Desymmetrization of 3-dimethyl(phenyl)silyl glutaric anhydride with Evans' oxazolidinone: An application to stereocontrolled synthesis of the antifungal agent (+)-preussin

Article abstract of DOI:10.1039/a808840c

A stereoselective total synthesis of (+)-preussin (1) has been achieved from the a-symmetric 3-dimethyI(phenyl)silyl substituted glutaric anhydride 4 featuring its desymmetrization using Evans' oxazolidinone 10. The first homochiral intermediate, the glutarate half-ester 9 was obtained from both the diastereoisomeric acids lia, and 12a in a convergent fashion. The dimethyl(phenyl)silyl group is not only acting as a masked hydroxy group but also restricts elimination reactions, and facilitates Curtius reaction. It also stereodirects ester enolate alkylation of 18, and hydrogenation of intermediate Δ¹-pyrroline 5.

Full text of DOI:10.1039/a808840c

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Desymmetrization of 3-dimethyl(phenyl)silyl glutaric anhydride
with Evans’ oxazolidinone: an application to stereocontrolled
synthesis of the antifungal agent (؉)-preussin
Rekha Verma and Sunil K. Ghosh*
Bio-Organic Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India
Received (in Cambridge) 12th November 1998, Accepted 9th December 1998
A stereoselective total synthesis of (ϩ)-preussin (1) has been achieved from the σ-symmetric 3-dimethyl(phenyl)silyl
substituted glutaric anhydride 4 featuring its desymmetrization using Evans’ oxazolidinone 10. The first homochiral
intermediate, the glutarate half-ester 9 was obtained from both the diastereoisomeric acids 11a and 12a in a
convergent fashion. The dimethyl(phenyl)silyl group is not only acting as a masked hydroxy group but also restricts
elimination reactions and facilitates Curtius reaction. It also stereodirects ester enolate alkylation of 18 and
hydrogenation of intermediate ∆1-pyrroline 5.
OH
Introduction
X
(ϩ)-Preussin, (2S,3S,5R)-1-methyl-5-nonyl-2-benzylpyrrolidin-
3-ol (also known as L-657,398) (1) was isolated from the
H
19C9
H19C9
N
N
Ph
Ph
CH3
1
OMe
5
OR
X
OAc
HO
X
X
H19C9
N
H19C9
H19C9
N
H
Ph
O
O
O
CH3
O
Ph
O
Ph
CON3
NH2
R = H;
R = Ac; 2
1
3
4
6
7
fermentation broth of Aspergillus ochraceus ATCC 22947 and
Preussia sp. by scientists at Squibb and Merck.1 This structur-
ally novel pyrrolidine alkaloid antibiotic and its acetate ester
2 show a broader spectrum antifungal activity against both
filamentous fungi and yeasts than the structurally related anti-
biotic anisomycin (3).1c The first synthesis was reported by Pak
and Lee2 using -glucose as a substrate. A few more syntheses
based on the chiral pool have been published subsequently
using -mannose,3 -arabinose,4 (S)-phenylalanine5 and its
enantiomer, (R)-phenylalanine6 as starting materials. Recently,
a chiral induction based strategy for 1 has also been reported by
Greene.7
Our interest was to develop a versatile route for preussin by
which either enantiomer could be synthesized from the same
starting material as well as having inherent flexibility to produce
its analogs with different substituents at positions 1, 2 and 5
for biological screening. In the preceding paper,8 we have
discussed a methodology for desymmetrization of σ-symmetric
anhydrides. In a sequel, we envisioned a retrosynthetic analysis
for 1 from 3-hydroxyglutaric anhydride (4; X = OH; Scheme 1).
Preussin could be prepared via stereoselective reductive methyl-
ation of ∆1-pyrroline 5 preceded by the amino ketone 6 which in
turn could be obtained from the δ-keto acyl azide 7 via a Cur-
tius reaction. The latter could be obtained from the keto-ester 8,
synthesis of which might be accomplished from 4 (X = OH) via
the glutarate half-ester 9. The O-silyl/alkyl protected intermedi-
ates like 8 tend to undergo elimination during ester enolate
alkylation9 reaction, thereby making the alkylation rather
difficult. Alternatively, β-hydroxy acids are known to undergo
dianion alkylation with very high anti-selectivity,10 but, as
pointed out by Livinghouse,5a an intermediate like 5 is unable to
provide a tetrahydropyrrole derivative due to ease of elimin-
ation of either a protected or unprotected OH group. Therefore,
X
X
O
O
CO2R
CO2R
HO
H19C9
8
9
Scheme 1
this retrosynthesis in the present form probably could not be
applicable for preussin synthesis. Hence, a suitable substitute
for the OH group in the retrosynthetic sequence is desirable
which would resist elimination, could stereospecifically be
converted to a hydroxy group when desired, could possibly
stereodirect both saturation of the ∆1-pyrroline system and
introduction of the benzyl group in 8 and possibly facilitate the
Curtius reaction of 7. Considering all these requirements, we
envisaged that a dimethyl(phenyl)silyl (PhMe2Si) group can be
an ideal substitute for the OH group. It is known to be a poor
leaving group and as shown by Fleming,11 it could be stereo-
specifically converted into a hydroxy group with retention of
configuration. It has further been shown that the β-silyl ester
enolate alkylations occur with high anti stereoselectivity.12 Also,
it is expected that the steric bulk of a PhMe2Si group is large
enough to stereodirect the hydrogenation in intermediate 5.
