ed
Ar gin in e a n d Or n ith in e An a logu es Ba sed
on th e 3-Su bstitu ted P yr r olid in e
F r a m ew or k
Ahmed Mamai, Norman E. Hughes,
Alexander Wurthmann, and J ose S. Madalengoitia*
F igu r e 1. PPII mimic design strategy.
Department of Chemistry, University of Vermont,
Burlington, Vermont 05405
Sch em e 1a
J madalen@zoo.uvm.edu
Received March 6, 2001
In tr od u ction
As part of our program focused on the synthesis of
mimics of the poly-L-proline type II (PPII) secondary
structure, we are pursuing the synthesis of unnatural
amino acids we call proline-templated amino acids
(PTAAs).1 OligoPTAAs are specifically designed to pref-
erentially populate the PPII conformation in solution due
to a combination of cyclic and acyclic conformational
control elements (Figure 1).1 OligoPTAAs are thus un-
usual in that they represent conformationally constrained
linear peptides. Since a number of receptor-bound PPII
helices include basic residues, we are particularly inter-
ested in the synthesis of arginine and ornithine PTAAs.2
Some of these analogues are known. For example, the
synthesis of the cis and trans 4-substituted arginine
analogues 1 was reported by Webb and Eigenbrot, while
our group has reported the synthesis of ornithine (2) and
arginine (3) analogues based on the 3-aza-bicyclo[3.1.0]-
hexane system.3,4,5 This work describes our contributions
to the synthesis of the 3-substituted ornithine and
arginine analogues suitably protected for Fmoc/Boc solid-
phase peptide synthesis.
a
Reagents and conditions: (a) LiCH2CN, THF, -78 °C; (b) 3.6
equiv of BH3‚THF, THF, reflux; (c) (BocNH)2CdNTf, Et3N, CH2Cl2;
(d) Pd-C, HCO2NH4, MeOH, reflux; (e) FmocCl, NaHCO3, dioxane/
H2O; (f) TEMPO, bleach, NaClO2.
instance when we scaled-up the conjugate addition
reaction, another product was obtained in 29% yield. The
mass spectrum of this compound was consistent with
dimerization of the bicyclic lactam and incorporation of
CH2CN. It is well precedented that with basic nucleo-
philes this class of bicyclic lactams is prone to enolization
(11) and dimerization affording structures such as 12
(Scheme 2).8 At first, it was surmised that addition of
LiCH2CN to 12 would afford the observed dimer (after
workup). However, COSY spectroscopy revealed that the
correct structure was the tetracycle 16 that presumably
Resu lts a n d Discu ssion
Both syntheses use the R,â-unsaturated lactam 4 as a
common intermediate. Conjugate addition of LiCH2CN
to the R,â-lactam 4 was smoothly accomplished in THF
at -78 °C in 79% yield (Scheme 1).6 This conjugate
addition reaction serves to introduce the desired stere-
ochemistry at C2 (which will become Câ of the PTAA)
and also the requisite ꢀ-nitrogen.7 Interestingly, in one
(6) The stereochemical assignment is based on relative NOE inten-
sities. The NOEs were determined in DMSO-d6 as it resolves the
resonances. The CH2O resonances were initially assigned based on the
relative NOE intensities with the methine hydrogen. From these
assignments, the C2-stereochemistry could then be assigned based on
the NOE intensities of endo and exo C8-hydrogens with the C2-
hydrogen.
(1) (a) Zhang, R.; Madalengoitia, J . S. Tetrahedron Lett. 1996, 37,
6235. (b) Zhang, R.; Brownewell, F.; Madalengoitia, J . S. J . Am. Chem.
Soc. 1998, 120, 3894. (c) Zhang, R.; Madalengoitia, J . S. J . Org. Chem.
1999, 64, 330. (d) Mamai, A.; Zhang, R.; Natarajan, A.; Madalengoitia,
J . S. J . Org. Chem. 2001, 66, 455.
