Total synthesis of 3-azasteroids via the transannular Diels-Alder strategy

Article abstract of DOI:10.1016/S0040-4020(01)00290-3

The total synthesis of four new 3-azasteroids is described, using the transannular Diels-Alder (TADA) reaction. Elaboration of the acyclic trienes, macrocyclizations and TADA reactions are detailed, as well as the stereochemical outcome of the reaction.

Full text of DOI:10.1016/S0040-4020(01)00290-3

TETRAHEDRON
Pergamon
Tetrahedron 57 12001) 4167±4177
Total synthesis of 3-azasteroids via the transannular
Diels±Alder strategy
²
 Â
Daniel Fortin, Frederic Gaudette, Eric Marsault and Pierre Deslongchamps
²
p
Á Â
Laboratoire de Synthese Organique, Institut de Pharmacologie de Sherbrooke, Universite de Sherbrooke,
3001, 12e av. Nord, Sherbrooke $QC), Canada J1H 5N4
This article is dedicated to Professor Jean FrancËois Normant on the occasion of his 65th birthday
Received 22 December 2000; revised 6 March 2001; accepted 7 March 2001
AbstractÐThe total synthesis of four new 3-azasteroids is described, using the transannular Diels±Alder 1TADA) reaction. Elaboration of
the acyclic trienes, macrocyclizations and TADA reactions are detailed, as well as the stereochemical outcome of the reaction. q 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
ties range from antibacterial,7 neuromuscular blockers,8
androgenic activity,9 to 5a-reductase inhibiting properties.10
The total synthesis of natural as well as unnatural products
has been one of the major endeavours of organic synthesis
for a few decades, allowing for the re®nement of both
synthetic strategies and tactics, as well as the development
of new synthetic methods addressing speci®c problems.
Architecturally complex molecules have become accessible
owing to the development of general or speci®c strategies.1
In this respect, steroids have always represented an impres-
sive synthetic challenge, owing to their polycyclic nature
combined with complex stereochemical issues.
In addition to its biological potential, this class of products
holds an obvious synthetic challenge, and we felt in position
to tackle its total synthesis using our uni®ed approach
towards steroids.11 Accordingly, 3-aza-5b-steroid 1 and
3-aza-5a-steroid 2 1Fig. 1) were selected, having respec-
tively the cis-anti-trans-anti-trans 1CATAT) and the
trans-syn-cis-anti-trans 1TSCAT) stereochemistry.12 These
azasteroids are related to 5b-androsterone and adreno-
sterone respectively 1Fig. 1).13 The present article
summarizes the total synthesis of 3-azasteroids 1 and 2, as
well as some interesting discoveries brought by this research.
In the past few years, the transannular Diels±Alder 1TADA)
reaction has emerged as a robust tool to approach polycyclic
diterpenes and steroids.2 This strategy allowed for the synth-
esis of a large variety of tricyclic or tetracyclic terpenoids.3
Its limits and potential have been very well delineated by
extensive model studies.4 The approach was also applied to
the total synthesis of steroidal molecules.5 Unnatural deri-
vatives mimicking natural products, particularly steroid-like
molecules possessing a heteroatom at the pro-C3 position 11
and 2, Fig. 1), are in principle within reach using such
strategy.
2. Results and discussion
As indicated in Fig. 2, tetracycle 1 was envisioned to be the
O
O
E
E
O
9
RN
RN
Steroids containing one or several heteroatoms on their
backbone have been the subject of several studies,6 and
were found to display a broad spectrum of biological
activities. As far as azastaroids are considered, these activi-
2 (TSCAT)
1 (CATAT)
O
O
O
Keywords: 3-azasteroids; transannular Diels±Alder strategy; acyclic
trienes.
3
3
5
HO
O
p
Corresponding author. Fax: 11-819-820-6823;
e-mail: pierre.deslongchamps@courrier.usherb.ca
Adrenosterone
5β-Androsterone
Figure 1. C3-modi®ed steroidal targets.