Moreover, we have recently shown that a silicon group at the
β-position facilitates the Curtius reaction of acyl azides.13
Based on the above factors, a retrosynthetic analysis was con-
ceived as shown in Scheme 1 (X = PhMe2Si). A communication
on this report has already been published by us.14
Results and discussion
The anhydride 4 (X = PhMe2Si) was opened up8 using the
J. Chem. Soc., Perkin Trans. 1, 1999, 265–270
265

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lithium anion of the Evans oxazolidinone 1015 to provide a
mixture of diastereoisomeric acids 11a and 12a which were
separated as their benzyl (11b and 12b) and tert-butyl (11c and
12c) esters (Scheme 2). The diastereoisomerically pure tert-
O
X
O
O
iii
100%
i, ii
C9H19
11a
N
O
92%
Bn
X = PhMe2Si; 16
O
O
HN
O
X
O
N
O
O
X
O
iv
O
O
C9H19
Bn
O
78%
C9H19
10 (NuH)
OMe
Bn
i,ii
100%
X = PhMe2Si, 18
X = PhMe2Si; 17
X
O
X
O
O
O
iii
+
100%
RO
Nu
Nu
OR
X
O
O
v,ii
9
X = PhMe2Si, R = H; 11a
X = PhMe2Si, R = Bn; 11b
X = PhMe2Si, R = tBu; 11c
X = PhMe2Si, R = H; 12a
iii
83%
87%
iv
85%
H19C9
OMe
X = PhMe2Si, R = Bn; 12b
X = PhMe2Si, R = tBu; 12c
X = PhMe2Si; 8
Scheme 2 Reagents: i, n-BuLi, THF; ii, 4; iii, Et3N, Piv-Cl, then
BnOH, DMAP; iv, (COCl)2, DMF, then t-BuOH, DMAP.
Scheme 4 Reagents: i, Et3N, Piv-Cl; ii, C9H19MgBr; iii, 1,2-bis-
(trimethylsilyloxy)ethane, TMS-OTf; iv, MeOMgBr; v, (COCl)2, DMF.
butyl esters were separately subjected to oxazolidinone removal
conditions15c (Scheme 3) to provide the benzyl tert-butyl
to the attack of the methoxide ion on the wrong carbonyl of the
oxazolidinone. We could recover the oxazolidinone 10 in 78%
yield (>99% considering the wrong attack on the oxazolidi-
none). A better modus operandi subsequently employed for the
preparation of this methyl ester 18 was from the half-ester 9.
Thus, the latter was converted to its acid chloride and then
reacted with nonylmagnesium bromide at Ϫ78 ЊC to provide
the keto ester 8 (X = PhMe2Si; R = Me) in very good yield. This
was quantitatively protected17 as the acetal to give the same
intermediate 18. The overall yield of the acetal 18 from the
anhydride 4 (X = PhMe2Si) was considerably high (58%) and no
side products were detected.
11c
12c
i
92%
i
95%
X
X
O
O
O
O
OBn
OBn
tBuO
tBuO
X = PhMe2Si; 13
X = PhMe2Si; ent-13
iv,iii
ii,iii
95%
90%
As expected, alkylation of 18 with benzyl bromide took place
with high anti selectivity12 (93:7) to give 19 (Scheme 5) which
was found to be resistant to hydrazinolysis. Alternatively, the
methyl ester 19 was hydrolyzed and converted to a primary
amide 20 via the acid imidazolide in 77% yield. On treatment
with lead tetraacetate18 and benzyl alcohol, the expected benzyl-
oxycarbonyl protected amine 21 was isolated in good yield. The
rearrangement was smooth and probably facilitated by the
presence of the β-silyl group.13 The acetal protection was sub-
sequently removed to give the ketone 22. At this stage we could
easily separate the unwanted minor diastereoisomer by chrom-
atography. The ketone 22 was subjected to hydrogenolysis
where upon removal of the benzyloxycarbonyl group took
place. The generated amine group condensed intramolecularly
with the carbonyl group spontaneously to provide the ∆1-
pyrroline 5 (X = PhMe2Si) which was hydrogenated in situ with
hydrogens coming from the least hindered surface, i.e. away
from the silicon and benzyl groups to provide the pyrrolidine
derivative with all three substituents having cis stereochemistry.
Subsequently, the NH group was protected as ethoxycarbonyl
derivative 23 and the silyl group in the molecule was converted
to a hydroxy group11 and then to its acetate 24. The NMR
spectra of the products 23 and 24 were complex and could not
be fully interpreted as these are known to be mixtures of amide
isomers. Lithium aluminium hydride reduction of 24 provided
(ϩ)-preussin (1) in 77% yield. Since we started with the homo-
chiral half-ester 9, and the synthetic sequence does not involve
any epimerization, the enatiomeric purity of (ϩ)-preussin
should undoubtedly be very high (>99%). It was further con-
firmed from the specific rotation value ([α]D25 ϩ31.1, c 1, CHCl3)
measured for 1 and also, the spectral data which were in good
agreement with the reported values2 for synthetic (ϩ)-preussin.
