Preparation of (2,2-Dimethylhexahydrofuro[2,3-c]pyrrol-6-yl)methanol: A Conformationally Restricted Congener of Nonproteinogenic 3-Hydroxy-4- methylproline

Article abstract of DOI:10.1055/s-2003-42426

Lactam 6 derived from (S)-pyroglutaminol was converted to a conformationally restricted congener of nonproteinogenic 3-hydroxy-4- methylproline. Preparation of precursor Sb was achieved via a diastereoselective epoxidation followed by a regioselective opening of the oxirane ring. Iodine-mediated cyclization was used to assemble the ether moiety of 2.

Full text of DOI:10.1055/s-2003-42426

PAPER
2643
Preparation of (2,2-Dimethylhexahydrofuro[2,3-c]pyrrol-6-yl)methanol:
A Conformationally Restricted Congener of Nonproteinogenic 3-Hydroxy-
4-methylproline
Preparation of
(
d
2,2-Dimethy
w
lhexahydrofuro[2,
i
3-
c
]pyr
n
rol-6-yl)methanolJao,* Stephane Bogen,* Anil K. Saksena, Viyyoor Girijavallabhan
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
Fax +1(908)7404642; E-mail: Stephane.bogen@spcorp.com
Received 14 July 2003; revised 14 August 2003
Abstract: Lactam 6 derived from (S)-pyroglutaminol was convert-
ed to a conformationally restricted congener of nonproteinogenic 3-
O
OH
hydroxy-4-methylproline. Preparation of precursor 5b was
O
achieved via a diastereoselective epoxidation followed by a regiose-
lective opening of the oxirane ring. Iodine-mediated cyclization was
used to assemble the ether moiety of 2.
O
N
H
N
N
OH
O
O
Ph
Ph
2
5b
6
Key words: nonpeptidic, conformationally rigid, prolinol
Scheme 1
Because of their unique conformational properties, substi-
tuted prolines are frequently used to modify the backbone
geometry and side-chain orientations of peptidic mole-
cules.1 In addition to backbone conformation, these non-
proteinogenic amino acids are also incorporated into
peptidic molecules in an attempt to improve their pharma-
cological profiles.2
For the synthesis of 3-hydroxy-4-methylproline (1), Lan-
glois used a two-step sequence to introduce the cis-methyl
substituent.4 First, a completely diastereoselective alkyla-
tion of -hydroxylactam 3 delivered the trans-methyl in-
termediate 4a. Then, partial inversion to 4b was realized
by sequential deprotonation with LDA and reprotonation
with pivalic acid. With the aim to synthesize the cyclic
ether core of 2, a similar route was investigated to incor-
porate the unsaturated moiety in 5b required for our key
cyclization (Scheme 2). Intermediate 5a was obtained in
20% yield by alkylation of lactam 3 with 3-bromo-2-me-
thylpropene but every attempt to establish desired config-
uration at C-4 was unsuccessful.
3-Hydroxy-4-methylproline (1), a common constituent of
several antifungal cyclopeptides, has been a popular target
for synthetic chemists in the last decade.3,4 In the course
of our chemistry program, we needed to prepare and in-
corporate into a peptidic molecule the novel amino alco-
hol 2 (Figure 1), a conformationally restricted congener of
3-hydroxy-4-methylproline (1), to elucidate structure-ac-
tivity relationships.
OH
1. LDA/THF-HMPA, R-X
O
N
2. LDA/THF-HMPA, H+
O
OH
O
3
Ph
R
R
OH
O
O
OH
O
N
H
N
H
4
4
OH
OH
O
O
N
+
N
1
2
Ph
Ph
Figure 1 Structures of compounds 1 and 2
4a: R= Me
5a: R=
4b: R=Me
5b: R=
As outlined in the retrosynthesis of 2 (Scheme 1), the
preparation of the cyclic ether moiety was anticipated to
proceed via cyclization of the hydoxyl of 5b onto the ad-
jacent methylpropene chain. Lactam 6,5 readily available
from (S)-pyroglutaminol [(S)-5-(hydroxymethyl)-2-pyr-
rolidinone], was chosen as the starting material.
