Application of ruthenium-induced macrocyclization for the construction of macrocyclic depsipeptides

Article abstract of DOI:10.1021/jo011106v

The synthesis of a biaryl ether containing macrocyclic depsipeptide 1 was achieved in 6% overall yield. The desired macrocycle was constructed by cyclization of a phenol into η⁶-ruthenium complex. The ruthenium metal was subsequently photolytically deprotected to obtain the macrocycle.

Full text of DOI:10.1021/jo011106v

3152
J . Org. Chem. 2002, 67, 3152-3155
Sch em e 1
Ap p lica tion of Ru th en iu m -In d u ced
Ma cr ocycliza tion for th e Con str u ction of
Ma cr ocyclic Dep sip ep tid es
Srikanth Venkatraman,* F. George Njoroge,
Viyyoor Girijavallabhan, and Andrew T. McPhail†
Schering Plough Research Institute, K-15, 3545, 2015
Galloping Hill Road, Kenilworth, New J ersey 07033 and
Department Of Chemistry, Duke University, 101, Paul M.
Gross Chemistry Lab, Durham, North Carolina 27708
Srikanth.Venkatraman@spcorp.com
Received November 27, 2001
Abstr a ct: The synthesis of a biaryl ether containing
macrocyclic depsipeptide 1 was achieved in 6% overall yield.
The desired macrocycle was constructed by cyclization of a
phenol into η6-ruthenium complex. The ruthenium metal
was subsequently photolytically deprotected to obtain the
macrocycle 1.
Sch em e 2a
Depsipeptides are isosteric replacements of amides
that lack the hydrogen bond acceptor, a structural
modification avidly incorporated in a wide variety of
natural products and pharmaceutical intermediates.1 The
choice of depsipeptides as peptide isosteres generates
depeptidized analogues which retain the peptidic exosk-
eleton and gives rise to inhibitors which are stable to
peptidases and have markedly improved pharmacokinetic
profile.1 In the course of depeptidizing our inhibitors we
were challenged to develop a synthesis of the depsipep-
tide biaryl ether macrocycle 1 (Scheme 1). A ruthenium-
based strategy was deemed appropriate for the construc-
tion of this macrocyclic ether.2 The use of ruthenium
based strategy has been explored for the construction of
peptidic macrocycles by the groups of Pearson and Rich.2
This has been elegantly demonstrated in the approaches
to syntheses of vancomycin, ristocetin A, teicoplanin,
OF4949III, and K-13. The retrosynthetic analysis of 1
led us to the fragments 3 and 4 used for construction of
the macrocyclic precursor 2.
a
Reagents and conditions: (a) CH3COONa, (CH3CO)2O, 90%;
(b) aq HCI reflux, 51%; (c) Pd/C, H2, C2H5OH, 100%; (d)
C6H5CH2OH, PPTS, benzene, 61%.
The synthesis of hydroxy ester 3 was initiated from
acetyl glycine and m-hydroxybenzaldehyde (Scheme 2).3
Refluxing a mixture of 3-hydroxybenzaldehyde 6 and
acetyl glycine 5 with acetic anhydride and sodium acetate
formed the oxazolone 7 in excellent yield, which was
subsequently hydrolyzed to the pyruvate 8 by refluxing
with aqueous HCl. The pyruvate 8 was further reduced
to the hydroxy acid 9 quantitatively using catalytic
hydrogenation with Pd/C.4 Attempts to synthesizes the
benzyl ester 3 with K2CO3 and BnBr produced a mixture
of benzyl ester and benzyl ether in low yields. However
refluxing a mixture of acid 9 in benzene with 2 equiv of
BnOH and TsOH with azeotropic removal of water
resulted in exclusive formation of benzyl ester 3 in 61%
yield.5
† Duke University.
(1) (a) Li, Z.; Chan, K. K. J . Pharm. Biomed. Anal. 2000, 22, 33. (b)
Chan, K. K.; Bakhtiar, R.; J iang, C. Invest. New Drugs 1997, 15, 195.