The overall yield of (ϩ)-preussin from the homochiral methyl
ester 18 is 17.2%.
X
O
O
X
O
O
OMe
tBuO
OBn
MeO
X = PhMe2Si; 15
X = PhMe2Si; 14
ii
iv
89%
91%
X
O
O
OMe
HO
X = PhMe2Si; 9
Scheme 3 Reagents: i, Ti(OBn)4, BnOH; ii, H2, Pd/C; iii, CH2N2;
iv, PhOH, TMS-Cl.
diesters 13 and ent-13, respectively. The former on hydrogen-
olysis and esterification gave methyl ester 14, and the latter
under tert-butyl ester removal conditions with phenol–chloro-
trimethysilane16 followed by esterification yielded methyl ester
15. The ester 14 was now subjected to tert-butyl ester removal
conditions while 15 underwent hydrogenolysis to provide the
same half-ester 9 (X = PhMe2Si; R = Me). The overall yield of
9 from the anhydride 4 (X = PhMe2Si) was 68%. The oxazolidi-
none 10 was also isolated in almost quantitative yield without
any loss of optical purity.
As communicated earlier by us,14 the major acid 11a
(obtained from 11b) was converted to its mixed pivaloic
anhydride which in situ was treated with nonylmagnesium
bromide at Ϫ25 ЊC to provide the ketone 16 in 60% yield (92%
based on 35% recovery of 11a) (Scheme 4). The ketone was
quantitatively protected17 as acetal 17 and the oxazolidinone
was removed with methoxymagnesium bromide15c to give the
homochiral methyl ester 18 in 78% yield. During the process an
undesired product (about 22%) was also formed probably due
266
J. Chem. Soc., Perkin Trans. 1, 1999, 265–270

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ϩ1.2 (c 4.46, MeOH); νmax(film)/cmϪ1 1731, 1252, 1113; δH(200
MHz, CDCl3) 0.30 (6 H, s), 1.40 (9 H, s), 1.80–2.00 (1 H, m),
2.10–2.52 (4 H, m), 5.00 (2 H, s), 7.29–7.52 (10 H, m) (Found:
C, 69.7; H, 7.9. C24H32O4Si requires C, 69.9; H, 7.8%).
X
O
O
O
i, ii
iii–v
H19C9
18
OMe
77%
88%
Ph
(3R)-tert-Butyl methyl 3-[dimethyl(phenyl)silyl]pentane-1,5-
X = PhMe2Si; 19
dioate 14
A mixture of benzyl ester 13 (446 mg, 1.08 mmol) and Pd/C
(10% in Pd) (20 mg) in ethyl acetate (5 cm3) was stirred under a
hydrogen atmosphere for 15 h. The mixture was passed through
a Celite pad and the residue was washed thoroughly with ethyl
acetate. The filtrate was evaporated under reduced pressure and
the residue was esterified with ethereal diazomethane to give the
methyl ester 14 (370 mg, 95%); Rf(hexane–EtOAc; 95:5) 0.51;
[α]D23 ϩ1.0 (c 2.28, CHCl3); νmax(film)/cmϪ1 1731, 1252, 1112;
δH(200 MHz, CDCl3) 0.31 (6 H, s), 1.41 (9 H, s), 1.81–1.93 (1 H,
m), 2.10–2.51 (4 H, m), 3.56 (3 H, s), 7.32–7.52 (5 H, m)
(Found: C, 64.0; H, 8.6. C18H28O4Si requires C, 64.2; H, 8.4%).
X
O
X
H
N
O
O
O
O
19C9
vi
OBn
H
H
19C9
NH2
75%
O
Ph
Ph
X = PhMe2Si; 21
X = PhMe2Si; 20
X
H
N
O
viii, ix
75%
OBn
vii
100%
H19C9
O
Ph
(3S)-Methyl hydrogen 3-[dimethyl(phenyl)silyl]pentane-1,5-
dioate 9
X = PhMe2Si; 22
Chlorotrimethylsilane16 (1 molar solution in CH2Cl2, 2 cm3, 2
mmol) was added to a stirred solution of tert-butyl ester 14 (110
mg, 0.327 mmol), phenol (188 mg, 2 mmol) in CH2Cl2 (2 cm3)
at room temperature. After 24 h, solvent and phenol were
removed under high vacuum to give the acid 9 (83 mg, 91%);
[α]D21 ϩ1.3 (c 0.92, CHCl3); νmax(film)/cmϪ1 3400–2400 (br), 1733,
1712, 1260, 1112; δH(200 MHz, CDCl3) 0.33 (6 H, s), 1.79–1.93
(1 H, m), 2.17–2.52 (4 H, m), 3.57 (3 H, s), 7.34–7.52 (5 H, m);
δC(50 MHz, CDCl3) 178.6, 173.5, 136.7, 133.9, 129.3, 127.9,
51.2, 34.5, 18.8, Ϫ4.5 (Found: C, 59.7; H, 7.4. C14H20O4Si
requires C, 60.0; H, 7.2%).
SiMe2Ph
SiMe2Ph
H
19C9
5
H19C9
N
H
O
Ph
H2N
Ph
OAc
SiMe2Ph
Ph
x, xi
xii
77%
This compound was also prepared in 89% yield from 15
following the procedure described for the preparation of 14
without CH2N2 treatment.