²
e
Present address: NeoKimia, Inc., 3001, 12 av. Nord, Building Z5,
Â
Fleurimont 1QC), Canada J1H 5N4
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020101)00290-3

4168
D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
O
E
O
O
E
E
O
I
THPO
O
4
E
a-c
+
RN
RN
X
1 (CATAT)
2 (TSCAT)
RO
8 X=OTHP, R=tBDPS
9 X=OH, R=tBDPS
10 X=I, R=tBDPS
tBDPSO
β-ketoester
alkylation
β-ketoester
alkylation
5
g-i
d
O
O
E
O
E
O
E
O
E
RN
amide
alkylation
RN
7 (TCC)
14 X=N3
15 X=NH2
3 (TTT)
amide
TsNH
11
X
alkylation
16 X=CF3CONH
OtBDPS
e, f
OtBDPS
e, f
O
O
I
E
E
O
TIPSO
E
I
Cl
6
TsNH
12 Y=OH
13 Y=Cl
THPO
CF3CONH
Y
tBDPSO
17 Y=OH
18 Y=Cl
4
Y
5
Figure 2. Retrosynthetic analysis
a. KH, toluene, rt then 4, rfx (78%); b. PPTS, iPrOH,
rfx (99%); c. PPh3, DEAD, MeI, toluene, rt (90%);
d. TsNH2, NaH, 18-C-6, THF:DMF, 80oC (52%);
e. TBAF, THF 0oC (82-95%); f. (Cl3C)2CO, PPh3, THF
-40oC (84-93%); g. NaN3, DMSO rt (98%);
h. PPh3, H2O, THF rt; i. TFAA, Et3N, CH2Cl2
0oC (95% 2 steps).
result of a TADA reaction on trans-trans-trans 1TTT)
trienic macrocycle 3. The predicted major product of the
cycloaddition was supposedly CATAT tetracycle 1, accord-
ing to our model studies on steroid synthesis.11 Macrocycle
3 was in principle accessible from two main fragments, i.e.
cyclopentanone 5 and iodide 4, connected via alkylation of
an amide. On the other hand, tetracycle 2 would be the
TADA adduct obtained from trans-cis-cis 1TCC) trienic
macrocycle 7. Here, only one geometry was to be expected.
Macrocycle 7 could be obtained from two fragments,
namely cyclopentanone 5 and iodide 6.
Scheme 1.
corresponding azide 14 in nearly quantitative yield. The
latter underwent a Staudinger reduction to the free amine
15, which was almost quantitatively transformed into
tri¯uoroacetamide 16. Subsequent deprotection of the silyl
ether 182%) followed by chlorination led to allylic chloride
18 in 93% yield and completed the synthesis of the second
acyclic TTT triene presursor.
2.1. Synthesis of the triene precursors
Accordingly, the enolate of b-ketoester 5 was alkylated with
iodide 4 to give acyclic triene 8 in 78% yield 1Scheme 1).14
The THP protection was removed, and the resulting alcohol
transformed into the corresponding iodide 10 in excellent
yields.15 Reaction with tosylamide in basic conditions
allowed for the introduction of the amide moiety and gener-
ated 11. Desilylation was followed by allylic chloride
formation in the presence of hexachloroacetone and tri-
phenylphosphine16 to give acyclic triene 13 ready for
tandem macrocyclization-TADA cycloaddition 1see the
following section).
The synthesis of TCC acyclic trienes involved a somewhat
different approach. Starting from the known Z iodide 6
1Scheme 2),17 displacement by sodium azide followed by
LAH reduction and subsequent amidation led to tri¯uoro-
acetamide 21 in high yields. The latter was alkylated with
allylic chloride 225a to connect the diene and dienophile
parts together and produce acyclic triene 23 in 57% yield.
The dimethoxycetal was then hydrolyzed to regenerate the
cyclopentanone moiety 24, and the silyl ether subsequently
removed using TBAF to free alcohol 25 in 90% yield. The
latter was oxidized with Dess±Martin periodinane18 to yield
Similarly, reaction of iodide 10 with sodium azide led to the

D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
4169
TIPSO
Cl
N
TIPSO
a-c
Cl
Cl
X
a,b
Cl
I
TIPSO
TIPSO
19 X=N3
20 X=NH2
21 X=CF3CONH
6
29 R=BOC
30 R=H
MeO
OMe
MeO2C
R
d-g
OH
Cl
Ts
28
Y
MeO
MeO2C
22
Cl
OMe
c-f
HO
Z
MeO2C
31
N
Y
Cl
CF3CO
23 Y=H,OTIPS; Z=(OMe)2
24 Y=H,OTIPS; Z=O
25 Y=H,OH; Z=O
26 Y=Z=O
Z
32 Y=H,OTIPS, Z=(OMe)2
33 Y=H,OTIPS, Z=O
34 Y=H,OH, Z=O
MeO2C
h
N
Ts
35 Y=Z=O
O
O
E
g
CF3CON
O
O
E
27
TsN
a. NaN3, DMSO (91%); b. LAH, Et2O; c. TFAA,
pyridine (93% 2 steps); d. 22, Cs2CO3, CH3CN rfx
(57%); e. TFA:H2O, CH2Cl2 0oC (93%);
f. TBAF, THF -20oC (90%); g. Dess-Martin periodinane
(74%); h. Cs2CO3, CH3CN 40oC (30%).