Scheme 2
Therefore, our initial approach was revised to investigate
the preparation of 5b via epoxide 9. It was anticipated that
regioselective SmI2-promoted reduction6 of the epoxide
could lead to a 1:1 ratio of distereomers 5a and 5b. As
shown in Scheme 3, lactam 6 was alkylated with 3-bro-
mo-2-methylpropene to obtain 7 in 67% yield.5 Stereo-
selectivity at C-4 was not an issue at this stage. Both
SYNTHESIS 2003, No. 17, pp 2643–2646
x
x.
x
x
.
2
0
0
3
Advanced online publication: 14.10.2003
DOI: 10.1055/s-2003-42426; Art ID: M03103SS
© Georg Thieme Verlag Stuttgart · New York

2644
E. Jao et al.
PAPER
epimers of 7 were deprotonated by LiN(TMS)2 to intro- give the protected amino alcohol 11 in 30% overall
duce the conjugated double bond in 59% yield by classical yield.11 N-Deprotection of 11 under classical hydrogena-
phenylselenation, followed by selenoxide elimination tion conditions (Pd/C, AcOH, 55 psi) followed by treat-
with hydrogen peroxide. The pyrrolidone 8 was then con- ment with 4 N HCl in dioxane gave the desired HCl salt
verted in high yield and in complete diastereoselectivity to of amino alcohol 2 in 95% yield.
the desired epoxide 9.7,8
In summary, we have described the preparation of a novel
amino alcohol 1 from lactam 6, which in turn is derived
from (S)-pyroglutaminol. Regioselective cleavage of ep-
oxide 9 with SmI2 was used as an efficient way to intro-
LiN(TMS)2, THF
duce diastereoselectively the unsaturated chain for iodine-
4
O
N
promoted cyclization. The conformationally restricted
amino alcohol has been incorporated into peptidic mole-
cules in our medicinal chemistry program. The structure-
activity relationships and the effects on the overall profile
of the molecules will be described later.
O
N
O
Br
O
Ph
6
67%
Ph
7 (trans/cis: 2/1)
O
t-BuOOH
1. LiN(TMS)2
Triton B
THF
2. PhSeCl
3. H2O2
59%
O
Anhydrous solvents were purchased from Aldrich or Acros and
used without further purification. Other solvents or reagents were
purchased from commercial suppliers and used as acquired. Analyt-
ical TLC was performed on pre-coated silica gel plates available
from Analtech. Flash chromatography was performed using HPFC
N
O
N
O
O
8
9
Ph
92%
Ph
SmI2, THF/ MeOH
-78 °C
5a (14%) / 5b (14%)
5a (10%) / 5b (44%)
9
1
Biotage with cartridges preloaded with silica. H and 13C NMR
spectra were recorded at either 300 or 400 or 500 MHz in CDCl3
(unless otherwise indicated) and internally referenced to residual
CHCl3.
1. SmI2, THF/ i-PrOH
9
2. MeOH, -78 °C
Scheme 3
(3R,7aS)-6-(2-Methylallyl)-3-phenyltetrahydropyrrolo[1,2-
c]oxazol-5-one (7)
To a –78 °C solution of LiN(TMS)2 (365 mmol, 365 mL of 1 M so-
lution in THF) was slowly added lactam 6 (331 mmol, 67.27 g) in
THF (100 mL). The stirring was continued for 1 h at –78 °C, then
3-bromo-2-methylpropene (331 mmol, 46 g) was added rapidly. Af-
ter stirring for an additional 2 h at the same temperature, the reaction
was quenched with AcOH (20 mL). The mixture was partitioned be-
tween EtOAc (1 L) and H2O (500 mL). The organic layer was sep-
arated, washed successively with aq sat. NaHCO3 (2 × 250 mL) and
brine (250 mL), dried (Na2SO4), and concentrated to dryness. The
residue was loaded on a Biotage 75+L (silica) cartridge and chro-
matographed with (5–10% EtOAc–hexane) to provide 57 g of 7
(67%) as a 2:1 mixture of trans/cis-isomers.