1
H
19C9
H
19C9
N
N
68%
Ph
CO2Et
CO2Et
23
24
(3S)-Benzyl tert-butyl 3-[dimethyl(phenyl)silyl]pentane-1,5-
dioate ent-13
Scheme 5 Reagents: i, Li-TMP; ii, BnBr; iii, KOH; iv, Im2CO; v, NH3;
vi, Pb(OAc)4, BnOH; vii, TsOH, Me2CO–H2O; viii, H2, Pd/C; ix, EtO-
COCl, Et3N; x, KBr, AcOOH, NaOAc; xi, Ac2O, DMAP; xii, LiAlH4.
This compound was prepared in 95% yield from 12c following
the procedure described for the preparation of 13; [α]D24 Ϫ1.8 (c
2.88, MeOH); νmax(film)/cmϪ1 1731, 1252, 1112; δH(200 MHz,
CDCl3) 0.30 (6 H, s), 1.40 (9 H, s), 1.80–2.00 (1 H, m), 2.10–
2.55 (4 H, m), 5.00 (2 H, s), 7.29–7.52 (10 H, m).
Experimental
All mps are recorded with a Fisher-Johns apparatus. The H
1
NMR and 13C NMR spectra are recorded on a Bruker (model
AC200) 200 MHz or Varian (model VXR300) 300 MHz
instrument. 1H NMR chemical shifts (δ) are given in ppm
downfield from internal tetramethylsilane (δ = 0.00) or from
residual chloroform (δ = 7.26) and J (coupling constant) values
in Hz. The IR spectra are recorded on a Perkin-Elmer 783 spec-
trophotometer or Nicolet Impact 410 FT IR spectrometer.
Optical rotations are measured in a JASCO DIP polarimeter.
Mass spectra are recorded on a Shimadzu GCMS-QP 1000A
instrument. Air sensitive reactions were carried under Ar or N2
atmosphere. Solvents were freshly dried and distilled prior to
use. The preparations of 4, 11a–c and 12a–c, described in the
preceding paper,8 are not included in the experimental.
(3R)-Benzyl methyl 3-[dimethyl(phenyl)silyl]pentane-1,5-dioate
15
This compound was prepared in 90% yield from ent-13 follow-
ing the procedure described for the preparation of 9 from 14
followed by esterification with CH2N2; [α]D23 ϩ1.0 (c 0.8, CHCl3);
νmax(film)/cmϪ1 1737, 1252, 1113; δH(200 MHz, CDCl3) 0.31 (s,
6 H), 1.85–1.99 (1 H, m), 2.23–2.54 (4 H, m), 3.55 (3 H, s), 5.02
(2 H, s), 7.29–7.51 (10 H, m); δC(50 MHz, CDCl3) 173.4, 172.9,
136.9, 136.2, 134.0, 129.3, 128.5, 128.2, 128.1, 127.9, 66.3, 51.3,
34.8, 34.6, 19.0, Ϫ4.4 (Found: C, 68.0; H, 7.2. C21H26O4Si
requires C, 68.1; H, 7.1%).
(3S)-Methyl 3-[dimethyl(phenyl)silyl]-5-oxotetradecanoate 8
(3R)-Benzyl tert-butyl 3-[dimethyl(phenyl)silyl]pentane-1,5-
dioate 13
Oxalyl chloride (0.5 cm3, 5.2 mmol) was added to a stirred solu-
tion of acid 9 (370 mg, 1.32 mmol) and DMF (0.02 cm3) in
dichloromethane (4 cm3) at 0 ЊC. After 2 h at room temperature,
the solvent and excess oxalyl chloride were removed under
vacuum. The residue was dissolved in dry ether (5 cm3) and
nonylmagnesium bromide (0.5 M in ether) (3 cm3, 1.5 mmol)
was added to it at Ϫ78 ЊC under argon atmosphere. The reac-
tion mixture was slowly brought to room temperature (20 h).
The reaction mixture was diluted with ether, washed with water
and with brine, dried (Na2SO4) and evaporated under reduced
pressure. The residue was purified by chromatography (SiO2,
Titanium tetrakis(benzyl oxide)15c (0.375 M in benzyl alcohol)
(2.25 cm3, 0.85 mmol) was added to the ester 11c (272 mg,
0.585 mmol) and the mixture was heated at 75 ЊC for 24 h
under argon. Water (5 cm3) was added to the reaction mixture
with stirring and filtered through a pad of Celite. The filtrate
was evaporated under reduced pressure and then under high
vacuum to remove the benzyl alcohol. The residue was chrom-
atographed to give ester 13 (225 mg, 94%) and oxazolidinone 10
(92 mg, 92%). For ester 13: Rf(hexane–EtOAc; 95:5) 0.64; [α]D24
J. Chem. Soc., Perkin Trans. 1, 1999, 265–270
267

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hexane–EtOAc) to give ketone 8 (450 mg, 87%); Rf(hexane–
EtOAc; 98:2) 0.17; [α]D21 Ϫ0.8 (c 0.79, CHCl3); νmax(film)/cmϪ1
1738, 1715, 1250, 1112; δH(200 MHz, CDCl3) 0.30 (6 H, s), 0.87
(3 H, t, J 6.7), 1.20–1.24 (12 H, br), 1.41–1.50 (2 H, m), 1.88–
2.01 (1 H, m), 2.13–2.44 (6 H, m), 3.56 (3 H, s), 7.34–7.63 (5 H,
m); δC(50 MHz, CDCl3) 209.9, 173.7, 137.3, 134.0, 129.2, 127.9,
51.2, 42.9, 42.7, 34.7, 31.9, 29.4, 29.3, 23.9, 22.6, 17.7, 13.9,
Ϫ4.2, Ϫ4.4 (Found: C, 70.5; H, 10.0. C23H38O3Si requires C,
70.7; H, 9.8%).