36
a. TsNHBOC, PPh3, DEAD, THF (95%); b. DMSO,
180oC (95%); c. 31, PPh3, DIAD (75%); d. TFA:H2O,
CH2Cl2 0oC (93%); e. TBAF, THF -20oC (90%);
f. Dess-Martin periodinane (74%); g. Cs2CO3, CH3CN 40oC
(60%).
Scheme 2.
Scheme 3.
chloroketone 26 ready for macrocyclization. Macrocycli-
zation was carried out at low temperature under pseudo-
high dilution,19 by adding chloroketone 26 to a warm
1408C) suspension of cesium carbonate in acetonitrile
during 1.7 h, followed by 2.5h stirring at the same tempera-
ture 1the ®nal concentration being 2 mM). In this case, a
modest 30% yield of the desired macrocycle 27 was
obtained, attributed to the instability of the precursor chloro-
ketone.
5.2:1 ratio and 55% overall yield. Selective crystallization
of the major adduct 38b allowed for a single crystal X-ray
analysis and secured the assigned structure 1see Fig. 3).
Even though not isolated from the major adduct, the
minor isomer was assigned TACST structure 38a based
on previous studies and molecular modeling calcu-
lations.11,23,24 No trienic macrocycle remained as could be
expected in the TTT series, as a consequence of the easily
accessible s-cisoid geometry of the diene.4a When tosylamide
In a more convergent approach 1Scheme 3), dienophile
alcohol 2820 underwent
a Mitsunobu reaction with
TsNHBOC,21 to give the corresponding carbamate 29 in
95% yield. The BOC group was subsequently pyrolyzed
to regenerate tosylamide 30,22 which was coupled under
Mitsunobu conditions with dienic alcohol 315a in 75%
yield. Further elaboration of 32 as already mentioned led
to chloroketone 35 in good yields. The latter underwent the
macrocyclization smoothly in the above described con-
ditions, giving access to TCC macrocyclic triene 36 in
60% yield.
2.2. TADA reactions *Scheme 4)
In the TTT series, when allylic chloride 18 was exposed to
the macrocyclization conditions 112 h slow addition of the
triene solution to a re¯uxing suspension of cesium carbonate
in acetonitrile followed by 12 h re¯ux, ®nal concentration
1 mM), a separable mixture of tetracycles was obtained in a
Figure 3. X-Ray analysis of tetracycle 38b.

4170
D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
analogue 13 was subjected to the same conditions, the
E
O
O
E
H
results were essentially identical and tetracycles 37b and
37a were obtained as an unseparable mixture 1CATAT:
TACST 4.5:1, 59% yield). There again, macrocyclization
and TADA occurred in a tandem fashion.
RN
H
RN
RN
H
CATAT
TS1 cbc
The obtention of a ca 5:1 ratio in favour of the CATAT geo-
metry is also in agreement with our previous observations
and theoretical studies,11 as well as Takahashi's predictions
in the 3-ketosteroid series 1see Fig. 4).25 Four transition
states are actually competing. The more easily accessible
one 1TS1) possesses the chair-boat-chair 1cbc) geometry in
which the dienophile methyl group is oriented in a b fashion
and the diene assumes the a orientation. This transition state
leads to the major CATAT product. The second transition
state 1TS2) also has the chair-boat-chair conformation with
the diene adopting this time the b orientation, albeit
possesses an unfavourable transannular interaction and is
thus slightly higher in energy. In the third transition state
1TS3), the chair-boat-boat conformation accounts for
higher energy. The last transition state 1TS4) is excluded,
suffering both from unfavourable steric interaction and from
a chair-boat-boat conformation.