(2) Siligardi, G.; Drake, A. F. Pept. Sci. 1995, 37, 281.
(3) Webb, T. R.; Eigenbrot, C. J . Org. Chem. 1991, 56, 3009.
(4) Zhang, R.; Mamai, A.; Madalengoitia, J . S. J . Org. Chem. 1999,
64, 547.
(7) The intermediate 5 was reported by the Moloney group in the
synthesis of a pyroglutamate-derived ornithine analogue. Goswami,
R.; Moloney, M. G. Chem. Commun. 1999, 2333.
(5) Mamai, A.; Madalengoitia, J . S. Org. Lett. 2001, 3, 561.
(8) Nagasaka, T.; Imai, T. Chem. Pharm. Bull. 1997, 45, 36.
10.1021/jo010242x CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/23/2001

6484 J . Org. Chem., Vol. 66, No. 19, 2001
Notes
Sch em e 2
Sch em e 3a
arises from two tandem conjugate addition reactions
(Scheme 2). Interestingly, the dimer is formed as a single
isomer with five contiguous stereocenters. The stereo-
chemistry of the dimer has not been rigorously estab-
lished; however, the stereochemistry shown is the most
likely from the precedented behavior of this bicyclic
lactam.9 The formation of the dimer is most likely a result
of the low solubility of LiCH2CN in THF. Since there is
little LiCH2CN in solution, the enolate 14 formed from
the initial conjugate addition reaction can then begin to
compete with LiCH2CN for the R,â-unsaturated lactam
(even when lactam is added to LiCH2CN). The procedure
described in the Experimental Section utilizes a dilution
factor that minimizes formation of the dimer 16 to 1-5%.
With the introduction of the desired functionality at what
will become Câ of the PTAA, a method for the reduction
of the amide, oxazolidine, and nitrile was next investi-
gated. When the lactam 5 was subjected to LAH in
refluxing THF, the amine 6 was obtained with good mass
a
Reagents and conditions: (a) Boc2O, CH2Cl2; (b) Pd-C,
HCO2NH4, MeOH, reflux; (c) FmocCl, NaHCO3, dioxane/H2O; (d)
TEMPO, bleach, NaClO2.
1
resulting secondary amine with FmocCl gave the N-Fmoc
protected prolinol 19 in 46% yield for both steps. Oxida-
tion of the primary alcohol with TEMPO gave the PTAA
20 in 96% yield.
In conclusion, we have developed practical routes to
two conformationally constrained PTAAs appropriately
protected for Fmoc/Boc solid-phase peptide synthesis. The
routes are concise and amenable to the synthesis of
multigram quantities of PTAAs. These amino acids
should find utility in the synthesis of conformationally
constrained peptides. The results from these studies will
be reported in due course.
recovery (∼100%).10 However, inspection of the crude H
NMR spectrum revealed significant baseline impurities.
Consequently, when the crude amine 6 was guanidiny-
lated with the Goodman reagent (BocNH)2NTf, the pro-
linol 7 was obtained, but in 35% yield for both steps.11
In contrast, reduction of the nitrile 5 with BH3 in
refluxing THF afforded the amine 6 with significantly
improved purity such that guanidinylation of the primary
amine functionality with (BocNH)2NTf afforded the pro-
linol 7 in 77% yield for both steps. N-Debenzylation of
prolinol 7 was accomplished with HCO2NH4, Pd-C.12
Protection of the resultant secondary amine 8 with
FmocCl in aqueous NaHCO3/dioxane gave the Fmoc-
prolinol 9 in 50% yield for both steps. Finally, TEMPO
oxidation of the primary alcohol afforded the PTAA 10
appropriately protected for Fmoc/Boc solid-phase peptide
synthesis.13 To demonstrate the practical nature of this
route, 22 g of PTAA 10 were synthesized in 11 steps from
pyroglutamic acid.