(1 H, d, J 12), 2.40 (1 H, dd, J 6.6, 16), 2.55 (1 H, dd, J 5, 16),
3.54 (3 H, s), 3.79–3.90 (4 H, m), 7.31–7.38 (3 H, m), 7.49–7.52
(2 H, m) (Found: C, 68.9; H, 10.0. C25H42O4Si requires C, 69.1;
H, 9.7%).
This compound was also prepared in 100% yield from 8 fol-
lowing the procedure described for the preparation of acetal 17.
(2R,3S)-Methyl 3-[dimethyl(phenyl)silyl]-5,5-(ethylenedioxy)-2-
benzyltetradecanoate 19
Butyllithium (1.54 M in hexane) (4.3 cm3, 6.6 mmol) was added
to a stirred solution of 2,2,6,6-tetramethylpiperidine in THF
(18 cm3) at Ϫ78 ЊC under argon atmosphere. After 20 min at
0 ЊC, the reaction mixture was cooled to Ϫ78 ЊC and DMPU (9
cm3) was added followed by a solution of the acetal 18 (1.92 g,
4.41 mmol) in THF (25 cm3 THF). The reaction mixture was
stirred for 1 h and slowly allowed to attain Ϫ50 ЊC and stirred
for 10 min. Benzyl bromide (1.05 cm3, 8.82 mmol) was added to
this at Ϫ78 ЊC and stirred for 12 h. After further stirring at
Ϫ50 ЊC for 48 h, the reaction mixture was quenched with citric
acid solution and extracted with ether. The organic extract was
washed with water and with brine, dried (Na2SO4) and evapor-
ated under reduced pressure. The residue was chromatographed
to give the acetal 19 (2 g, 88%); Rf(hexane–EtOAc; 95:5) 0.46;
[α]D22 ϩ24.2 (c 1.36, EtOAc); νmax(film)/cmϪ1 1732, 1248, 1110;
δH(300 MHz, CDCl3) 0.38 (3 H, s), 0.45 (3 H, s), 0.89 (3 H, t,
J 7), 1.26 (16 H, br), 1.41–1.47 (1 H, m), 1.70 (1 H, dd, J 3.3,
15), 1.92 (1 H, dd, J 8, 15), 2.55 (1 H, dd, J 6, 13.8), 2.95 (1 H,
dd, J 9, 13.8), 3.18–3.25 (1 H, m), 3.51 (3 H, s), 3.67–3.85 (4 H,
m), 7.02–7.60 (10 H, m) (Found: C, 73.3; H, 9.4. C32H48O4Si
requires C, 73.2; H, 9.2%).
(3ЈS,4S)-3-{3-[Dimethyl(phenyl)silyl]-1,5-dioxotetradecyl}-4-
benzyloxazolidin-2-one 16
A solution of pivaloyl chloride (0.41 cm3, 3.3 mmol) in THF
(1 cm3) was added to a stirred solution of acid 11a (1.40 g, 3.29
mmol) and triethylamine (0.46 cm3, 3.3 mmol) in THF (17 cm3)
at Ϫ78 ЊC. The reaction mixture was stirred at 0 ЊC for 1 h and
cooled to Ϫ78 ЊC followed by an addition of nonyl magnesium
bromide (0.9 M in THF) (4.4 cm3, 4 mmol). The reaction mix-
ture was slowly allowed to attain to Ϫ25 ЊC and stirred for
48 h. The reaction mixture was diluted with water and extracted
with ethyl acetate. The organic extract was washed with water
and with brine, dried (Na2SO4) and evaporated under reduced
pressure. The residue was purified by chromatography (SiO2,
hexane–EtOAc) to give ketone 16 (1.04 g, 60%). Also, the start-
ing acid 11a (500 mg, 35%) was also recovered. For 16:
Rf(hexane–EtOAc; 90:10) 0.65; [α]D25 ϩ22.8 (c 1.2, CHCl3);
νmax(film)/cmϪ1 1784, 1701, 1249, 1112; δH(200 MHz,
CDCl3) 0.34 (6 H, s), 0.87 (3 H, t, J 6.7), 1.23 (12 H, br), 1.45
(2 H, t, J 6.6), 2.05–2.10 (1 H, m), 2.26–2.37 (3 H, m), 2.41–2.45
(2 H, m), 2.68 (1 H, dd, J 10, 14), 3.23 (1 H, dd, J 3.2, 14), 3.37
(1 H, dd, J 3.7, 14), 4.09 (1 H, dd, J 2.4, 8.8), 4.25 (1 H, t, J 8.5),
4.34–4.54 (1 H, m), 7.15–7.53 (10 H, m) (Found: C, 71.5; H, 8.7;
N, 2.6. C32H45O4NSi requires C, 71.7; H, 8.5; N, 2.6%).