O
E
H
(
E
O
)
H
H
H
RN
RN
H
TS2 cbc
TACST
O
E
H
E
O
RN
TS3 cbb
TACAT
O
E
()
H
O
E
RN
H
On the other hand, in the TCC series, diverging results were
obtained. The TCC series exempli®es at its best the power
of the TADA strategy, allowing for the Diels±Alder reac-
tion of a trans-cis diene, which often is a poor coupling
partner with respect to intermolecular and intramolecular
settings.25 Transannular effects force this diene to approach
H
RN
H
TS4 cbb
CATST
Figure 4.
O
O
E
O
E
Cs2CO3, CH3CN
82oC, 12 h
E
+
RN
RN
RN
H
Cl
37β (R=Ts)
38β (R=CF3CO)
37α (R=Ts) β:α 4.5:1 (55%)
38α (R=CF3CO) β:α 5.2:1 (59%)
13 (R=Ts)
18 (R=CF3CO)
O
E
O
O
toluene
195oC, 12 h
O
E
CF3CON
CF3CON
39 (78%)
27
3
O
O
O
toluene, Et3N
220oC, 12 h
O
E
TsN
TsNH
36
40 (50%)
Scheme 4.

D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
4171
Et3N, toluene
220oC
O
O
O
O
E
O
E
O
TsN
CF3CO
N
27
40
TsNH
36
Base
(-BH+)
IMDA
O
E
O
O
CF3CON
TsNH
O
39
41
Figure 5.
Figure 7.
the s-cisoid geometry, although the asynchronicity of the
transition state26 usually allows for slight deviation from
the purely s-cisoid arrangement. Typically, TADA tempera-
tures are higher than in the TTT series, where the trans-
trans diene readily adopts a productive conformation.
in the closure of the observed 8-membered ring and for-
mation of [6.8.5] tricycle 40. We assumed that the base
was also responsible for the observed decarboxylation.
The presence of the ester group on intermediate 41 would
create an unfavourable interaction with the cis portion of the
diene. Using more hindered bases than triethylamine
1HuÈnig's base or 2,6-di-tert-butylpyridine) led to no reac-
tion up to 2608C and degradation at higher temperatures,
supporting this assumption.
Firstly, upon heating TCC macrocyclic triene 27 up to
1958C in toluene in a sealed tube, the desired azasteroid
39 was obtained in 78% yield after 12 h 1Scheme 4). In
the TCC series, only the trans-syn-cis 1TSC) geometry
can be obtained on the newly formed tricycle, based on
geometrical constraints 1Fig. 5). On the other hand, when
TCC macrocyclic triene 36 was submitted to the TADA
conditions in the absence of a base, only decomposition
was observed. To our surprise, in the presence of triethyl-
amine, 50% of rearrangement product 40 was obtained at
2208C. The stereochemistry of tricycle 40 was secured by a
single crystal X-ray analysis 1see Fig. 6). Moreover, the
product was completely decarboxylated. The obtention of
this rearrangement product could in principle be explained
by the intervention of an intramolecular Diels±Alder
reaction 1IMDA) on the open product 41 derived from
macrocycle 36 1Fig. 7). One may reasonably argue that in
the presence of a base, elimination taking place via a retro-
Michael reaction expels the tosyl-stabilized amide moiety of
the molecule 1Fig. 7). The newly created diene 41 would be
in position to undergo an intramolecular Diels±Alder reac-
tion with the trans ole®n of the other diene moiety, resulting
Finally, similar precursors were prepared aiming at the
3-thio series. However, tandem macrocyclization-TADA
on TTT triene derived from 18 1CF3CONHvSH) met
with failure. In the TCC series, a macrocycle analogous to
27 was synthesized 1CF3CONvS), but decomposed when
heated up to the high temperatures required for the TADA
reaction to occur.27
In conclusion, we have synthesized two new types of
3-azasteroids related to androsterone and adrenosterone.
The synthesis makes use of the TADA strategy and empha-
sizes the direct link between the macrocyclic triene geo-
metry and the stereochemistry of the resulting tetracycle,
as well as the good stereocontrol associated with this
strategy. Knowing that the precursor to the only chiral frag-
ment cyclopentanone 5 can be produced in enantiomerically
pure form,28 this formally constitutes an enantioselective
approach towards 3-azasteroids.