The initial attempt to open epoxide 9 following Molan-
der’s procedure6 was successful and delivered a 1:1 mix-
ture of 5a/5b in 28% yield.9,10 Encouraged by this initial
result, other conditions aimed at improving the yield of
this sequence were investigated. An interesting finding
was made when i-PrOH was used as a co-solvent which in
addition to an improved yield (54%) provided a change in
the diastereomeric distribution in favor of 5b (de 63%).
I
O
trans-Isomer
I2, NaHCO3
LAH, THF
5-b
[ ]D +218.3 (c = 0.7, CHCl3).
Et2O / H2O
86%
O
0 °C to reflux
30%
N
1H NMR (CDCl3, 500 MHz): = 7.51–7.31 (m, 5 H), 6.39 (s, 1 H),
4.85 (s, 1 H), 4.78 (s, 1 H), 4.31–4.29 (m, 1 H), 4.15 (quint, J = 6.5
Hz, 1 H), 3.59–3.56 (m, 1 H), 3.16–3.09 (m, 1 H), 2.79 (dd,
J = 14.9, 3.2 Hz, 1 H), 2.61–2.56 (m, 1 H), 2.08 (dd, J = 14.9, 10.4
Hz, 1 H), 1.79 (s, 3 H), 1.62–1.58 (m, 2 H).
13C NMR (CDCl3, 125 MHz): = 178.2, 142.9, 138.6, 128.5, 128.4
(2 C), 126.0 (2 C), 112.0, 86.9, 72.5, 56.7, 43.3, 39.2, 32.2, 22.2.
O
10
Ph
O
1. H2, Pd/C, AcOH
2
HCl
2. 4 N HCl / dioxane
95%
N
HO
Ph
11
HMRS: m/z calcd for C16H20NO2 (M + H): 258.1494; found:
258.1495.
Scheme 4
cis-Isomer
[ ]D +126.3 (c = 0.9, CHCl3).
Acid-catalyzed ring closure failed owing to the lability of
the N,O-benzylidene acetal. However, treatment of 5b
with excess iodine under buffered conditions resulted in a
smooth cyclization that led to diastereomers 10 in 86%
yield (Scheme 4). Dehalogenation, reduction of the lac-
tam and N,O-benzylidene deprotection were accom-
plished in one-pot with excess LiAlH4 in refluxing THF to
1H NMR (CDCl3, 500 MHz): = 7.51–7.32 (m, 5 H), 6.39 (s, 1 H),
4.89 (s, 1 H), 4.80 (s, 1 H), 4.29 (dd, J = 8, 6.5 Hz, 1 H), 4.16–4.13
(m, 1 H), 3.51–3.47 (m, 1 H), 2.94–2.88 (m, 1 H), 2.69 (dd, J = 14.0,
3.5 Hz, 1 H), 2.29 (dd, J = 14.0, 10.5 Hz, 1 H), 2.19–2.09 (m, 3 H),
1.80 (s, 3 H).
13C NMR (CDCl3, 125 MHz): = 181.2, 143.0, 139.4, 128.9 (3 C),
126.3 (2 C), 113.1, 87.8, 71.7, 57.6, 43.5, 41.0, 27.8, 22.4.
