Asymmetric Synthesis of a C-3 Substituted Pipecolic Acid

Full text of DOI:10.1021/jo991293l

1222
J . Org. Chem. 2000, 65, 1222-1224
Sch em e 1
Asym m etr ic Syn th esis of a C-3 Su bstitu ted
P ip ecolic Acid
Andrew J . Souers and J onathan A. Ellman*
University of California at Berkeley, Department of
Chemistry, Berkeley, California 94720
Received August 13, 1999
Sch em e 2a
The design and synthesis of conformationally con-
strained amino acids has attracted considerable attention
from the synthetic and medicinal chemistry communi-
ties.1 The replacement of constrained amino acids for
natural amino acids in both peptides and peptidomimet-
ics is a proven strategy for probing the structural
requirements of receptor-bound ligand conformations,2
increasing potency of receptor-ligand interactions,3 and
imparting proteolytic stability.4 In the course of our
ongoing peptidomimetic efforts, we required access to
enantiomerically and diastereomerically enriched pipe-
colic acid derivatives with substitution5 at the C-3
position.6 For our purposes, it was important not only
that the compound be suitable for incorporation into
solid-phase synthesis but also that a “functional handle”
be present for postsynthetic modification. Based upon a
recent report by Piscopio,7 we designed and synthesized
the novel amino acid 1 through a modular and efficient
route that is highly amenable to analogue synthesis.
We envisioned the cyclic amino acid 1 coming from the
N-allylated amino acid 7 via sequential ring closing
metathesis and hydrogenation (Scheme 1). This densely
functionalized amino acid would be accessed by the 3,3
Claisen rearrangement of chiral ester 5, which is derived
from chiral allylic alcohol 4 (Scheme 2) and N-Boc glycine.
As illustrated in Scheme 2, the synthesis was initiated
by Wittig condensation of known aldehyde 28 and the
ylide of acetonyltriphenylphosphonium chloride. Reflux-
ing the reaction solution for 24 h in 3:1 dioxane/H2O
afforded the R,â-unsaturated ketone 3 in 73% yield. As
expected, only the E-alkene isomer was detected by
proton NMR spectroscopy. Asymmetric reduction of this
ketone with (S)-2-methyl-CBS-oxazaborolidene9 and
a
Key: (a) acetonyltriphenylphosphonium chloride (1.2 equiv),
Na2CO3 (1.2 equiv), 3:1 dioxane/H2O, reflux, 24 h; (b) catechol-
borane (1.98 equiv), CBS-(S)-oxazaborolidene (0.14 equiv), tolu-
ene, -78 °C; (c) N-Boc-Gly (1.2 equiv), DMAP (0.4 equiv), DIC (1.2
equiv), CH2Cl2; (d) LDA (3 equiv), THF, -20 °C f -78 °C then
ZnCl2/THF (1.2 equiv) -78 °C f rt, 10 h.
catecholborane afforded the (R)-allylic alcohol 4 in 94%
yield and 88% ee as determined by HPLC analysis of the
corresponding Mosher esters.10 The absolute configura-
tion was inferred from ample literature precedent.11
After coupling alcohol 4 with N-Boc-Gly to afford ester
5, we employed a modified version of the Kazmaier 3,3
Claisen rearrangement procedure to set the two contigu-
ous stereocenters of amino acid 6.12 Under the optimized
conditions (see the Experimental Section), the rearrange-
ment proceeded from the zinc-chelated Z-ester enolate
to afford acid 6 in 85-90% yield. A single diastereomer
was observed by HPLC and NMR analysis. On the basis
of the literature precedent of Kazmaier12 and Bartlett,13
acid 6 was assigned as the syn diastereomer with
E-alkene stereochemistry as would be expected from a
chair transition state.
We then turned our attention to the selective electro-
philic allylation of the Boc-nitrogen in the presence of
the carboxylic acid moiety (Scheme 3). Although several
different conditions have appeared in the literature,14 the
best reported yield for the allylation of a Boc-protected
amino acid was 50%. It was found that allylation using
allyl iodide and NaH in THF over several days proceeded
in 62-68% yield on a multigram scale, with starting
(1) For recent reviews, see: (a) Gibson, S. E.; Thomas, N.; Guillo,
N.; Tozer, M. J . Tetrahedron. 1999, 55, 585-615. (b) Gante, J . Angew.