3. Experimental
3.1. General
All reactions were performed under N2 atmosphere with
oven or ¯ame dried glassware. Solvents were distilled by
the usual means. Analytical TLC were performed on pre-
coated glass plates 10.25mm) with silica gel 60F-250
1Merck). Flash chromatography was performed with 230±
400 mesh silica gel 60 1Merck). Melting points were
recorded on a BuÈchi Schmelz punk bestimmungs and are
1
uncorrected. H and 13C NMR spectra were recorded on a
BruÈker AC-300 and are referenced with respect to the
residual signals of the solvent; they are described using
standard abbreviations. IR spectra were recorded on a
Figure 6. X-Ray analysis of tricycle 40.

4172
D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
Perkin±Elmer 1600 FT-IR. Mass spectra were recorded on a
ZAB-1F micromass spectrometer.
12H, d, Jˆ8.0 Hz), 7.33±7.29 12H, d, Jˆ8.0 Hz), 6.43±6.11
12H, m), 5.83±5.62 12H, m), 5.04 11H, brt, Jˆ6.0 Hz), 12H,
t, Jˆ6.0 Hz), 4.10 12H, d, Jˆ6.5Hz), 3.66 13H, s), 2.98 12H,
q, Jˆ6.5Hz), 2.8511H, q, Jˆ8.0 Hz), 2.65±2.56 11H, m),
2.43 13H, s), 2.35±1.60 17H, m), 1.44 13H, s). 13C NMR 175
MHz, CDCl3) d 214.8, 170.2, 136.9, 135.9, 134.4, 133.6,
133.4, 131.9, 131.2, 129.7, 128.3, 127.1, 127.0, 123.8, 52.1,
48.3, 40.5, 38.9, 38.3, 31.7, 26.1, 22.8, 21.5, 15.4. IR 1®lm)
n 3031, 2955, 1750, 1731, 1599, 1435, 1405, 1331, 1240,
1160, 1094, 990. MS 1EI): 507 1M1), 471 1M-HCl)1. HRMS
1M1) calc. for C26H34ClNO5S: 507.1846; found: 507.1825.
3.1.1. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-4-methyl-
6-toluenesulfonamidohex-3-en-1-yl]-3-[*1E,3E)-5-*tert-
butyldiphenylsiloxy*penta-1,3-dien-1-yl]cyclopentanone
*11). To a solution of Cs2CO3 1900 mg, 2.76 mmol) and
tosylamide 1525 mg, 3.07 mmol) in CH3CN 14 mL) at
808C, was added via canula a solution of iodide 10
1101 mg, 0.147 mmol) in CH3CN 12 mL). The mixture
was stirred for 15h, cooled down to rt, ®ltered on celite
and the solvent removed in vacuo. The product was puri®ed
by ¯ash chromatography 1hexanes±ethyl acetate 7:3) to
3.1.4. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-6-azido-4-
methylhex-3-en-1-yl]-3-[*1E,3E)-5-*tert-butyldiphenyl-
siloxy)penta-1,3-dien-1-yl]cyclopentanone *14). To a
1
give 11 154.5 mg, 52%). H NMR 1300 MHz, CDCl3) d
7.78±7.7512H, d, Jˆ8.0 Hz), 7.70±7.6514H, m), 7.45±
7.3516H, m), 7.32±7.2512H, d), 6.26 11H, dd), 6.17 11H,
dd, Jˆ10.5Hz, 14.5Hz), 5.7511H, dt, Jˆ7.0 Hz, 14.5Hz),
5.58 11H, dd, Jˆ8.5, 14.5 Hz), 5.05 11H, t, Jˆ6.0 Hz), 4.52
12H, t, Jˆ6.0 Hz), 4.24 12H, d, Jˆ5.0 Hz), 3.67 13H, s), 2.99
12H, q, Jˆ6.0 Hz), 2.87 11H, q, Jˆ8.5Hz), 2.61±2.54 11H,
m), 2.42 13H, s), 2.35±1.70 18H, m), 1.45 13H, s), 1.07 19H,
s). 13C NMR 175MHz, CDCl 3) d 215.2, 170.2, 143.2, 136.8,
135.4, 133.5, 132.3, 132.2, 131.73, 131.42, 130.39, 129.60,
129.02, 127.59, 127.00, 63.93, 63.03, 51.96, 48.27, 40.5,
38.8, 38.4, 31.6, 26.7, 26.1, 25.2, 22.7, 21.4, 19.2, 15.3.