Synthesis 2003, No. 17, 2643–2646 © Thieme Stuttgart · New York

PAPER
Preparation of (2,2-Dimethylhexahydrofuro[2,3-c]pyrrol-6-yl)methanol
2645
HMRS: m/z calcd for C16H20NO2 (M + H): 258.1494; found:
Et2O (50 mL) and H2O (50 mL). The solid was removed by filtra-
258.1493.
tion. The organic layer of the filtrate was separated, washed succes-
sively with aq sat. NaHCO3 (50 mL) and brine (50 mL), dried
(Na2SO4), and concentrated to dryness. The residue was directly
loaded on a Biotage 25+M (silica) cartridge and chromatographed
with (10–25% EtOAc–hexane) to provide 0.1 g of 5a (11%) and
0.44 g of 5b (44%).
(3R,7aS)-6-(2-Methylallyl)-3-phenyl-1,7a-dihydropyrrolo[1,2-
c]oxazol-5-one (8)
To a –78 °C solution of LiN(TMS)2 (112 mmol, 112 mL of 1 M so-
lution in THF ) was slowly added 7 (93 mmol, 24 g) in THF (100
mL). The stirring was continued for 2 h at –78 °C when phenylsele-
nenyl chloride (103 mmol, 19.67 g) in THF (50 mL) was added at
once. After stirring for an additional 2 h at the same temperature, the
reaction was quenched with AcOH (20 mL). The mixture was par-
titioned between EtOAc and H2O. The organic layer was separated,
washed successively with aq sat. NaHCO3 and brine, dried
(Na2SO4) and concentrated to dryness. To a solution of the above
crude product in CH2Cl2 (500 mL) and pyridine (25 mL) was care-
fully added H2O2 (120 mL, 30% in H2O) at 0 °C. After stirring for
1 h at the same temperature the reaction was quenched with aq 10%
Na2S2O3 (100 mL). After stirring for 20 min, the mixture was parti-
tioned between EtOAc (1 L) and H2O (500 mL). The organic layer
was separated, washed successively with aq sat. NaHCO3 (250 mL)
and brine (250 mL), dried (Na2SO4) and concentrated to dryness.
The residue was loaded on a Biotage 75+M (silica) cartridge and
and chromatographed with (8% EtOAc–hexane) to provide 14.37 g
of 8 (59%) as an oil; [ ]D +225.4 (c = 0.41, CHCl3).
5a
[ ]D +141.8 (c = 0.5, CHCl3).
1H NMR (CDCl3, 500 MHz): = 7.44–7.27 (m, 5 H), 6.39 (s, 1 H),
4.92 (s, 1 H), 4.88 (s, 1 H), 4.21 (dd, J = 9.0, 6.5 Hz, 1 H), 4.08–
4.05 (m, 1 H), 3.97–3.93 (m, 1 H), 3.82 (dd, J = 9.0, 5.5 Hz, 1 H),
3.05 (ddd, J = 11.0, 9.0, 4.0 Hz, 1 H), 2.73 (dd, J = 14.0, 4.0 Hz, 1
H), 2.19 (dd, J = 14.0, 11.0 Hz, 1H), 1.84 (s, 3 H).
13C NMR (CDCl3, 125 MHz): = 176.5, 144.8, 138.2, 129.1, 128.9
(2 C), 126.5 (2 C), 113.4, 87.7, 80.3, 70.3, 63.9, 50.9, 38.0, 22.5.
HMRS: m/z calcd for C16H20NO3 (M + H): 274.1443; found:
274.1431.
5b
[ ]D +126.5 (c = 0.38, CHCl3).
1H NMR (CDCl3, 500 MHz): = 7.43–7.27 (m, 5 H), 6.39 (s, 1 H),
4.91 (s, 1 H), 4.89 (s, 1 H), 4.51–4.48 (m, 1 H), 4.26 (dd, J = 8.0,
7.0 Hz, 1 H), 4.01–3.97 (m, 1 H), 3.58 (t, J = 8.0 Hz, 1 H), 3.04–
2.99 (m, 1 H), 2.62–2.60 (m, 2 H), 2.25 (d, J = 4.0 Hz, OH), 1.85 (s,
3 H).
1H NMR (CDCl3, 500MHz): = 7.60–7.31 (m, 5 H), 6.94 (d, J = 1.5
Hz, 1 H), 6.24 (s, 1 H), 4.93 (s, 1 H), 4.86 (s, 1 H), 4.59–4.56 (m, 1
H), 4.32 (dd, J = 15.0, 7.0 Hz, 1 H), 3.42 (t, J = 8.5 Hz, 1 H), 3.10–
3.02 (m, 2 H), 1.82 (s, 3 H).