(c) Ghosh, A. K.; Liu, C. Org. Lett. 2001, 3, 635. (c) Sparidans, R. W.;
Stokvis, E.; J imeno, J . M.; Lopez-Lazaro, L.; Schellens, J . H.; Beijnen,
J . H. Anticancer Drugs 2001, 12, 575. (d) Chen, W. Y.; Hsu, M. L.;
Olsen, R. K. J . Org. Chem. 1975, 40, 3110. (e) Dorr, F. A.; Kuhn, J . G.;
Phillips, J .; von Hoff, D. D. Eur. J . Cancer. Clin. Oncol. 1998, 24, 1699.
(f) Hurley, T. R.; Bunge, R. H.; Wilmer, N. E.; Hokanson, C. G.; French,
J . C. 1986, 39, 1651. (g) Sato, T.; Ishiyama, D.; Honda, R.; Senda, H.;
Konno, H.; Tomumasu, S.; Kanazawa S. J . Antibiot. 2000, 53, 597.
(2) (a) J anetka, J . W.; Raman, P.; Satyshur, K.; Flentke, G. R.; Rich,
D. H. J . Am. Chem. Soc. 1997, 119, 9, 441. (b) J anetka, J . W.; Rich, D.
H. J . Am. Chem. Soc. 1995, 117, 10585. (c) West, C. W.; Rich, D. H.
Org. Lett. 1999, 1, 1819. (d) Elder, A. M.; Rich, D. H. Org. Lett. 1999,
1, 1433. (e) Pearson, A. J .; Bignan, G.; Zhang, P.; Chelliah, M. J . Org.
Chem. 1996, 61, 3940. (f) Pearson, A. J .; Bignan, G. Tetrahedron Lett.
1996, 37, 735. (g) Pearson, A. J .; Lee, K. J . Org. Chem. 1995, 60, 7153.
(h) Pearson, A. J .; Lee, K. J . Org. Chem. 1994, 59, 2304. (i) Pearson,
A. J .; Park, J . G. J . Org. Chem. 1992, 57, 1744. (j) Pearson, A. J .; Heo,
J .-N. Org. Lett. 2000, 2, 2987. (k) Pearson, A. J .; Heo, J .-N. Tetrahedron
Lett. 2000, 41, 5991. (l) Pearson, A. J .; Belmont, P. O. Tetrahedron
Lett. 2000, 41, 1671. (m) Pearson, A. J .; Zhang, P.; Lee, K. J . Org.
Chem. 1996, 61, 6581. (n) J anetka, J .; Rich, D. H. J . Am. Chem. Soc.
1997, 119, 6488.
To enable an efficient ester formation of the less
reactive alcohol the diol 3 was selectively protected as
(3) (a) Wong, H. N. C.; Xu, Z. L.; Chang, H. M.; Lee, C. M. Synthesis
1992, 793. (b) Shaw, K. N. F.; Armstrong, M. D. J . Org. Chem. 1956,
21, 1149. (c) Wong, H. N. C.; Xu, Z. L.; Chang, H. M.; Lee, C. M.
Synthesis 1992, 793.
(4) (a) Hahn, H.; Hansel, A. Chem. Ber. 1938, 71, 2163. (b) EP
696566 (J une 10, 1996), Hikari, M.; Hiroyuki, M. (Nitto Chemical
Industry Co.).
(5) Eicher, T.; Ott, M.; Speicher, A. Synthesis 1996, 755.
10.1021/jo011106v CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/27/2002

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3153
Sch em e 3a
F igu r e 1. Ball and stick representation of X-ray structure of
(S)-diastereomer of macrocycle 1.
CpRu(CH3CN)3 15 in refluxing dichloroethane using the
procedure of Gill and Mann.9 The ruthenium complex
crystallized from the reaction mixture on cooling to form
colorless solid. Complex 4 was coupled with amine 13
using standard EDCI and HOBt10 conditions to obtain
the macrocyclic precursor 2 in excellent yields. The crude
mixture was directly cyclized by the treatment with 5
equiv of Cs2CO3 to form the macrocyclic depsipeptide 16.
The ruthenium was decomplexed by photolysis of 16 at
λ ) 350 nm in acetonitrile to form the macrocylic
depsipeptide 1 as a mixture of diastereomers.
a
Reagents and conditions: (a) Alloc-Cl, Et3N, CH2Cl2, -78 °C
to rt, 91%; (b) Boc-Chg-OH, DCC, DMAP, (iPr)2EtN; (c) 5 mol%
Pd(PPh3)4, dimedone, CH2Cl2, 78%; (d) 4 M HCI/dioxane.