(2R,3S)-3-[Dimethyl(phenyl)silyl]-5,5-(ethylenedioxy)-2-
benzyltetradecanamide 20
The methyl ester 19 (1.868 g, 3.56 mmol) was dissolved in
potassium hydroxide solution (2.5 M) in MeOH–THF–H2O
(3:5:2) and heated under reflux for 32 h. The solvent was
removed, the residue was acidified with citric acid solution and
extracted with ethyl acetate. The organic extract was washed
with water and with brine, dried (Na2SO4) and evaporated
under reduced pressure to give (2R,3S)-3-[dimethyl(phenyl)-
silyl]-5,5-(ethylenedioxy)-2-benzyltetradecanoic acid (1.8 g,
100%); νmax(film)/cmϪ1 3500–2400 (br), 1703, 1249, 1110; δH(300
MHz, CDCl3) 0.37 (3 H, s), 0.47 (3 H, s), 0.89 (3 H, t, J 7), 1.25
(15 H, br), 1.44–1.55 (2 H, m), 1.72 (1 H, dd, J 3.4, 15.3), 1.92 (1
H, dd, J 9.3, 15), 2.53 (1 H, dd, J 6.4, 14), 2.98 (1 H, dd, J 8.4,
13.7), 3.23 (1 H, m), 3.71–3.86 (5 H, m), 7.05–7.58 (10 H, m). A
solution of 1,1-carbonyldiimidazole (710 mg, 4.4 mmol) in
dichloromethane (5 cm3) was added to a stirred solution of the
above acid (1.477 g, 2.89 mmol) in dichloromethane (10 cm3)
under argon atmosphere. After 30 min at room temperature,
liquid ammonia (10 cm3) was introduced into the same flask
and the mixture was stirred until the ammonia evaporated.
The mixture was diluted with water and extracted with ethyl
acetate. The organic extract was washed with water and with
brine, dried (Na2SO4) and evaporated under reduced pressure.
The residue was chromatographed to give the amide 20 (1.13 g,
77%); Rf(hexane–EtOAc; 70:30) 0.5; [α]D22 ϩ20.5 (c 1.02,
EtOAc); νmax(film)/cmϪ1 3422, 3339, 3178, 1682, 1600, 1454,
1246, 1108; δH(300 MHz, CDCl3) 0.37 (3 H, s), 0.57 (3 H, s),
0.64–0.70 (1 H, m), 0.90 (3 H, t, J 7), 0.94–1.33 (16 H, br), 1.71–
1.74 (2 H, m), 2.61 (1 H, dd, J 5.5, 12), 2.97–3.12 (2 H, m), 3.78–
3.94 (4 H, m), 5.38 (1 H, br s), 6.12 (1 H, br s), 7.15–7.36 (8 H,
m), 7.55–7.58 (2 H, m) (Found: C, 72.8; H, 9.5; N, 2.6.
C31H47O3NSi requires C, 73.0; H, 9.3; N, 2.7%).
(3ЈS,4S)-3-{3-[Dimethyl(phenyl)silyl]-5,5-(ethylenedioxy)-1-
oxotetradecyl}-4-benzyloxazolidin-2-one 17
Trimethylsilyl trifluoromethanesulfonate17 (0.03 cm3, 0.155
mmol) was added to a stirred solution of ketone 16 (3.85 g, 7.2
mmol) and 1,2-bis(trimethylsilyloxy)ethane (7 cm3, 29 mmol)
in dry dichloromethane (7 cm3) at Ϫ78 ЊC under argon atmos-
phere. The reaction mixture was stirred at Ϫ20 ЊC for 48 h,
quenched with sodium bicarbonate solution and extracted with
ether. The organic extract was washed with water and with
brine, dried (Na2SO4) and evaporated under reduced pressure
to give the acetal 17 (4.1 g, 100%); Rf(hexane–EtOAc; 95:5)
0.43; [α]D28 ϩ43.8 (c 1.74, EtOAc); νmax(film)/cmϪ1 1782, 1698,
1250, 1110; δH(300 MHz, CDCl3) 0.32 (3 H, s), 0.33 (3 H, s),
0.88 (3 H, t, J 7), 1.23 (15 H, br), 1.58–1.63 (2 H, m), 1.76–1.82
(1 H, dd, J 2.5, 15), 1.84–1.89 (1 H, m), 2.60 (1 H, dd, J 10, 14),
3.09 (2 H, dd, J 1.1, 6), 3.27 (1 H, dd, J 3, 13), 3.82–3.90 (4 H,
m), 3.99–4.07 (2 H, m), 4.32–4.40 (1 H, m), 7.17–7.31 (2 H, m),
7.32–7.36 (6 H, m), 7.51–7.55 (2 H, m) (Found: C, 70.4; H, 8.6;
N, 2.2. C34H49O5NSi requires C, 70.4; H, 8.5; N, 2.4%).