13C NMR (CDCl3, 125 MHz): = 177.4, 142.1, 141.3, 140.4, 139.2,
129.0, 128.9 (2 C), 126.7 (2 C), 113.4, 87.9, 69.2, 63.4, 34.2, 22.8.
13C NMR (CDCl3, 125 MHz): = 179.4, 144.4, 138.2, 128.6, 128.4
(2 C), 125.9 (2 C), 111.6, 87.8, 70.5, 68.3, 65.3, 47.9, 33.7, 22.6.
HMRS: m/z calcd for C16H18NO2 (M + H): 256.1338; found:
256.1340.
HMRS: m/z calcd for C16H20NO3 (M + H): 274.1443; found:
274.1445.
(1R,4R,4aR,5aR)-5a-(2-Methylallyl)-4-phenyltetrahydro-1,3-
dioxa-4a-azacyclopropa[a]pentalen-5-one (9)
(1R,3aR,3bS,6aR)-5-Iodomethyl-5-methyl-1-phenylhexahydro-
2,4-dioxa-7a-azacyclopenta[a]pentalen-7-one (10)
To a 4 °C solution of 8 (48.23 mmol, 12.3 g) in THF (200 mL) was
slowly added tert-butyl peroxide (241 mmol, 43.8 mL of 5.5 M so-
lution in toluene), followed by Triton B (4.82 mmol, 2.19 mL of a
40% solution in MeOH). The stirring was continued for 3 h at 0 °C,
and then overnight at 10 °C. The reaction was quenched with aq sat.
NH4Cl (300 mL). The mixture was partitioned between EtOAc (500
mL) and H2O (200 mL). The organic layer was separated, washed
successively with aq sat. NaHCO3 (250 mL) and brine (250 mL),
dried (Na2SO4), and concentrated to dryness. The residue was load-
ed on a Biotage 75+M (Silica) cartridge and chromatographed with
(5–10% EtOAc–hexane) to provide 12.1 g of 9 (92%) as a white sol-
id; [ ]D +211.2 (c = 0.5, CHCl3).
1H NMR (CDCl3, 500MHz): = 7.41–7.32 (m, 5 H), 6.35 (s, 1 H),
4.92 (s, 1 H), 4.82 (s, 1 H), 4.20–4.15 (m, 2 H), 3.93 (s, 1 H, H3)
2.90 (d, J = 5.5 Hz, 1 H, H6), 2.62 (d, J = 5.5 Hz, 1H, H6), 1.81 (s,
3 H).
13C NMR (CDCl3, 125 MHz): = 175.3, 139.6, 138.1, 128.6, 128.5
(2 C), 125.9 (2 C), 114.3, 88.1, 65.7, 62.0, 61.1, 58.6, 33.1, 23.6.
I2 (13.2 mmol, 3.36 g) was added to a mixture of 5b (10.98 mmol,
3 g) and NaHCO3 (21.96 mmo1, 0.845 g) in Et2O (600 mL) and H2O
(120 mL) at 0 °C. The reaction mixture was stirred for 4 h, and then
quenched with aq 10% Na2S2O3 (90 mL). The organic layer was
separated, washed with brine (100 mL), dried (Na2SO4), and con-
centrated to dryness. The residue was rapidly filtered through a plug
of silica to provide 3.78 g of 10, which was used without further pu-
rification for the preparation of 11.