IR 1CHCl3) n 3368, 3028, 2952, 2859, 1731, 1428, 1375,
1248, 1160. MS 1EI) 727 1M1); 670 1M-C4H9)1. HRMS
1M1) calc. for C42H53NO6SSi: 727.3363; found: 727.3355.
solution of iodide 10 1159 mg, 0.233 mmol) in DMSO
11.7 mL) at rt was added NaN3 130.3 mg, 0.466 mmol).
The mixture was stirred for 14 h. Water 13.4 mL) was
added, and the mixture was extracted with ether 13£
10 mL). The combined organic layers were washed with
water 12£10 mL), dried on MgSO4, and the solvent was
removed in vacuo. The product was puri®ed by ¯ash chro-
matography 1hexanes±EtOAc 6:4) to give azide 14
1132 mg, 95%) as a colorless oil. 1H NMR 1300 MHz,
CDCl3) d 7.70±7.6514H, m), 7.48±7.3516H, m), 6.30±
6.10 12H, m), 5.75 11H dt, Jˆ5.0, 14.5 Hz), 5.57 11H, dd,
Jˆ8.0, 14.5Hz), 5.2511H, t, Jˆ6.5Hz), 4.24 12H, d, Jˆ
5Hz), 3.67 13H, s), 3.21 12H, t, Jˆ7.0 Hz), 2.89 11H, q,
Jˆ9.0 Hz), 2.60 11H, dt, Jˆ5.5, 18.0 Hz), 2.28 12H, t, Jˆ
7 Hz), 2.31±1.55 17H, m), 1.64 13H, s),1.08 19H, s). 13C
NMR 1300 MHz, CDCl3) d 214.9, 170.2, 135.4, 133.5,
132.1, 131.9, 130.5, 130.3, 129.6, 129.1, 127.6, 126.5,
63.9, 63.2, 51.9, 49.6, 48.2, 38.6, 38.3, 31.5, 26.7, 26.1,
22.8, 19.2, 15.8. IR 1®lm) n 2946, 2867, 2845, 2099,
1750, 1727, 1428, 1224, 1162. MS 1EI): 599 1M1), 542
1M-C4H9)1. HRMS 1M-C4H9)1 calc. for C31H36N3O4Si:
542.2475; found: 542.2469.
3.1.2. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-4-methyl-6-
toluenesulfonamidohex-3-en-1-yl]-3-[*1E,3E)-5-hydroxy-
penta-1,3-dien-1-yl]cyclopentanone *12). To a solution of
tosylamide 11 166.5mg, 0.0915mmol) in THF 12 mL) at rt
was added TBAF 11.0 M in THF, 0.101 mL, 0.101 mmol)
and the mixture was stirred for 2 h at rt. The solvent was
removed in vacuo and the product puri®ed by ¯ash chroma-
tography 1EtOAc:CH2Cl2:MeOH 30:70:1) to give 12
143 mg, 95%) as a colorless oil. 1H NMR 1300 MHz,
CDCl3) d 7.75±7.72 12H, d, Jˆ8.0 Hz), 7.33±7.2512H, d,
Jˆ9.0 Hz), 6.25±6.10 12H, m), 5.81 11H dt, Jˆ5.5,
14.5 Hz), 5.58 11H, dd, Jˆ8.0, 14.5Hz), 5.03 11H, t, Jˆ
7.0 Hz), 4.51 11H, t, Jˆ6.0 Hz), 4.17 12H, d, Jˆ6 Hz),
3.6513H, s), 2.98 12H, q, Jˆ6.5Hz), 2.85 11H, q, Jˆ
8.0 Hz), 2.61±2.54 11H, m), 2.42 13H, s), 2.35±1.60 19H,
m), 1.43 13H, s). 13C NMR 175MHz, CDCl 3) d 215.1,
170.2, 143.3, 136.8, 132.1, 131.8, 131.5, 131.2, 130.6,
130.2, 129.7, 127.1, 63.1, 52.0, 48.3, 40.6, 38.8, 38.3,
31.6, 26.1, 25.2, 22.7, 21.5, 15.3. IR 1®lm) n 3611, 3378,
3030, 2953, 1749, 1731, 1600, 1458, 1331, 1240, 1094. MS
1EI): 489 1M1); 471 1M-H2O)1. HRMS 1M1) calc. for
C26H35NO6S: 489.2185; found: 489.2178.