(3S)-Methyl 3-[dimethyl(phenyl)silyl]-5,5-(ethylenedioxy)tetra-
decanoate 18
Ethylmagnesium bromide15c (2.5 M in ether) (1.38 cm3, 3.45
mmol) was added to methanol (25 cm3) at 0 ЊC. After attaining
room temperature, a solution of the oxazolidinone 17 (1 g, 1.72
mmol) in methanol (3 cm3) was added to it and the reaction
mixture was stirred for 15 h. The solvent was evaporated and
the residue was diluted with benzene. The reaction mixture was
washed with water and with brine, dried (Na2SO4) and evapor-
ated under reduced pressure. The residue was chromatographed
to give the acetal 18 (590 mg, 78%); Rf(hexane–EtOAc; 70:30)
0.25; [α]D23 Ϫ2.1 (c 2.04, EtOAc); νmax(film)/cmϪ1 1737, 1698,
1249, 1112; δH(300 MHz, CDCl3) 0.28 (3 H, s), 0.29 (3 H, s),
0.88 (3 H, t, J 6.4), 1.22–1.25 (14 H, m), 1.49–1.59 (4 H, m), 1.75
(2R,3S)-3-[Dimethyl(phenyl)silyl]-5,5-(ethylenedioxy)-1-phenyl-
2-(benzyloxycarbonylamino)tetradecane 21
Lead tetraacetate18 (5 g, 11.5 mmol) was added to a stirred
268
J. Chem. Soc., Perkin Trans. 1, 1999, 265–270

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solution of amide 20 (1.13 g, 2.22 mmol) and benzyl alcohol
(2.3 cm3, 22.2 mmol) in DMF (20 cm3) at 40 ЊC under argon
atmosphere. After 15 h at 100 ЊC, the reaction mixture was
passed through a silica gel pad and eluted with ether. The sol-
vent was evaporated under reduced pressure and the excess
DMF was removed under high vacuum. The residue was
chromatographed to give the urethane 21 (930 mg, 75%);
Rf(hexane–EtOAc; 90:10) 0.6; [α]D24 Ϫ7.4 (c 1, EtOAc);
νmax(film)/cmϪ1 3381, 1721, 1504, 1249, 1110; δH(300 MHz,
CDCl3) 0.44 (6 H, s), 0.89 (3 H, t, J 6.6), 0.94–1.08 (1 H, m),
1.15–1.31 (14 H, br), 1.44–1.54 (2 H, m), 1.75–1.85 (2 H, m),
2.48–2.61 (2 H, m), 3.84–3.98 (4 H, m), 4.26–4.34 (1 H, m), 4.95
(2 H, AB quartet, J 12.6), 5.98 (1 H, d, J 10), 6.93–7.60 (15 H,
m) (Found: C, 73.9; H, 8.9; N, 2.6. C38H53O4NSi requires C,
74.1; H, 8.7; N, 2.3%).
1 day at room temperature and evaporated under vacuum. The
residue was diluted with water and extracted with ethyl acetate.
The organic extract was washed with water and with brine,
dried (Na2SO4) and evaporated under reduced pressure. The
residue was dissolved in Et3N (1 cm3) and acetic anhydride (0.5
cm3, 5.25 mmol) was added followed by a catalytic amount of
DMAP. After 1 day at room temperature, water was added,
stirred for 0.5 h and extracted with ether. The organic extract
was washed with water and with brine, dried (Na2SO4) and
evaporated under reduced pressure. The residue was chromato-
graphed to give the acetate 24 (78 mg, 68%); Rf(EtOAc-hexane;
10:90) 0.58; [α]D23 Ϫ48.2 (c 0.66, CHCl3); νmax(film)/cmϪ1 1744,
1703, 1698, 1234; δH(300 MHz, at 70Њ C in C6D6) 0.82–1.02
(6 H, m), 1.20–1.40 (16 H, m), 1.50–1.80 (1 H, m), 1.58, 1.60
and 1.65 (3 H, three singlets overlapping with preceding multi-
plet), 1.96–2.40 (2 H, m), 2.70–3.32 (2 H, m), 3.62–4.10 (3 H,
m), 4.28–4.38 (1 H, m from one isomer), 4.44–4.52 (1 H, m,
from one isomer), 4.68–4.78 (1 H, m, from one isomer), 4.90–
5.00 (1 H, m, from one isomer), 5.00–5.07 (1 H, m, from one
isomer), 6.85–7.50 (5 H, m); m/z (EI) 341 (1.9%), 326 (100), 284
(15.7) (Found: C, 71.7; H, 9.5; N, 3.2. C25H39O4N requires C,
71.9; H, 9.4; N, 3.4%).