Chem., Int. Ed. Engl. 1994, 33, 1699-1720. (c) Duthaler, R. O.
Tetrahedron 1994, 50, 1539-1650.
(2) (a) Tellier, F.; Archer, F.; Brabet, I.; Pin, J .-P.; Azerad, R. Bioorg.
Med. Chem. 1998, 6, 195-208. (b) Charette, A. B.; Cote, B. J . Am.
Chem. Soc. 1995, 117, 12721-12732.
(3) Holladay, M. W.; Lin, C. W.; May, C. S.; Garvey, D. S.; Witte,
D.; Miller, T. R.; Wolfram, C. A. W.; Nadzan, A. M. J . Med. Chem.
1991, 34, 455-457.
(4) Ogawa, T.; Yoshitomi, H.; Kodama, H.; Waki, M.; Stammer, C.;
Shimohgashi, Y. FEBS. Lett. 1989, 250, 227.
(5) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D. J . Org. Chem. 1999,
64, 1993-2002 and ref 18 therein.
(6) (a) Murray, P. J .; Starkey, I. D. Tetrahedron Lett. 1996, 37,
1875-1878. (b) Christie, B. D.; Rappoport, H. J . Org. Chem. 1985, 50,
1239-1246. (c) Angle, S. R.; Arnaiz, D. O. Tetrahedron Lett. 1989, 30,
515-518 and references therein.
(7) (a) Miller, J . F.; Termin, A.; Koch, K.; Piscopio, A. D. J . Org.
Chem. 1998, 63, 3158-3159. (b) For related work, see: Burke, S. D.;
Ng, R. A.; Morrison, J . A.; Alberti, M. J . J . Org. Chem. 1998, 63, 3160-
3161.
(8) Ikeda, Y.; Uka, J .; Ikeda, N.; Yamamoto, H. Tetrahedron. 1987,
43, 731-741.
(9) (a) Corey, E. J .; Helal, C. J . Angew. Chem., Int. Ed. Engl. 1998,
37, 1986-2012.
(10) Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95, 512-
519.
(11) For reductions of related R,â-unsaturated ketones, see: Lo¨gers,
M.; Overman, L. E.; Welmaker, G. S. J . Am. Chem. Soc. 1995, 117,
9139-9150. (b) Corey, E. J .; Bakshi, R. K.; Shibata, S.; Chen, C. P.;
Singh, V. K. J . Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E.
J .; Helal, C. J . Tetrahedron Lett. 1995, 36, 9153-9156. (d) Wipf, P.;
Lim, S. Chimia 1996, 50, 157-167.
(12) Kazmaier, U. Angew. Chem., Int. Ed. Engl. 1994, 33, 998-999.
(b) Kazmaier, U.; Krebs, A. Angew. Chem. Int. Ed. Engl. 1995, 34,
2012-2014. (c) Kazmaier, U.; Maier, S. Tetrahedron. 1996, 52, 941-
954.
(13) Bartlett, P. A.; Barstow, J . F. J . Org. Chem. 1982, 47, 3933-
3941. (b) Bartlett, P. A.; Tanzella, D. J .; Barstow, J . F. Tetrahedron
Lett. 1982, 23, 619-622.
10.1021/jo991293l CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/03/2000

Notes
J . Org. Chem., Vol. 65, No. 4, 2000 1223
Sch em e 3a
without further purification. When used as a reaction solvent,
CH2Cl2 was distilled from CaH2, and THF and dioxane were
distilled under N2 from sodium benzophenone ketyl, all im-
mediately prior to use. Deoxygenation of nondistilled solvents
and of reaction mixtures was achieved by bubbling N2 or Ar
through them for 15-20 min.