Sch em e 4a
These isomers were easily separated using flash chro-
matography, and the relative stereochemisty was deter-
mined by single-crystal X-ray structure analysis. As
shown in Figure-1, the ball and stick representation of
the nonpolar diastereomer (TLC, hexane/CH2Cl2/Et2O:
6:3:1) was determined to be the (S)-diastereomer.
In conclusion, an efficient synthesis of the macrocyclic
depsipeptide 1 was accomplished by the application of
the cationic ruthenium cyclization. The depsipeptide was
obtained as mixture of diastereomers that were easily
separable. The cyclization of the depsipeptide demon-
strates the versatility of ruthenium complexes to induce
cyclization of even conformationally unrestricted com-
pounds such as depsipeptides.
Exp er im en ta l Section
Gen er a l Meth od s. All glassware were dried in an oven at
150 °C prior to use. Dry solvents were purchased from Aldrich
or Acros and used without further purification. Other solvents
or reagents were used as acquired except when otherwise noted.
Analytical thin-layer chromatography (TLC) was performed on
precoated silica gel plates available from Analtech. Column
chromatography was performed using Merck silica gel 60
(particle size 0.040-0.055 mm, 230-400 mesh). Visualization
was accomplished with UV light or by staining with basic
KMnO4 solution, methanolic H2SO4, or Vaughn’s reagent. NMR
spectra were recorded in CDCl3 unless otherwise noted in either
300 or 400 MHz (1H NMR) or 75 or 100 MHz (13C NMR).
Ben zyl 2-Hyd r oxy-3-(3-h yd r oxyp h en yl)p r op ion a te (3). A
solution of acid 9 (4.5 g, 25.0 mmol) in dioxane (30 mL) and
benzene (80 mL) was treated with BnOH (8.0 g, 74 mmol, 3.0
equiv) and TsOH‚H2O (713 mg, 3.75 mmol, 15 mol %). The
reaction mixture was heated at reflux for 5 h, and the water
was separated using a Dean-Stark apparatus. The reaction
mixture was concentrated in vacuo, and the residue was purified
by chromatography (SiO2, EtOAc/Hex 3:7) to yield benzyl ester
3 as a colorless oil (4.2 g, 61%); Rf : 0.22 (EtOAc/hexanes 3:7);
1H NMR (CD3OD, 300 MHz) δ, 7.37-7.26 (m, 4 H), 7.05 (t, 1 H,
a
Reagents and conditions: (a) (CH2Cl)2, reflux, 2 h, 73%; (b)
13, EDCI, HOBt, (iPr)2EtN, rt, 12 h (c) Cs2CO3, DMF, rt, 12 h; (d)
CH3CN, λ ) 350 nM, 24 h, 33% over two steps.
the allyl carbamate,6 which could be efficiently depro-
tected under neutral conditions (Scheme 3). Reaction of
3 with alloc chloride and Et3N resulted in the exclusive
reaction of the phenol to form the mono protected alcohol
10 in 91% yield. The alcohol 10 was coupled with Boc-
protected cyclohexylglycine using DCC and DMAP to
form the ester 11.7 The allyl carbamate was deprotected
using Pd(PPh3)4 and dimedone to generate phenol 12.8
Deprotection of the Boc group with 4 M HCl in dioxane
formed hydrochloride salt 13, which was used for the
synthesis of macrocyle.
As outlined in Scheme 4, complex 4 was synthesized
by the reaction of 4-chlorophenylpropionic acid 14 with
(9) (a) Gill, T. P.; Mann, K. R. Organometallics 1982, 1, 485. (b)
Zelonka, R. A.; Baird, M. C. J . Organomet. Chem. 1972, 44, 383. (c)
Zelonka, R. A.; Baird, M. C. Can. J . Chem. 1972, 50, 3063.
(10) (a) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788. (b) Ko¨nig,
W.; Geiger, R. Chem. Ber. 1970, 103, 2024. (c) Ko¨nig, W.; Geiger, R.
Chem. Ber. 1970, 103, 2034.