Exp er im en ta l Section
Gen er a l. Unless otherwise specified, all reagents were pur-
chased from commercial sources and were used without further
purification. Reagent (BocHN)2CdNTf was prepared according
to Goodman’s procedure.11 THF was distilled from sodium
benzophenone ketyl, and CH2Cl2 was distilled from CaH2. When
required, reactions were carried out under a N2 atmosphere.
Flash chromatography was carried out on Selecto silica gel (230-
400 mesh). NMR spectra were collected in CDCl3 unless other-
wise noted using standard pulse sequences provided by Brucker.
(1S,2S,6R)-2-(5-Aza -7-oxa -4-oxo-6-p h en ylb icyclo[3.3.0]-
oct-2-yl)eth a n en itr ile (5). Freshly distilled CH3CN (6.00 mL,
116 mmol) in THF (80 mL) was cooled to -78 °C. LDA (60.0
mL, 120 mmol) was added dropwise over 30 min as a 2 M
solution in hexanes. After 20 min, a solution of lactam 4 (11.67
g, 58.00 mmol) in THF (60 mL) was added dropwise to the
mixture. The solution was maintained at -78 °C for 20 min then
treated with saturated aqueous NaHCO3 (20 mL). After warming
to room temperature, the layers were separated and the aqueous
layer was extracted with EtOAc (3 × 60 mL). The combined
organic fractions were dried over Na2SO4 and concentrated.
The ornithine PTAA was obtained in a manner similar
to the arginine PTAA (Scheme 3). Starting from the
pyrrolidine 6, the primary amine was protected with
Boc2O in 61% yield. N-Debenzylation of the tertiary
amine (HCO2NH4, Pd-C) followed by reprotection of the
(9) (a) Hanessian, S.; Ratovelomenana, V. Synlett 1990, 501. (b)
Hanessian, S.; Ratovelomenana, V. Synlett 1991, 222.
(10) Thottahil, J . K.; Moniot, J . L.; Mueller, R. H.; Wong, M. K. Y.;
Kissick, T. P. J . Org. Chem. 1986, 51, 3140.
(11) Feichtinger, K.; Zapf, C.; Sings, H. L.; Goodman, M. J . Org.
Chem. 1998, 63, 3804.
(12) Ram, S.; Spicer, L. D. Tetrahedron Lett. 1987, 28, 515.
(13) Zhao, M.; Li, J .; Mano, E.; Song, Z.; Tsachen, D. M.; Grabowski,
E. J . J .; Reider, P. J . J . Org. Chem. 1999, 64, 2564.

Notes
J . Org. Chem., Vol. 66, No. 19, 2001 6485
Purification by flash chromatography with EtOAc:/hexanes (50:
ter t-Bu tyl 3-[(2-{(2S,3S)-1-[(F lu or en -9-ylm eth yl)oxyca r -
bon yl]-2-(h yd r oxym eth yl)p yr r olid in -3-yl}eth yl)a m in o]-2-
a za -3-[(ter t-bu toxy)ca r bon yla m in o]p r op -2-en oa te (9). A
solution of the guanidine 7 (38.0 g, 79.8 mmol), 10% Pd-C (12
g), and ammonium formate (30.7 g, 479 mmol) in MeOH (400
mL) was heated at reflux for 30 min. After cooling, the mixture