(3aR,6aS,6R)-(5-Benzyl-2,2-dimethylhexahydrofuro[2,3-c]pyr-
rol-6-yl)methanol (11)
To a 0 °C solution of 10 (5.76 mmol, 2.3 g) in THF (50 mL) was
slowly added LiAH4 (34.56 mmol, 1.3 g). After addition, the reac-
tion mixture was warmed up to r.t., and refluxed for 8 h. Upon cool-
ing down to r.t., the reaction mixtutre was worked up following the
procedure described by Micovic.12 The solid was removed by filtra-
tion and washed with THF. The combined filtrate was dried
(Na2SO4), and concentrated to dryness. The residue was chromato-
graphed on silica gel (15–60% EtOAc–hexane) to provide 0.46 g of
11 (30%) as a white solid; [ ]D –54.25 (c = 0.59, CHCl3).
HMRS: m/z calcd for C16H17NO3 (M + H): 272.1287; found:
272.1288.
1H NMR (CDCl3, 500 MHz): = 7.33–7.30 (m, 5 H), 4.49 (dd,
J = 7.0, 2.9 Hz, 1 H), 3.96 (d, J = 13 Hz, 1 H), 3.69 (br s, 2 H), 3.43
(d, J = 13 Hz, 1 H), 3.17 (t, J = 9.0 Hz, 1 H), 2.82 (br s, 1 H), 2.74–
2.66 (m, 1 H), 2.29 (t, J = 9.0 Hz, 1 H), 1.90 (dd, J = 12.7, 8.7 Hz,
1 H), 1.52 (dd, J = 12.7, 4.0 Hz, 1 H), 1.38 (s, 3 H), 1.20 (s, 3 H).
13C NMR (CDCl3, 125 MHz): = 139.3, 129.1 (2 C), 128.8 (2 C),
127.6, 86.4, 84.5, 71.5, 61.1, 60.7, 58.4, 43.3 (2 C), 29.9, 28.0.
(3R,6S,7aR,7S)-7-Hydroxy-6-(2-methylallyl)-3-phenyltetrahy-
dropyrrolo[1,2-c]oxazol-5-one (5a) and (3R,6R,7aR,7S)-7-Hy-
droxy-6-(2-methylallyl)-3-phenyltetrahydropyrrolo[1,2-
c]oxazol-5-one (5b)
To a –78 °C solution of SmI2 (10 mmol, 100 mL of 0.1% solution
in THF plus 1 mL of i-PrOH) was added epoxide 9 (3.68 mmol, 1
g) in THF (4 mL). After 1 h, MeOH (2 mL) was added and the stir-
ring was continued for an additional 45 min. The reaction mixture
was quenched with aq 20% K2CO3 (10 mL) and partitioned between
HMRS: m/z calcd for C13H24N3O2 (M + H): 262.1807; found:
262.1807.
Synthesis 2003, No. 17, 2643–2646 © Thieme Stuttgart · New York

2646
E. Jao et al.
PAPER
(3aR,6aS,6R)-(2,2-Dimethylhexahydrofuro[2,3-c]pyrrol-6-
yl)methanol (2)
epoxidation was confirmed by J(H2/H3)= ca. 0 Hz. NOE
between H-3 and H-6 was detected (Figure 2).
Compound 11 (1.57 mmol, 0.41 g) was hydrogenated with 10% Pd/
C (0.5 g) as catalyst in AcOH (30 mL) at 55 psi of H2 for 3 h. The
catalyst was removed by filtration and the filtrate was concentrated
to dryness. Aq 4 N HCl in dioxane (5 mL) was added to the residue
and the mixture was concentrated down to provide 0.31 g of 2
(95%) as its HCl salt.