(6) (a) Corey, E. J .; Suggs, J . W. J . Org. Chem. 1973, 38, 3223. (b)
Kruse, C.; Holden, K. G. J . Org. Chem. 1985, 50, 2792.
(7) Neises, B.; Steglich, W. Org. Synth. 1985, 63, 183.
(8) Guibe, F.; Saint M’Leux, Y. Tetrahedron Lett. 1981, 22, 3596.

3154 J . Org. Chem., Vol. 67, No. 9, 2002
Notes
J ) 7.8 Hz), 6.68-6.61 (m, 3 H), 5.12 (s, 2 H), 4.38 (dd, 1 H, J
) 5.4, 2.1 Hz), 3.01-2.82 (m, 2 H); 13C NMR (CH3OD, 75 MHz,)
δ, 175.1, 158.2, 139.7, 137.0, 130.3, 129.5, 129.3, 121.7, 117.4,
114.5, 73.1, 67.6, 41.6; MS (FAB) m/z, relative intensity: 351
([M + DMSO]+, 70), 273 ([M + 1]+, 100), 255 (20), 227 (30), 181
(40); HRMS calculated for C16H17O4 (M + 1)+: 272.1049;
Found: 272.1054.
intensity: 412 ([M+, 100); HRMS: Calculated for C24H30NO5 (M
- Boc)+ 412.2123: Found 412.2139.
[η6-3-(4-Ch lor op h en yl)-1-p r op ion ic a cid ](η5-cyclop en ta -
d ien yl)r u th en iu m Hexa flu or op h osp h a te (4). A solution of
4-chlorophenylpropionic acid 14 in dichloroethane (200 mL) was
treated with CpRu(CH3CN)3PF6 15 (4.7 g, 10.8 mmol, 1.0 equiv)
and heated at reflux for 2 h. The reaction mixture was cooled to
room temperature, when colorless crystals of the ruthenium
complex 4 precipitated out. The crystals were filtered and
washed with a mixture of Et2O/CH2Cl2 (1:1 v/v) and dried in
vacuo. The colorless crystals (3.3 g, 73%) were analytically
pure: 1H NMR (d6-DMSO, 400 MHz,) δ 6.64 (d, 2 H, J ) 6.6
Hz), 6.22 (d, 2 H, J ) 6.3 Hz), 5.35 (s, 5 H), 2.49 (t, 2 H, J ) 9.6
Hz), 2.74 (dd, 2 H, J ) 4.3 Hz); 13C NMR 139.6, 131.6, 129.7,
128.6, 128.5, 100.3, 35.5, 28.9; MS (ES) m/z, relative intensity:
350 [(C14H14ClRu+), M+, 100]. Anal. Calculated for C14H14ClF6O2-
PRu: C, 33.92; H, 2.85; Cl, 7.15. Found: C, 34.04; H, 3.04; Cl,
7.09.
Ben zyl 2-Hyd r oxy-3-[3-[(a llyloxyca r bon yl)oxy]p h en yl]-
p r op ion a te (10). A solution of benzyl ester 3 (3.8 g, 12.9 mmol)
in CH2Cl2 (100 mL) was treated with Et3N (1.55 g, 15.4 mmol,
2.2 mL) and cooled to -78 °C, and a solution of allyl chlorofor-
mate (1.84 g, 15.36 mmol, 1.1 equiv) in CH2Cl2 (10 mL) was
added dropwise. The reaction mixture was allowed to warm to
the room temperature and diluted with aq HCl (1 M, 100 mL).
The reaction mixture was extracted with EtOAc (3 × 100 mL).
The combined organic layers were washed with aq HCl (100 mL,
1 M) and brine (100 mL), dried (MgSO4), and concentrated in
vacuo to yield 10 (4.3 g, 93%) which was used in the next step
without further purification. Rf: 0.43 (EtOAc/Hex 7:13); 1H NMR
(CD3OD, 300 MHz) δ, 7.35-7.23 (m, 5 H), 7.05 (dd, 1 H, J )
1.2, 6.7 Hz), 7.09-6.98 (m, 2 H), 6.05-5.94 (m, 1H), 5.42-5.26
(m, 2 H), 5.10 (bs, 2 H), 4.69 (m, 1 H), 4.67 (bt, 1 H, J ) 15 Hz),
4.39 (dd, 1 H, J ) 5.1, 2.1 Hz), 3.10-2.88 (m, 2 H); 13C NMR
(CH3OD, 75 MHz), δ, 174.8, 162.5, 155.0, 152.5, 140.3, 137.1,
132.8, 130.3, 129.6, 129.5, 129.4, 128.4, 123.2, 120.3, 119.4, 72.7,
70.1, 67.8, 41.2, 29.9.