was filtered through Celite, and the Celite plug was washed with
MeOH (3 × 150 mL) and CH2Cl2 (3 × 200 mL). The filtrate was
concentrated to yield the corresponding amino-alcohol 8 (30.3
g) as a colorless foam which was used without further purifica-
tion: 1H NMR (500 MHz, CDCl3) δ 11.51 (br s, 1H) 8.48 (br s,
1H), 6.35-6.25 (m, 2H), 3.90 (dd, J ) 3.7, 10.2 Hz, 1H) 3.74-
3.70 (m, 1H), 3.46-3.34 (m, 2H), 3.26-3.21 (m, 1H), 3.11-3.05
(m, 1H), 2.42-2.32 (m, 1H), 2.05-2.01 (m, 1H), 1.79-1.75 (m,
1H), 1.62-1.55 (m, 3H), 1.48 (s, 18H); 13C NMR (125 MHz,
CDCl3), 163.4, 156.0, 153.2, 83.0, 79.1, 65.8, 61.3, 45.2, 39.8, 38.4,
34.7, 33.4, 28.2, 28.0; FTIR (film) 3328, 3292, 1723, 1717, 1684;
MS (CI) m/z 387 (MH). The amino-alcohol 8 was dissolved in a
1:1 mixture of dioxane and a saturated aqueous NaHCO3
solution (600 mL) and cooled to 0 °C. FmocCl (20.3 g, 78.2 mmol)
was slowly added, and the solution was maintained at 0 °C for
4 h. The mixture was extracted with EtOAc (4 × 200 mL). The
combined organic layers were dried over Na2SO4 and concen-
trated. The residue was purified on silica gel eluting with EtOAc/
hexanes (30:70) and then CH2Cl2/acetone (10:90) to afford The
Fmoc-prolinol 9 (24.3 g, 50%) as a colorless foam: [R]25D ) -9.9°
(c 2.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 11.48 (s, 1H), 8.30
(br s, 1H), 7.72 (d, J ) 7.4 Hz, 2H), 7.55 (d, J ) 7.4 Hz, 2H),
7.35 (t, J ) 7.4 Hz, 2H), 7.27 (t, J ) 7.4 Hz, 2H), 4.43-4.39 (m,
2H), 4.23-4.18 (m, 2H), 3.69-3.65 (m, 1H), 3.60-3.52 (m, 2H),
3.49-3.41 (m, 2H), 3.27-3.21 (m, 2H), 2.18-2.12 (m, 1H), 2.07-
2.01 (m, 2H), 1.94-1.88 (m, 1H), 1.82-1.76 (m, 1H), 1.48 (s, 9H),
1.47 (s, 9H); 13C NMR (125 MHz, CDCl3) 163.5, 156.5, 156.2,
153.3, 143.9, 141.4, 127.7, 127.1, 125.0, 119.9, 83.2, 79.2, 67.4,
66.1, 65.5, 60.3, 47.4, 46.1, 39.3, 39.0, 32.8, 28.3, 28.1 ppm; FTIR
(film) 3330, 3295, 1718, 1700, 1685, 1636, cm-1; MS (CI) m/z
609 (MH).
50 then 75:25) afforded the nitrile 5 as a colorless solid (11.14
1
g, 79%): mp 97-98 °C; [R]20 ) +177.4° (c ) 0.83, CHCl3); H
D
NMR (500 MHz, CDCl3) δ 7.47-7.24 (m, 5H), 6.40 (s, 1H), 4.32
(dd, J ) 6.5, 8.6, 1H), 3.96 (apparent q, ddd, J ) 6.6, 6.6, 6.6
Hz, 1H), 3.72 (dd, J ) 6.8, 8.6 Hz, 1H), 2.78 (m, 1H), 2.70-2.53
(m, 4H); 13C NMR (125 MHz, CDCl3) 175.2, 137.9, 128.8, 128.6,
126.0, 117.1, 87.5, 63.5, 60.4, 39.6, 36.3, 21.6 ppm; IR (film) 2248,
1707 cm-1; MS (CI) m/z 243 (MH). Anal. Calcd for C14H14N2O2:
C, 69.41; H, 5.82; N, 11.56. Found: C, 69.22; H, 5.76; N, 11.45.