(2R,3S)-3-[Dimethyl(phenyl)silyl]-1-phenyl-2-(benzyloxy-
carbonylamino)tetradecan-5-one 22
A solution of acetal 21 (924 mg, 1.62 mmol) and toluene-4-
sulfonic acid (100 mg, 0.6 mmol) in acetone–water (98:2) (70
cm3) was heated under reflux for 2.5 h. The acetone was
removed and the residue was dissolved in ethyl acetate. The
solution was washed with sodium bicarbonate solution and
with brine, dried (Na2SO4) and evaporated under reduced
pressure to give the ketone 22 (816 mg, 100%); Rf(hexane–
EtOAc; 90:10) 0.37; [α]D22 Ϫ22.2 (c 1.2, CHCl3); νmax(film)/cmϪ1
3348, 1712, 1251, 1111; δH(300 MHz, CDCl3) 0.36 (3 H, s),
0.38 (3 H, s), 0.87 (3 H, t, J 6.4), 1.24–1.29 (12 H, br), 1.46
(2 H, br t), 1.96–2.08 (1 H, m), 2.27–2.35 (2 H, m), 2.37–2.41
(1 H, m), 2.46 (1 H, dd, J 4.5, 17), 2.59–2.75 (2 H, m), 4.05 (1 H,
br s), 4.36 (1 H, d, J 8), 4.91 (2 H, s), 6.93–7.53 (15 H, m)
(Found: C, 75.5; H, 8.7; N, 2.2. C36H49O3SiN requires C,
75.6; H, 8.6; N, 2.5%).
(2S,3S,5R)-1-Methyl-5-nonyl-2-benzylpyrrolidin-3-ol 1
A solution of the acetate 24 (125 mg, 0.29 mmol) in THF (3
cm3) was added to a stirred suspension of LiAlH4 (100 mg,
2.5 mmol) in THF (3 cm3) and the mixture was stirred at
room temp. for 24 h. The reaction was decomposed with a
saturated solution of sodium sulfate in water and triturated
with ethyl acetate. The solvent was removed to give 1 (74
mg, 77%); Rf(hexane–EtOAc; 90:10) 0.32; [α]D25 31.1 (c 1,
CHCl3); lit.,2 [α]D25 31.08 (c 1, CHCl3); νmax(film)/cmϪ1 3406;
δH(300 MHz, CDCl3) 0.88 (3 H, t, J 6.9), 1.20–1.46 (16 H,
m), 1.65–1.80 (1 H, m), 2.00–2.33 (4 H, m), 2.34 (3 H, s),
2.80–2.94 (2 H, AB multiplet), 3.80–3.83 (1 H, m), 7.16–7.32
(5 H, m); 13C NMR δC(50 MHz, CDCl3) 139.5, 129.3, 128.3,
125.9, 73.6, 70.3, 65.8, 39.4, 38.5, 34.7, 33.6, 31.8, 29.6, 29.2,
26.2, 22.6, 13.9.
(2S,3S,5R)-3-[Dimethyl(phenyl)silyl]-1-ethoxycarbonyl-2-
benzyl-5-nonylpyrrolidine 23
A solution of the ketone 22 (800 mg, 1.4 mmol) in ethanol (285
cm3) and acetic acid (15 cm3) was hydrogenated in a Parr appar-
atus (53 psi) in the presence of Pd/C (10% Pd) (200 mg) over 7
h. The reaction mixture was passed through a Celite pad and
washed with ethanol. The solvent was removed under reduced
pressure and the residue was dissolved in CH2Cl2 followed by
addition of ethyl chloroformate (0.27 cm3, 2.8 mmol) and tri-
ethylamine (0.42 cm3, 3 mmol). After 18 h at room temperature,
the reaction mixture was diluted with benzene, washed with
water and with brine, dried (Na2SO4) and evaporated under
reduced pressure to give the pyrrolidine 23 as a mixture (about
2:1) of geometrical and/ or atropisomers (518 mg, 75%);
Rf(EtOAc–hexane; 2:98) 0.2; [α]D22 Ϫ85.9 (c 0.61, CHCl3);
νmax(film)/cmϪ1 1694, 1252, 1112; δH(300 MHz, CDCl3) 0.41
(6 H, s, from major), 0.45 (6 H, s, from minor), 0.67 (3 H, t, J 7
major), 0.89 (3 H, t, J 6.8), 1.20–1.40 (16 H, m), 1.57–1.78 (1 H,
m, in addition to that an overlapped triplet from minor
accounting for 3 H), 2.25–2.44 (3 H, m), 2.68 (1 H, br d, J 11),
3.30–3.38 (1 H, m), 3.56–3.70 (2 H, m, from major), 3.82–3.92
(2 H, m, from minor), 4.18–4.24 (1 H, m, from major), 4.39–
4.52 (1 H, m, from minor), 6.95–7.21 (5 H, m), 7.35–7.57 (5
References
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H, m); m/z (EI) 493 (M ϩ, 0.9%), 403 (M ϩ H Ϫ Bn, 100), 402
᝽
(M ϩ H Ϫ Bn, 71.4), 340 (5.6), 326 (19.2), 135 (Me2PhSi, 41.8),
91 (Bn, 14.5) (Found: C, 75.3; H, 9.9; N, 2.6. C31H47O2NSi
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(2S,3S,5R)-3-Acetoxy-1-ethoxycarbonyl-2-benzyl-5-
nonylpyrrolidine 24
Peracetic acid11 (about 30% solution in acetic acid) (4 cm3) was
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mmol), potassium bromide (45 mg, 0.38 mmol) and sodium
acetate (200 mg) at 0 ЊC. The reaction mixture was stirred for
12 R. A. N. C. Crump, I. Fleming, J. H. M. Hill, D. Parker, N. L. Reddy
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J. Chem. Soc., Perkin Trans. 1, 1999, 265–270
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Paper 8/08840C
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J. Chem. Soc., Perkin Trans. 1, 1999, 265–270