Chromatography was carried out using 230-240 mesh silica
gel. Components were visualized either by ultraviolet light or
p-anisaldehyde staining. Unless otherwise noted, all organic
layers were dried over anhydrous Na2SO4, and all solvents were
removed with a rotary evaporator under aspirator pressure.
NMR spectra were recorded on a 500 MHz machine. NMR
chemical shifts are expressed in ppm downfield, relative to
internal solvent peaks. Coupling constants, J , are listed in
hertz.13C NMR analyses of compounds 6,7, and 1 were compli-
cated by rotameric mixtures of amide rotamers and are not
reported. Reversed-phase HPLC was performed on a Dynamax
f HPLC system from Rainin using a Microsorb C18 column from
Rainin. Normal-phase HPLC was performed on a Microsorb Si
column from Rainin. Infrared spectra were recorded on a Perkin-
Elmer 1600 FT-IR spectrophotometer and taken as thin films
on NaCl plates. Elemental analyses were performed by M-H-W
Laboratories (Phoenix, AZ) or by the Microanalytical Laboratory
at the University of California at Berkeley.
a
Key: (a) allyl iodide (1.5 equiv), NaH (3 equiv), THF, 0 °C f
rt, 72 h; (b) Grubbs cat. (0.05 equiv), CH2Cl2; (c) 10% Pt/C, H2,
EtOAc, 50 psi, 16 h.
material accounting for the remaining mass. Attempts
to accelerate the reaction rate by elevating the reaction
temperature or by use of a more polar solvent, such as
DMF, resulted in appreciable amounts of O-alkylation.
No epimerization was detected in either the recovered
starting material or product as determined by HPLC
analysis. The densely functionalized amino acid 7 was
then subjected to ring closing metathesis conditions
using Grubb’s phosphorylidine catalyst [RuCl2(dCHPh)-
(PCy3)2].15 Although the reaction proceeded cleanly,
column chromatography was insufficient to completely
remove catalyst-derived impurities. The unpurified ma-
terial was therefore directly submitted to the hydrogena-
tion reaction at 50 psi H2 with 10% Pt/C. After filtration
over Celite, pure amino acid 1 was obtained in 86%
overall yield for the two steps.
Two experiments were performed to rigorously estab-
lish the diastereomeric and enantiomeric purity of the
final pipecolic acid 1. First, acid 1 was converted to the
methyl ester by diazomethane treatment. Upon subjec-
tion to base, an approximately 1:1 ratio of the methyl
ester of 1 and the corresponding epimer were obtained
as determined by HPLC-MS. HPLC analysis of the
methyl ester of 1 clearly established that, to the limits
of detection (<2%), this compound was not contaminated
with the C-2 epimer. Second, acid 1 was coupled with
both (S)-(-)-R- and (R)-(+)-R-methylbenzylamine. HPLC
analysis of the (S)- and (R)-amide products established
that the final product 1 was obtained in 94% enantio-
meric purity.
In summary, we have demonstrated a versatile and
efficient asymmetric synthesis route to constrained pipe-
colic acid derivatives. The overall synthesis yield of 1,
which starts from literature aldehyde 2, is 32% over
seven steps. The stereochemistry of the contiguous C-2
and C-3 stereocenters is relayed from scalemic allylic
alcohol 4. Additionally, other C-3 substituted pipecolic
acids could easily be prepared by employing different
aldehyde starting materials. The solid-phase incorpora-
tion of 1 into small molecule peptidomimetics and
subsequent modification of the TBDPS ether via activa-
tion/displacement with nucleophiles will be reported in
due course.
(3E)-7-[[(1,1-Dim eth yleth yl)d ip h en ylsilyl]oxy]-3-h ep ten -
2-on e (3). To a 250 mL three-neck flask were added Na2CO3
(1.99 g, 18.0 mmol), acetonyltriphenylphosphonium chloride
(6.36 g, 17.9 mmol), and 60 mL of a 3:1 dioxane/H2O solution.