Dim er 16. colorless solid: mp 178-180 °C; [a]25 ) +154.2° (c
D
0.9, acetone); 1H NMR (500 MHz, DMSO d6) δ 7.27-7.22 (m,
10H), 5.98 (s, 1H), 5.97 (s, 1H), 4.14-4.08 (m, 2H), 3.97 (dd,
J ) 5.6, 13.6 Hz, 1H), 3.85 (dd, J ) 7.3, 11.5 Hz, 1H), 3.57 (dd
apparent t, J ) 8.0 Hz, 1H), 3.49 (dd apparent t, J ) 8.0 Hz,
1H), 3.41 (dd apparent t, J ) 6.0 Hz, 1H), 2.63-2.51 (m, 5H)
2.39-2.33 (m, 1H); 13C NMR (125 MHz, CDCl3) 175.4, 175.0,
139.2, 129.1, 128.8, 128.5, 126.5, 126.2, 119.8, 87.1, 86.7, 70.8,
68.9, 62.9, 62.6, 41.6, 40.4, 40.1, 38.8, 37.6, 35.4, 30.0 ppm; FTIR
(KBr) 3060, 3035, 2361, 1705, 1701, 1399, 1356 cm-1; MS (CI)
m/z 444 (MH). Anal. Calcd for C26H25N3O4: C, 70.41; H, 5.68;
N, 9.47. Found: C, 70.21; H, 5.89; N, 9.64.
ter t-Bu tyl 3-({2-[(2S,3S)-2-(Hyd r oxym eth yl)-1-ben zylp yr -
r olid in -3-yl]et h yl}a m in o)-2-a za -3-[(ter t-b u t oxyca r b on yl-
a m in o]p r op -2-en oa te (7). Meth od A. A solution of nitrile 5
(10.74 g, 44.33 mmol) in THF (60 mL) was slowly added to a
suspension of LAH (5.93 g, 156 mmol) in 100 mL of THF. The
mixture was heated at reflux for 10 h and then cooled to 0 °C.
H2O (6 mL), NaOH (1 M in H2O, 6 mL), and then H2O (18 mL)
were successively added to the solution. The mixture was stirred
for 30 min at room temperature and filtered. The filtrate was
concentrated to afford the amine 6 (10.68 g) as a yellow oil which
was used without further purification: 1H NMR (500 MHz,
CDCl3) δ 7.27-7.13 (m, 5H), 3.91 (d, J ) 13.0 Hz, 1H), 3.54 (dd,
J ) 4.2, 10.7 Hz, 1H), 3.24 (d, J ) 13.0 Hz, 1H), 2.85-2.80 (m,
1H), 2.66-2.60 (m, 2H), 2.37-2.20 (m, 6H), 2.10-2.01 (m, 1H),
1.84-1.74 (m, 1H), 1.51-1.47 (m, 1H), 1.40-1.34 (m, 1H) 1.31-
1.25 (m, 1H); 13C NMR (125 MHz, CDCl3) 139.3, 128.7, 128.2,
127.1, 71.2, 61.5, 58.9, 52.7, 40.3, 38.7, 38.1, 29.7 ppm; FTIR
(film) 3350, 3290, 3200 cm-1; MS (CI) m/z 235 (MH). The crude
amine 6 (10.68 g) in CH2Cl2 (100 mL) was slowly added to a
solution of (BocNH)2CdNTf (16.0 g, 41.0 mmol) and triethyl-
amine (6.4 mL, 46 mmol). After 24 h at room temperature, the
solution was washed with a saturated aqueous NaHCO3 (50 mL)
and the aqueous layer was back extracted with CH2Cl2 (3 × 200
mL). The combined organic layers were dried over Na2SO4 and
then concentrated. The crude residue was purified by flash
chromatography (100% CH2Cl2 then 100% EtOAc) to afford the
(2S,3S)-3-[2-({-2-Aza -2-[(ter t-bu tyl)oxyca r bon yl]-1-[(ter t-
bu toxy)ca r bon yla m in o]vin yl}a m in o)eth yl]-1-[flu or en -9-yl-
m eth yl)oxyca r bon yl]p yr r olid in e-2-ca r boxylic Acid (10).