Cyclo-[[η6-3-(4-ch lor op h en yl)-1-p r op ion ic a cid ]-cyclo-
h exylglycin e-1-[(3-h yd r oxyp h en yl)m et h yl]-2-oxo-2-(p h e-
n ylm eth oxy)eth yl ester ](η5-cyclop en ta d ien yl)r u th en iu m
Hexa flu or op h osp h a te (16). A solution of [CpRu(η6-4-chlo-
rophenylpropionic acid)]PF6 4 (2.0 g, 4.03 mmol) in dry DMF
(20 mL) were treated with HOBt (835 mg, 6.0 mmol, 1.5 equiv)
and Hu¨nigs base (2.06 g, 2.95 mL, 16 mmol, 4.0 equiv). The
reaction mixture was cooled to 0 °C and treated with EDCI (1.15
g, 6.0 mmol, 1.5 equiv). The reaction mixture was stirred at 0
°C for 30 min, and the amine hydrochloride 13 (1.8 g, 4.03 mmol,
1.0 equiv) was added in dry DMF (10 mL). The reaction mixture
was stirred at room temperature for 12 h, and the DMF was
distilled out in vacuo. The residue was diluted with aq HCl (1
M, 100 mL) and extracted into CH2Cl2 (3 × 100 mL). The
combined organic layers were extracted with aq NaHCO3 (3 ×
50 mL) and brine (100 mL), dried (Na2SO4), filtered, and
concentrated in vacuo to yield a brown solid 2 (3.5 g) which was
used for cyclization; MS (ES) m/z, relative intensity 743 [(M -
PF6)+, 100], 304 (60); HRMS Calculated for C38H41NO6Cl102Ru
(M - PF6):+ 744.1666; Found: 744.1694.
N-[(1,1-Dim eth yleth oxy)car bon yl]cycloh exylglycin e 1-[(3-
Hydr oxyph en yl)m eth yl]-2-oxo-2-ben zyloxyeth yl Ester (12).
A solution of Boc-cyclohexylglycine monohydrate (6.02 g, 23.4
mmol, 2.0 equiv) was dissolved in CH2Cl2 and dried (MgSO4).
The mixture was filtered and concentrated in vacuo. The residue
was repeatedly azeotropically dried with toluene three times.
The residue was dissolved in CH2Cl2 and treated with HOBt
(4.73 g, 35.1 mmol, 2.9 equiv), EDCI (6.7 g, 35.1 mmol, 2.9 equiv),
and Hu¨nigs base (8.31 g, 64.3 mmol, 11 mL). It was stirred at
room temperature for 30 min, and the alloc-protected alcohol
10 (4.3 g, 12.04 mmol) was added. The reaction mixture was
stirred at room temperature for 36 h and diluted with aq HCl
(1 M, 100 mL) and extracted with EtOAc (3 × 100 mL). The
combined organic layers were extracted with aq NaOH (1 M,
100 mL) and brine (100 mL), dried, concentrated in vacuo, and
purified by chromatography (SiO2, EtOAc/Hex 1:4) to yield
compound 11 which was charecterized as the deprotected
material (7.1 g 100%). Rf: 0.18 (EtOAc/Hex 1:4); Calculated for
C28H34O7 (M - Boc)+ 496.2335; Found 496.2333.