O
4 3
N
H
6
H
O
2
O
1H NMR (CDCl3, 500 MHz): = 4.39 (d, J = 5.5 Hz, 1 H), 3.65–
3.51 (m, 3 H), 3.40 (dd, J = 11.0, 7.5 Hz, 1 H), 3.12–3.10 (m, 1 H),
3.08 (dd, J = 11.0, 4.0 Hz, 1 H), 2.05 (dd, J = 12.0, 9.0 Hz, 1 H),
1.90 (dd, J = 12.0, 6.5 Hz, 1 H), 1.29 (s, 3 H), 1.10 (s, 3 H).
13C NMR (CDCl3, 125 MHz): = 84.4, 82.9, 66.4, 58.9, 51.0, 44.4,
42.8, 28.7, 26.6.
Ph
9
Figure 2 Structure of compound 9
(9) The structure of 5a was confirmed by the presence of H3-
H1a, H3-H7a, H4-H7b and a small H3-H2 NOEs (Figure 3).
Acknowledgment
We thank Drs. T. M. Chan, A. Evans and Mrs. Rebecca Osterman
for HSQC, HSQC-TOCSY experiments and NOE studies, Dr. B.
Pramanik, Mr. P. Bartner for high-resolution mass spectral data and
Dr. G. Njoroge, Dr. M. Sannigrahi and Mr. R. Lovey for helpful
suggestions.
Figure 3 Structure of compound 5a
(10) The structure of 5b was confirmed by the presence of
H3OH-H6, H3OH-H2, H3-H1a, H4-H1a and H6-H1a NOEs
(Figure 4).
References
(1) (a) Beausoleil, E.; L’Archeveque, B.; Belec, L.; Atfani, M.;
Lubell, W. D. J. Org. Chem. 1996, 61, 9447. (b) Holmgren,
S. K.; Taylor, K. M.; Bretscher, L. E.; Raines, R. T. Nature
(London) 1998, 392, 666. (c) Valle, J. R.; Goodman, M. J.
Org. Chem. 2003, 68, 3923. (d) Trabocchi, A.; Cini, N.;
Menchi, G.; Guarna, A. Tetrahedron Lett. 2003, 44, 3489.
(2) West, M. L.; Fairlie, D. P. Trends Pharm.Sci. 1995, 16, 67.
(3) (a) Kurokawa, N.; Ohfune, Y. J. Am. Chem. Soc. 1986, 108,
6041. (b) Kurokawa, N.; Ohfune, Y. Tetrahedron 1993, 49,
6195. (c) Herdeis, C.; Aschenbrenner, A.; Kirfel, A.
Tetrehedron: Asymmetry 1997, 8, 2421.
(4) (a) Panday, S.; Langlois, N. Synth. Commun. 1997, 27,
1373. (b) Langlois, N.; Rakotondradany, F. Tetrahedron
2000, 56, 2437.
(5) (a) Thottahil, J. K.; Moniot, J. L.; Mueller, R. H.; Wong, M.
K. Y.; Kissick, T. P. J. Org. Chem. 1986, 51, 3140.
(b) Thottahil, J. K.; Przybyla, C.; Malley, M.; Gougoutas, J.
Z. Tetrahedron Lett. 1986, 27, 1533.
Figure 4 Structure of compound 5b
(11) The structure of 11 was confirmed by the presence of Me9-
H3, Me9-H4, Me10-H5b and H2-H5b NOEs (Figure 5).
9
10
7
O
Ha
Hb
4 3
5
2
N
1
HO
11
Ph
(6) Molander, G. A.; Hahn, G. J. Org. Chem. 1986, 51, 2596.
(7) Barros, M. T.; Maycock, C. D.; Ventura, M. R. J. Org.
Chem. 1997, 62, 3984.
Figure 5 Structure of compound 11
(8) The skeleton of the molecule is readily traced by HSQC,
NOESY and COSY experiments. The trans nature of the
(12) Micovic, V. M.; Mihailovic, M. L. J. J. Org. Chem. 1953, 18,
1190.
Synthesis 2003, No. 17, 2643–2646 © Thieme Stuttgart · New York