The mixture was heated to reflux for 45 min. A dropping funnel
containing 4.90 g of aldehyde 2 (14.9 mmol) in 15 mL of dioxane
was then added to the flask, and the aldehyde was added
dropwise at a slow rate. The reaction mixture was allowed to
proceed at reflux for 24 h. Upon cooling to room temperature,
the solvents were evaporated, and the residue was taken up in
150 mL of EtOAc. After the addition of 50 mL of 1 M NaHSO4,
the mixture was partitioned in a separatory funnel. The aqueous
layer was then washed with 1 M NaHSO4 and brine, dried, and
filtered. The organic extract was then concentrated in vacuo,
and the yellow flakey residue was taken up in 80 mL of hexanes
with a very small amount of EtOAc (ca 4-5 mL). After sitting
for approximately 1 h, the resultant precipitate (triphenylphos-
phine oxide) was filtered and rinsed with hexanes. The filtrate
was then concentrated and the residue loaded on a column and
eluted with 12-25% EtOAc/hexanes to afford 4.01 g (73%) of
the title compound as a yellow oil: IR (CH2Cl2) 3070, 2930, 2860,
1674 cm-1 1H NMR (500 MHz, CDC13): δ; 1.06 (s, 9H), 1.68
;
(m, 2H), 2.22 (s, 3H), 2.35 (m, 2H), 3.69 (t, J ) 6.1, 2H), 6.07 (d,
J ) 16.0, 1H), 6.79 (m, 1H), 7.37-7.45 (m, 6H), 7.66 (m, 4H);
13C NMR (125 MHz, CDCl3): δ 19.2, 23.3, 26.8, 28.9, 30.9, 62.9,
127.6, 129.6, 131.5, 133.7, 135.5, 148.0, 198.6. Anal. Calcd for
C23H30O2Si: C, 75.36; H, 8.25. Found: C, 75.13; H, 8.58.
(2R,3E)-7-[[(1,1-Dim eth yleth yl)d ip h en ylsilyl]oxy]-3-h ep -
ten -2-ol (4). To 4.01 g of enone 3 (11.0 mmol, dried by
azeotroping 2× with toluene) in dry toluene (83 mL) at -78 °C
was added a 1 M solution of (S)-2-methyl-CBS-oxazaborolidene
(1.60 mL, 1.61 mmol) in toluene. After 5 min, a 1 M solution of
catecholborane (2.30 mL, 21.7 mmol) in toluene was added over
20 min, and the solution was maintained at -78 °C for 6 h. The
solution was then quenched with MeOH, slowly warmed to room
temperature, and washed successively with 0.5 M NaOH (3×),
1 M NaHSO4, and brine. After drying and filtering, the residue
was loaded on a column and eluted with 15-30% EtOAc/hexanes
to afford 3.78 g of a clear oil in 94% yield and in 88% ee as
determined by Mosher ester formation according to the standard
procedure.8 Normal-phase HPLC analysis was performed with
a 4.6 mm × 25 cm Si Microsorb column (Rainin, Walnut Creek,
CA) and a flow rate of 1 mL/min with 99:1 hexanes-i-PrOH as
the mobile phase ((R,S)-ester, Rf ) 3.43 min; (R,R)-ester, Rf )
Ma ter ia ls a n d Meth od s
Rea gen ts a n d Gen er a l Meth od s. Unless otherwise noted,
all reagents were obtained from commercial suppliers and used
3.25 min); IR (CH2Cl2) 3349, 2930, 2860 cm-1 1H NMR (500
;
(14) (a) Mouna, A. M.; Nguyen, C.; Rage, I.; Xie, J .; Nee, G.;
Mazaleyrat, J . P.; Wakselman, M. Synth. Commun. 1994, 24, 2429-
2435. (b) Hon, Y.; Chang, R. Heterocycles 1991, 32, 1089-1099. (c)
Pitzele, B. S.; Hamilton, R. W.; Kudla, K. D.; Tsymbalov, S.; Stapelfeld,
A.; Savage, M. A.; Clare, M. J .; Hammond, D. L.; Hansen J r., D. W. J .
Med. Chem. 1994, 39, 888-896.