A solution of alloc-protected ester 11 (7.8 g, 13.0 mmol) in
dry THF (200 mL) was treated with dimedone (3.27 g, 23.4
mmol, 2.0 equiv) and under N2 was treated with Pd(Ph3P)4 (780
mg, 0.67 mmol, 5 mol %). The reaction mixture was stirred at
room temperature for 1 h, and the disappearance of starting
material was followed by TLC (EtOAc/Hex 1:4). The reaction
mixture was concentrated in vacuo, and the residue was purified
by chromatography (SiO2, EtOAc/Hexanes 1:4) to yield phenol
12 (5.2 g, 78%) as a colorless solid. Rf: 0.52 (EtOAc/Hex 3:7); 1H
NMR (CD3OD, 300 MHz), δ 7.33-7.19 (m, 4 H), 7.09-7.03 (m,
1 H), 6.73 (bd, 1 H, J ) 9.6 Hz), 6.69-6.63 (m, 2 H), 5.27-5.17
(m, 1 H), 5.12 (s, 1 H), 5.07 (d, 1 H, J ) 8.4 Hz), 4.10-4.02 (m,
1 H), 3.15-2.93 (m, 2 H), 1.70-1.57 (m, 5 H), 1.40 (m, 9 H),
1.19-0.82 (m, 6 H); 13C NMR (CH3OD, 75 MHz) δ, 171.7, 169.4,
169.3, 157.2, 156.7, 156.6, 137.2, 136.9, 135.3, 129.2, 128.2, 128.0,
127.9, 120.4, 120.2, 116.1, 116.0, 113.7, 79.3, 73.5, 66.8, 66.7,
60.2, 58.6, 40.0, 36.8, 29.1, 27.7, 27.4, 27.2, 25.6, 19.7, 13.2; MS
(ES) m/z, relative intensity: 1023.3 ([2M + 1]+, 20), 512 ([M +
1]+, 20), 412 (100), 202 (40); HRMS Calculated for C24H30NO5
(M - Boc):+ 412.2123; Found: 412.2119.
A solution of η6-ruthenium complex 2 (3.5 g, 3.93 mmol) in
dry DMF (300 mL) was degassed with dry N2, treated with Cs2-
CO3 (6.5 g, 19.95 mmol, 5.0 equiv), and stirred at room
temperature for 16 h. The reaction mixture was concentrated
in vacuo to remove the DMF, and the residue was diluted with
H2O (100 mL). The reaction mixture was extracted with CH2-
Cl2 (3 × 100 mL). The combined CH2Cl2 layers were extracted
with brine, dried (Na2SO4), filtered, and concentrated in vacuo
to yield 16 which was directly used for photolytic deprotection;
MS (ES) m/z, relative intensity, 708 [(M - PF6)+, 100]; HRMS
Calculated for C38H40NO6102Ru (M - PF6)+: 708.1892; Found:
708.1918.
Cyclo-[[η6-3-(4-ch lor op h en yl)-1-p r op ion ic a cid ]-cyclo-
h exylglycin e-1-[(3-h yd r oxyp h en yl)m et h yl]-2-oxo-2-(p h e-
n ylm eth oxy)eth yl ester ] (1). A solution of cyclized ruthenium
complex 16 (3.5 g, 3.9 mmol) in CH3CN (60 mL) was degassed
and photolyzed in a quartz tube at λ ) 350 nm in two batches
for 48 h each. The reaction mixture were pooled together and
was purified by chromatography (SiO2, CH2Cl2/Et2O 9/1) to yield
cyclic depsipeptide as a mixture of diastereomers. (700 mg, 33%).
The diastereomers were separated by additional chromatography
(Hex/CH2Cl2/ Et2O 6:3:1) to yield the two diasteromers of 1 (370
mg, 216 mg) as colorless solid. Rf 0.28 (Hex:EtOAc 3:2); [R]D
)
25 (c 0.15, CHCl3, 20 °C): IR (neat) cm-1 3329 (w), 2960 (m)
2926 (s), 2854 (s), 1745 (s), 1680 (m), 1589 (m), 1506 (m), 1446
(m), 1365 (w), 1259 (s) 1099 (m), 1030 (s), 800 (s), 752 (m), 698
(w) 619 (w): 1H NMR (CDCl3, 300 MHz) δ, 7.40-7.23 (m, 5 H),
7.18-6.99 (m, 4 H), 6.81 (d, 1 H, J ) 7.5 Hz), 6.74 (dd, 1 H, J )
2.7, 5.7 Hz), 6.30 (s, 1 H), 5.74 (d, 1 H, J ) 7.2 Hz), 5.60 (dd, 1
H, J ) 2.4 Hz, 5.4 Hz), 5.18, 5.16 (AB, 2 H, J ) 12.3 Hz), 4.23
(dd, 1 H, J ) 4.2 Hz, 3.3 Hz), 3.26-3.16 (m, 2 H), 3.10-2.97 (m,
1 H), 2.91-2.86 (m, 1 H), 2.40-2.30 (m,1H) 2.40-2.30 (m,
1H),1.76-1.51 (m, 6 H), 1.51-0.89 (M, 5H); 13C NMR (CDCl3,
75 MHz) δ, 177.3, 171.1, 168.7, 159.8, 155.3, 138.6, 135.4, 134.9,
131.2, 129.7, 129.2, 128.7, 126.6, 126.1, 123.3, 120.8, 120.8, 117.5,
114.2, 71.8, 57.5, 56.9, 41.5, 39.0, 35.7, 32.6, 31.3, 29.0, 27.6,
26.0, 25.9. MS (FAB) m/z, relative intensity 542 [(M + 1)+ 100],
514 (15), 450 (5), 307 (8), 232 (5), 154.1 (17), 136 (14) HRMS:
Calcd for C33H36NO6 (M + 1)+ 542.2543, Found: 542.2541.