3.1.5. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-4-methyl-
6-tri¯uoroacetamidohex-3-en-1-yl]-3-[*1E,3E)-5-*tert-
butyldiphenylsiloxy)penta-1,3-dien-1-yl]cyclopentanone
*16). To a solution of azide 14 182 mg, 0.136 mmol) in THF
11.5mL) at rt, was added PPh 3 171 mg, 0.27 mmol) and
water 1103 mL, 5.71 mmol). The mixture was stirred over-
night at rt, then a solution of NaHCO3 15mL) was added and
the organic layer extracted with CH2Cl2 13£10 mL). The
organic layers were dried on MgSO4 and the solvent
removed in vacuo.
To a solution of the crude amine in CH2Cl2 11.7 mL) at 08C,
was added pyridine 155 mL, 0.68 mmol) and TFAA 138 mL,
0.027 mmol). The mixture was stirred at 08C for 15min,
water 110 mL) was added and the mixture was extracted
with CH2Cl2 13£10 mL). The combined organic layers
were dried on MgSO4 and the solvent removed in vacuo.
The product was puri®ed by ¯ash chromatography 1hexanes:
EtOAc 7:3) to give amide 16 188 mg, 95%) as a colorless
3.1.3. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-4-methyl-
6-toluenesulfonamidohex-3-en-1-yl]-3-[*1E,3E)-5-chloro-
penta-1,3-dien-1-yl]cyclopentanone *13). To a solution of
alcohol 12 138.1 mg, 0.0779 mmol) in THF 11 mL) at
2408C were added PPh3 130.7 mg, 0.117 mmol) and 2,6-
lutidine 113.6 mL, 0.117 mmol). Hexachloroacetone 117.7
mL, 0.117 mmol) was then added and the mixture was
stirred for 30 min then heated up to rt. The solvent was
removed in vacuo and the product puri®ed by ¯ash chroma-
tography 1hexanes±EtOAc 7:3) to give 13 133 mg, 84%) as
1
oil. H NMR 1300 MHz, CDCl3) d 7.70±7.6514H, m),
7.48±7.3516H, m), 6.58 11H, s), 6.30±6.10 12H, m), 5.75
11H dt, Jˆ5.0, 14.5 Hz), 5.56 11H, dd, Jˆ8.0, 14.5Hz), 5.21
11H, t, Jˆ6.5Hz), 4.2512H, d, Jˆ5Hz), 3.67 13H, s), 3.43
12H, q, Jˆ6.5Hz), 2.88 11H, q, Jˆ8.5Hz), 2.65±2.52 11H,
m), 2.24 12H,t, Jˆ6.5Hz), 2.31±1.70 17H, m), 1.64 13H, s),
1
a colorless oil. H NMR 1300 MHz, CDCl3) d 7.75±7.70

D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
4173
1.08 19H, s). 13C NMR 175MHz, CDCl 3) d 215.1, 170.2,
157.0 1q), 135.4, 133.5, 132.6, 132.3, 131.7, 130.3, 129.6,
129.0, 127.6, 127.1, 115.8 1q), 63.9, 63.0, 51.9, 48.5, 38.3,
37.4, 31.6, 29.5, 26.7, 26.1, 22.7, 19.2, 15.5. IR 1®lm) n
3340, 2953, 2857, 1750, 1719, 1555, 1458, 1428, 1209,
1164, 1112, 1056. MS 1EI): 669 1M1), 612 1M-C4H9)1.
HRMS 1M- C4H9)1 calc. for C33H35F3NO5Si: 612.2393;
found: 612.2397.
13.17 g, 9.2 mmol) in ether 170 mL) at 08C, was added LAH
11.0 M in ether, 196 mL, 196 mmol). The mixture was
stirred for 3 h at 258C, treated with a saturated solution of
NaHCO3 170 mL), then with 1 M NaOH 115mL), then
extracted three times with ether. The combined organic
layers were dried on MgSO4 and the solvent removed in
vacuo. The amine was used as such for the following step.