The primary alcohol 9 (23.9 g, 39.2 mmol), TEMPO (0.42 g, 2.5
mmol), and NaClO2 (7.4 g, 79 mmol) were added to a mixture of
acetonitrile (85 mL) and NaH2PO4 (0.67 M) (75 mL). This
mixture was warmed to 35 °C, and bleach (1.1 mL) was slowly
added over 15 min. After 5 h at 35 °C, the reaction mixture was
cooled to room temperature and poured over a solution of Na2-
SO3 (10.5 g), water (22 mL), and ice (60 g). The layers were
separated, and the aqueous layer was extracted with EtOAc
(3 × 150 mL). The combined organic fractions were dried over
Na2SO4 and concentrated. Purification of the residue on silica
gel eluting with 96.5:3.3:0.2 CH2Cl2-MeOH-AcOH afforded the
acid 10 (22.2 g, 90%) as a colorless solid: mp 116-118 °C;
guanidine 7 (7.58 g, 35% from 5) as a colorless foam: [R]25
)
D
-6.1° (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 10.55-10.45
(br s, 1H), 8.25 (s, 1H), 7.21-7.16 (m, 5H), 3.9 (d, J ) 12.8 Hz,
1H), 3.58 (d, J ) 8.6 Hz, 1H), 3.45-3.38 (m, 5H), 3.26 (d, J )
12.8 Hz, 1H), 2.87-2.84 (m, 1H), 2.33-2.27 (m, 2H), 2.12-2.06
(m, 2H), 1.87-1.79 (m, 1H), 1.69-1.63 (m, 1H), 1.43 (s, 9H), 1.41
(s, 9H); 13C NMR 163.5, 156.1, 153.2, 138.9, 128.7, 128.3, 127.1,
83.0, 79.1, 71.1, 60.8, 58.6, 52.7, 39.5, 38.2, 34.7, 29.5, 28.3, 28.0
ppm; FTIR (film) 3330, 3250, 1721, 1642 cm-1; MS (CI) m/z 477
(MH). Anal. Calcd for C25H40N4O5: C, 63.00; H, 8.46; N, 11.76.
Found: C, 62.88; H, 8.36; N, 11.72. Meth od B: BH3‚THF (380
mL, 380 mmol) was added dropwise as 1.0 M solution in THF
to a solution of the nitrile 5 (25.5 g, 105 mmol) in THF (200
mL), and the resultant mixture was heated at reflux for 1 h.
After the solution cooled to room temperature, the solvent was
removed under reduced pressure, and the residue was dissolved
in methanolic HCl (500 mL). The solution was heated at reflux
for 2 h, and the methanol was removed under reduced pressure.
The resulting oil was dissolved in CH2Cl2 (200 mL) and washed
with a 20% aqueous K2CO3 (200 mL). The aqueous layer was
extracted with CH2Cl2 (4 × 200 mL), and the combined organic
fractions were dried over Na2SO4 and concentrated to afford the
amino-alcohol 6 (25.5 g) as a yellow oil. The amino-alcohol 6
(25.5) was allowed to react with (BocNH)2CdNTf (38.3 g, 97.9
mmol) according to the procedure described above. This modified
procedure afforded 38.8 g (77% from the nitrile 5) of the
guanidine 7 as a colorless foam.
[R]25 ) -23.8° (c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
11.42-11.19 (br s, 1H), 8.41 (br s, 1H), 7.74 (d, J ) 7.4 Hz, 1H),
7.69 (d, J ) 7.4 Hz, 1H), 7.59-7.52 (m, 2H), 7.39-7.20 (m, 4H),
4.45-4.39 (m, 1H), 4.34 (dd apparent t, J ) 8.7 Hz, 1H), 4.23
(dd apparent t, J ) 6.9 Hz, 1H), 4.15-4.09 (m, 1H), 3.64-3.48
(m, 4H), 2.41-2.36 (m, 1H), 2.17-2.08 (m, 1H), 1.92-1.84 (m,
1H), 1.72-1.60 (m, 2H), 1.53-1.45 (m, 1H), 1.49 (s, 18H); 13C
NMR (125 MHz, CDCl3) 175.9, 174.8, 163.3, 156.3, 155.3, 154.5,
153.3, 144.1, 143.8, 141.3, 127.7, 127.1, 125.1, 119.9, 83.4, 79.5,
67.7, 64.5, 63.9, 47.3, 46.1, 45.7, 42.4, 41.0, 39.2, 33.2, 33.0, 31.1,
30.2, 29.5, 28.3, 28.1 ppm; FTIR (KBr) 3326, 3284, 1725, 1718,
1701, 1685, 1653, cm-1; MS (CI) m/z 623 (MH). Anal. Calcd for
C
33H42N4O8: C, 63.65; H, 6.80; N, 9.00. Found: C, 63.40; H, 6.85;
N, 8.99.