Cycloh exylglycin e 1-[(3-Hyd r oxyp h en yl)m eth yl]-2-oxo-
2-(p h en ylm eth oxy)eth yl Ester Hyd r och lor id e (13). A solu-
tion of Boc-protected amine 12 (5.2 g, 10.7 mmol) was stirred
with HCl (4 M, dioxane, 200 mL, 800 mmol, 80 equiv) until the
starting material 12 disappeared to the baseline as indicated
by TLC (EtOAc/Hex 3:7). The reaction mixture was concentrated
in vacuo and dried in high vacuum to yield 13 that was directly
used in the next step. 1H NMR (CD3OD, 300 MHz) δ, 7.40-3.23
(m, 5 H), 7.07 (q, 1 H, J ) 13 Hz) 6.77-6.6 (m, 3 H), 5.33-5.41
(m, 1 H), 5.3-5.05 (AB, 2 H) 3.99-3.85 (m, 1 H) 3.35-22 (m, 2
H) 2.00-1.5 (m, 5 H), 1.50-0.80 (m, 6 H); MS (FAB) m/z, relative

Notes
Rf 0.18 (Hex:EtOAc 3:2) ; [R]D ) 37.3 (c 0.15, CHCl3, 20 °C);
J . Org. Chem., Vol. 67, No. 9, 2002 3155
(FAB) m/z, relative intensity 542 [(M + 1)+ 100], 514 (15), 466
1H NMR (CDCl3, 300 MHz) δ, 7.36-7.40 (m, 3 H), 7.28-7.16
(m, 6 H), 7.06 (dd, 1 H, J ) 1.8, 5.4 Hz), 6.95-6.91 (m, 2 H),
6.69 (d, 1 H, J ) 7.2 Hz), 6.07 (bt, 1 H), 5.59 (d, 1 H, J ) 9.0
Hz), 5.16-5.11 (m, 1 Hz), 5.05 (d, 1 H, J ) 8.7 Hz), 4.45 (dd, 1
H, J ) 6.6, 2.1 Hz), 3.19-3.09 (m, 3 H), 2.86 (dt, 1 H, J ) 4.2,
14.1 Hz), 2.68 (dt, 1 H, J ) 5.1, 4.5 Hz), 2.34-2.25 (m, 1 H),
1.80-1.50 (m, 8H), 1.30-0.85 (m, 6 H). 13C NMR (CDCl3, 75
MHz) δ, 171.4, 170.4, 168.4, 165.1, 160.7, 154.1, 137.7, 137.9,
135.1, 131.4, 129.8, 129.4, 128.7, 128.6, 128.3, 122.5, 116.5, 115.1,
74.6, 67.3, 57.5, 42.0, 39.6, 36.7, 31.2, 29.1, 28.5, 26.1, 25.9; MS
(5), 344 (8), 232 (5), 154.1 (17), 136 (14). HRMS: Calcd for C33H36-
NO6 (M + 1)+ 542.2543, Found: 542.2541.
Su p p or tin g In for m a tion Ava ila ble: Experimental for
1
the syntheses of compounds 8 and 9; H and 13C spectra for
compounds 3, 4, 10, 12, and 1; X-ray structure data of 1. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O011106V