(15) (a) Schwab, P.; Grubbs, R. M.; Ziller, J . W. J . Am. Chem. Soc.
1996, 118, 100-110. (b) Dias, E. L.; Nguyen, S. T.; Grubbs, R. H. J .
Am. Chem. Soc. 1997, 119, 3887-3897.
MHz, CDCl3) δ 1.05 (s, 9H), 1.24 (d, J ) 6.33, 3H), 1.66 (m, 2H),
2.13 (m, 2H), 3.68 (t, J ) 6.31, 2H), 3.71 (m, 1H), 4.22 (m, 1H),
5.50 (dd, J ) 6.51, 15.4, 1H), 5.57 (m, 1H), 7.37-7.46 (m, 6H),
7.66-7.68 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 19.18, 23.3,
26.8, 28.3, 31.9, 63.1, 68.9, 127.6, 129.5, 130.5, 134.0, 134.4,
135.5. Anal. Calcd for C23H32O2Si: C, 74.95; H, 8.75. Found: C,
75.06; H, 8.78.

1224 J . Org. Chem., Vol. 65, No. 4, 2000
Notes
N-[(1,1-Dim eth yleth oxy)ca r bon yl]glycin e (1R,2E)-6-1,1-
Dim eth yleth yl)d ip h en ylsilyl]oxy]-2-h exen yl Ester (5). The
alcohol 4 (3.76 g, 10.2 mmol) was dissolved in 51 mL of distilled
CH2Cl2 and 2.15 g of N-Boc-Gly (12.3 mmol) was added, followed
by 0.4 equiv of DMAP (0.50 g, 4.1 mmol). The solution was then
cooled to 0 °C, and 1.2 equiv of DIC (1.92 mL, 12.3 mmol) was
added via syringe. The solution was allowed to slowly warm to
room temperature and was then stirred overnight. The solvents
were evaporated in vacuo, and the residue was taken up in
EtOAc. After being washed with 1 M NaHSO4 (3×), saturated
NaHCO3 (3×), and brine, the organic layer was dried and
filtered. After concentration in vacuo, the residue was loaded
on a small plug of silica gel and eluted with 15% EtOAc/hexanes.
The title compound (5.30 g) was obtained as a clear oil in 99%
of amino acid 7 and 71 mL of CH2Cl2. The solution was degassed,
and 218 mg (0.270 mmol, 5%) of Grubbs phosphorylidine catalyst
was added. The solution turned bright purple upon addition, and
was stirred at room temperature overnight. The reaction solution
was then concentrated in vacuo, and the contents were loaded
on a short plug of silica gel. Elution with CH2Cl2 afforded the
product in 86% yield by mass. The resultant oil was slightly
discolored by ruthenium complexes, although they were unde-
tectable by NMR and TLC. The oil was then taken up in 50 mL
of EtOAc and added to a 150 mL Parr shaker bottle. After the
addition of 1.78 g of 10% platinum on carbon (50% water weight,
0.460 mmol), the mixture was purged with hydrogen and then
shaken for 16 h at 50 psi. After the mixture was filtered over
Celite, the pure product was isolated as a colorless oil in 86%
yield over the two steps (2.40 g, 4.57 mmol): IR (CH2Cl2) 2932,
1
yield: IR (CH2Cl2) 3372, 2930, 2860, 1715 cm-1; H NMR (500
1
MHz, CDCl3) δ 1.00 (s, 9H), 1.25 (d, J ) 6.33, 3H), 1.42 (s, 9H),
1.65 (m, 2H), 2.14 (m, 2H), 3.66 (t, J ) 6.20, 2H), 3.87 (m, 2H),
5.01 (br s, 1H), 5.36 (m, 1H), 5.45 (dd, J ) 6.70, 16.0, 1H), 5.71
(m, 1H), 7.37-7.46 (m, 6H), 7.76-7.68 (m, 4H); 13C NMR (125
MHz, CDCl3) δ 17.4, 18.5, 21.7, 22.8, 25.1, 26.5, 26.7, 30.0, 61.3,
70.7, 125.8, 127.3, 127.5, 127.8, 132.2, 133.8, 154.4, 168.4. Anal.