N-{2-[(2S,3S)-2-(Hyd oxym eth yl)-1-ben zylp yr r olid in -3-yl]-
eth yl}(ter t-bu toxy)ca r boxa m id e (17). A solution of the amine
6 (1.00 g, 4.27 mmol), Boc2O (1.0 g, 4.7 mmol), and DIEA (0.82
mL, 4.7 mmol) in CH2Cl2 (40 mL) was stirred for 6 h under N2
and then concentrated. The residue was purified by flash
chromatography over silica eluting with EtOAc to afford 1.03 g
(61%) of compound 17 as a colorless foam: [R]25D ) -6.5° (c 2.1,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.31-7.22 (m, 5H), 4.66
(br s, 1H), 3.96 (d, J ) 13.1 Hz, 1H), 3.67 (dd, J ) 3.6, 11.0 Hz,
1H), 3.47 (dd, J ) 1.4, 11.0 Hz, 1H), 3.32 (d, J ) 13.0 Hz, 1H),
3.23-3.17 (m, 1H), 3.12-3.05 (m, 1H), 2.96-2.91 (m, 1H), 2.37

6486 J . Org. Chem., Vol. 66, No. 19, 2001
Notes
(dd, J ) 9.3, 17.1 Hz, 1H), 2.33-2.30 (m, 1H), 2.18-2.09 (m,
1H), 1.93-1.85 (m, 1H), 1.65-1.61 (m, 1H), 1.52-1.43 (m, 3H),
1.47 (s, 9H); 13C NMR (125 MHz, CDCl3) 156.1, 139.0, 128.7,
128.3, 127.1, 79.0, 71.1, 60.8, 58.7, 52.8, 39.1, 37.9, 35.2, 29.4,
28.5 ppm; FTIR (film) 3353, 1691, cm-1; MS (CI) m/z 335 (MH).
Anal. Calcd for C19H30N2O3: C, 68.23; H, 9.04; N, 8.38. Found:
C, 68.21; H, 9.02; N, 8.24.
F lu or en -9-ylm eth yl(2S,3S)-3-{2-{(ter t-bu toxy)ca r bon yl-
a m in o]et h yl}-2-(h yd r oxym et h yl)p yr r olid in eca r b oxyla t e
(19). Compound 17 (0.54 g, 1.6 mmol) was debenzylated follow-
cm-1; MS (CI) m/z 467 (MH). Anal. Calcd for C27H34N2O5: C,
69.50; H, 7.35; N, 6.00. Found: C, 69.35; H, 7.78; N, 6.33.