Calcd for C30H43NO5Si: C, 68.53; H, 8.24; N, 2.66. Found: C,
68.23; H, 8.03; N, 2.69.
2858, 1698 cm-1; H NMR (500 MHz, MeOH-d4) δ 1.14 (s, 9H),
1.36 (m, 1H), 1.51-1.55 (m, 2H), 1.52 (s, 9H), 1.67-1.74 (m, 6H),
3.26 (m, 1H), 3.4 (m, 1H), 3.75 (m, 1H), 3.94 (m, 1H), 4.69-4.80
(m, 1H), 7.42-7.51 (m, 6H), 7.69-7.78 (m, 4H). Anal. Calcd for
C30H43NO5Si: C, 68.53; H, 8.24; N, 2.66. Found: C, 68.39; H,
8.10; N, 2.73.
LC-MS An a lysis of Am in o Ester . To assess the diastereo-
meric purity of acid 1, a small aliquot was converted to the
corresponding methyl ester by diazomethane treatment. An
aliquot was injected on a reversed-phase LC-MS with a Zorbax
SB-C18 column (2.1 mm × 5 cm, Agilent Technologies, Wilm-
ington, DE) (0.5 mL/min, 10%-100% CH3CN/H2O over 10 min,
254 nm) to afford a single peak (Rf ) 11.9 min, mass + Na )
562.3). A 20 mg (0.030 mmol) aliquot of the methyl ester was
then taken up in 0.5 mL of THF and the solution cooled to -78
°C. After addition of 0.06 mL of a 1.2 M KHMDS/THF solution
(0.070 mmol), the reaction solution was stirred at -78 °C for 20
min. Following this, 0.5 mL of a saturated NH4Cl solution was
added, and the mixture was allowed to warm to room temper-
ature. The mixture was then extracted twice with EtOAc, the
organic layers were combined and dried, and the resultant
solution was evaporated to afford a clear oil. The oil was taken
up in CH3CN, and a small aliquot was injected on an LC-MS
using the previously described parameters. Analysis afforded two
peaks in a roughly 1:1 ratio (Rf ) 11.9 min, mass + Na ) 562.3,
and 12.0 min, mass + Na ) 562.3), demonstrating that the C-2/
C-3 diastereomer was not present in acid 1 to the levels of
detection (<2%) by HPLC analysis.
HP LC An a lysis of r-Meth ylben zyl Am id e Der iva tives.
To establish the enantiomeric purity of final amino acid 1, a 30
mg (0.060 mmol) aliquot was coupled with (S)-(-)-R-methyl-
benzylamine (15 mg,0.12 mmol) using HATU (46 mg, 0.12 mmol)
and i-Pr2EtN (42 µL, 0.24 mmol) in CH2Cl2. Upon disappearance
of the starting material by TLC, the solution was washed with
1 M NaHSO4, dried, and filtered. Evaporation of the volatiles
afforded a clear oil. The same procedure was performed with
(R)-(+)-R-methylbenzylamine. Co-injection of the (S)- and (R)-
amide products on a reversed-phase Microsorb C18 column (4.6
mm × 25 cm, Rainin, Walnut Creek) [1 mL/min, 10-50% CH3-
CN/H2O (0.1% TFA) over 30 min, 254 nM] provided two peaks
with retention times of 34.8 and 35.3 min. Individual HPLC
analysis of the (R)-amide showed the same two peaks (34.8 and
35.3 min) in a 32.5:1 ratio, respectively. As expected, similar
analysis of the (S)-amide showed the same two peaks in a 1:32
ratio. The enantiomeric excess of amino acid 1 is therefore 94%.
(2R,3R,4E)-2-[[(1,1-Dim eth yleth oxy)ca r bon yl]a m in o]-3-
[3-[[(1,1-d im et h ylet h yl)d ip h en ylsilyl]oxy]p r op yl]-4-h ex-
en oic Acid (6). A solution of LDA was prepared by the slow
addition of n-BuLi (2.20 M, 14.0 mL, 30.6 mmol) to diisoprop-
ylamine (4.71 mL, 33.7 mmol) in 135 mL of THF at -20 °C. After
being stirred for 20 min, the solution was cooled to -78 °C, and
35 mL of a 0.29 M solution of ester 5 (5.36 g, 10.2 mmol) in THF
was slowly added. After 5 min, 24.5 mL of a ZnCl2 solution in
THF (0.500 M, 12.3 mmol) was added in one portion, and the
reaction mixture was allowed to warm to room temperature over
the course of 8-10 h. After this time, the reaction was quenched
with 5 mL of 1 M NaHSO4, and the solvents were removed in
vacuo. The residue was taken up in 120 mL of EtOAc, washed
with 1 M NaHSO4 (3 × 50 mL) and brine, dried, and filtered.
Column chromatography with 35-75% EtOAc/hexanes afforded
4.68 g (87%) of the title compound as a pale yellow oil: IR (CH2-
Cl2) 3058, 2918, 2860, 1715 cm-1 1H NMR (500 MHz, MeOH-
;
d4) δ 1.02 (s, 9H), 1.39-1.46 (m, 2H), 1.43 (s, 9H), 1.62 (m, 2H),
1.66 (d, J ) 6.03, 3H), 2.32 (m, 1H), 3.64 (m, 2H), 4.01 (m, 1H),
5.20 (m, 1H), 5.46 (m, 1H), 7.37-7.42 (m, 6H), 7.64-7.66 (m,
4H). Anal. Calcd for C30H43NO5Si: C, 68.53; H, 8.24; N, 2.66.
Found: C, 68.38; H, 8.40; N, 2.62.
(2R ,3R ,4E )-2-[[(1,1-Dim e t h yle t h oxy)ca r b on yl]-2-p r o-
p e n yla m in o]-3-[3-[[(1,1-d im e t h yle t h yl)d ip h e n ylsilyl]-
oxy]p r op yl]-4-h exen oic Acid (7). The acid 6 (4.60 g, 8.76
mmol) was dissolved in 53 mL of THF and cooled to 0 °C. NaH
(65%, 1.07 g, 26.7 mmol) was added in portions over a period of
45 min, followed by the addition of allyl iodide (1.22 mL, 13.4
mmol). The reaction mixture was allowed to warm to room
temperature and then stirred vigorously for ca. 72 h. After this
time, the reaction was quenched with 10 mL of 1 M NaHSO4,
and the solvents were evaporated. The residue was taken up in
EtOAc, washed with 1 M NaHSO4 (3×) and brine, dried, and
filtered. Chromatography with 9:1 CH2Cl2/EtOAc with 1% AcOH
afforded 3.10 g of the title compound in 63% yield: IR (CH2Cl2)
3070, 2918, 2860,1697 cm-1 1H NMR (500 MHz, MeOH-d4) δ
;
1.02 (s, 9H), 1.42 (s, 9H), 1.41-1.49 (m, 2H), 1.63 (m, 2H), 1.67
(d, J ) 6.03, 3H), 2.54 (m, 1H), 3.67 (m, 2H), 3.96 (m, 2H), 4.54
(m, 1H), 5.05-5.19 (m, 3H), 5.52 (m, 1H), 5.85 (m, 1H), 7.39-
7.46 (m, 6H), 7.65-7.67 (m, 4H). Anal. Calcd for C33H47NO5Si:
C, 70.05; H, 8.37; N, 2.48. Found: C, 70.08; H, 8.17; N, 2.50.
1-(1,1-Dim et h ylet h yl) H yd r ogen (2R,3R)-3-[3-[[(1,1-Di-
m et h ylet h yl)d ip h en ylsilyl]oxy]p r op yl]-1,2-p ip er id in ed i-
ca r boxyla te (1). To a 250 mL flask were added 3 g (5.31 mmol)
Ack n ow led gm en t. This work was supported by a
grant from the National Institutes of Health (GM53696).
A.J .S. would like to thank Pharmacia-Upjohn for finan-
cial support.
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