(2S,3S)-3-{2-[(ter t-Bu toxy)ca r bon yla m in o]eth yl}-1-[(flu -
or en -9-ylm eth yl)oxycar bon yl]pyr r olidin e-2-car boxylic Acid
(20). The primary alcohol 19 (0.35 g, 0.75 mmol) was oxidized
following the same procedure described for the oxidation of 9 to
afford the acid 20 (0.34 g, 96%) as a colorless solid: mp 88-90
°C; [R]25 ) -25.5° (c 0.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ
D
11.16-11.01 (br s, 1H), 7.76 (d, J ) 7.4 Hz, 1H), 7.73 (d, J ) 7.4
Hz, 1H), 7.62 (d, J ) 7.4 Hz, 1H), 7.59 (d, J ) 7.4 Hz, 1H), 7.43-
7.35 (m, 2H), 7.33-7.26 (m, 2H), 5.03-4.98 (m, 1H), 4.49-4.42
(m, 1H), 4.37 (dd apparent t, J ) 8.9 Hz, 1H), 4.35-4.31 (m,
1H), 4.26 (dd apparent t, J ) 6.7 Hz, 0.5H), 4.19 (dd apparent
t, J ) 6.2 Hz, 0.5H), 4.15-4.10 (m, 0.5H), 4.08-4.04 (m, 0.5H),
3.65-3.59 (m, 1H), 3.24-3.17 (m, 2H), 2.40-2.36(m, 1H), 217-
2.12 (m, 1H), 1.80-1.75 (m,1H), 1.60-1.52 (m, 2H), 1.57 (s, 9H);
13C NMR (125 MHz, CDCl3) 175.6, 175.1, 156.5, 155.4, 154.7,
144.2, 144.1, 143.8, 141.3, 127.7, 127.1, 125.2, 120.0, 81.3, 79.8,
79.6, 67.9, 67.7, 64.3, 63.9, 47.3, 47.2, 46.1, 45.8, 42.0, 40.7, 39.7,
38.8, 33.8, 30.7, 29.7, 29.5, 28.5 ppm; FTIR (KBr) 3337, 3090,
1725, 1701, 1705, 1695, cm-1; MS (CI) m/z 461 (MH).
ing the same procedure as
7 to afford the corresponding
secondary aminol 18 (0.37 g) as a white foam: 1H NMR (500
MHz, CDCl3) δ 4.96 (br s, 1H), 4.66 (br s, 2H), 3.60 (dd, J ) 3.6,
11.5 Hz, 1H), 3.42 (dd, J ) 6.6, 11.5 Hz, 1H), 3.10-3.01 (m, 2H),
2.99-2.94 (m, 1H), 2.92-2.86 (m, 2H), 2.02-1.96 (m, 1H), 1.79-
1.69 (m, 1H), 1.64-1.55 (m, 1H), 1.42-1.34 (m, 2H), 1.38 (s, 9H);
13C NMR (125 MHz, CDCl3) 156.3, 78.9, 65.8, 62.4, 53.5, 45.0,
38.0, 34.0, 32.1, 28.4 ppm; FTIR (film) 3327, 1700, 1690, 1455
cm-1; MS (CI) m/z 245 (MH). The amino-alcohol 18 was N-Fmoc
protected using the same conditions as for the protection of 8
above to afford 19 (0.35 g, 46%) as a colorless foam: [R]25
)
D
-20.3° (c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J )
7.4 Hz, 2H), 7.56 (d, J ) 7.4 Hz, 2H), 7.37 (dd apparent t, J )
7.4 Hz, 2H), 7.29 (dd apparent t, J ) 7.0 Hz, 2H), 4.86 (dd
apparent t, J ) 5.6 Hz, 1H), 4.44-4.36 (m, 2H), 4.20 (dd
apparent t, J ) 6.5 Hz, 1H). 3.65-3.50 (m, 3H), 3.26 (dd, J )
7.5, 17.3 Hz, 1H), 3.16-3.04 (m, 3H), 2.06-2.01 (m, 1H), 1.94-
1.89 (m, 1H), 1.70-163 (m, 1H), 1.47-1.36 (m, 3H), 1.43 (s, 9H);
13C NMR (125 MHz, CDCl3) 156.5, 156.1, 143.9, 141.4, 127.8,
127.1, 125.0, 120.0, 79.2, 67.4, 65.9, 65.4, 60.4, 47.4, 46.2, 38.6,
33.7, 29.9, 28.5 ppm; FTIR (film) 3360, 3065, 1700, 1684, 1653
Ack n ow led gm en t. Support for this work has been
provided by NSF and NIH.
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
NMR spectra for compounds 5-10 and 16-20. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O010242X