To a solution of the amine 12.9 g, 9.09 mmol) in ether
1100 mL) at 08C, were added pyridine 13.67 mL,
45.5 mmol) and TFAA 12.57 mL, 18.2 mmol). The mixture
was stirred at rt for 15min, treated with water 180 mL), then
extracted three times with CH2Cl2. The combined organic
layers were dried on MgSO4 and the solvent was removed in
vacuo. The product was puri®ed by ¯ash chromatography
1hexanes:ethyl acetate 8:2), to give tri¯uoroacetamide 21 as
3.1.6. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-4-methyl-
6-tri¯uoroacetamidohex-3-en-1-yl]-3-[*1E,3E)-5-hydroxy-
penta-1,3-dien-1-yl]cyclopentanone *17). The procedure
for the synthesis of 12 was followed 1on 87 mg of 16).
Puri®cation by ¯ash chromatography 1EtOAc:CH2Cl2:
MeOH, 30:70:0.5) gave alcohol 17 146 mg, 82%) as a
1
thick colorless oil. H NMR 1300 MHz, CDCl3) d 6.70
1
11H, s), 6.25±6.08 12H, m), 5.78 11H dt, Jˆ5.5, 14.5 Hz),
5.55 11H, dd, Jˆ8.0, 14.5Hz), 5.1511H, t, Jˆ6.5Hz), 4.15
12H, d, Jˆ6.0 Hz), 3.63 13H, s), 3.39 12H, q, Jˆ6.5Hz),
2.8511H, q, Jˆ8.0 Hz), 2.65±2.52 11H, m), 2.20 12H, t,
Jˆ7.0 Hz), 2.29±1.62 18H, m), 1.59 13H, s). 13C NMR
175MHz, CDCl 3) d 215.1, 170.2, 156.8 1q, Jˆ39.0 Hz),
132.0, 131.9, 131.7, 131.3, 130.4, 126.9, 115.8 1q,
Jˆ288.0 Hz), 63.0, 52.0, 52.0, 48.3, 38.5, 38.2, 37.5, 31.6,
26.0, 22.6, 15.4. IR 1®lm) n 3402, 3342, 3097, 2953, 1749,
1716, 1558, 1448, 1456, 1213, 1192, 1160, 1087. MS 1EI):
431 1M1), 413 1M-H2O)1. HRMS 1M- H2O)1 calc. for
C21H26F3NO4: 413.1814; found: 413.1821.
a clear oil 13.53 g, 93% 1two steps)). H NMR 1300 MHz,
CDCl3) d 6.59 11H, s), 5.32 11H, d, Jˆ8.0 Hz), 4.63±4.56
11H, m), 3.60±3.30 14H, m), 2.61±2.51 11H, m), 2.31±2.20
11H, m), 1.78 13H,s), 1.06 121H, s). 13C NMR 175MHz,
CDCl3) d 157.4 1q, Jˆ20.0 Hz), 134.1, 130.2, 115.7 1q,
Jˆ280.5Hz), 69.2, 48.5, 37.8, 31.2, 22.6, 17.8, 12.3. IR
1®lm) n 3302, 3105, 2945, 2867, 1704, 1557, 1463, 1383,
1342, 1308, 1184, 1116, 1065. MS 1EI): 372 1M-C3H7)1.
HRMS 1M-C3H7)1 calc. for C15H26ClF3NO2Si: 372.1373;
found: 372.1367.
3.1.10. *^)-*3Z,9E,11Z)-7-Aza-1-chloro-4-methyl-12-*2-
methoxycarbonyl-3,3-dimethoxy)cyclopentyl-7-tri¯uoro-
acetyl-2-triisopropylsiloxydodeca-3,9,11-triene *23). To a
solution of amide 21 12.79 g, 6.3 mmol) in acetonitrile
190 mL) at rt, were added Cs2CO3 114.4 g, 44.1 mmol)
and the diene solution 11.21 g, 4.21 mmol) in acetonitrile
110 mL). The solution was re¯uxed for 19 h, cooled down
to rt, ®ltered on celite, rinsed with CH2Cl2 and dried on
MgSO4 then concentrated in vacuo. The product was puri-
®ed by ¯ash chromatography 1hexanes:EtOAc 8:2), to give
3.1.7. *^)-*2R,3S)-2-Methoxycarbonyl-2-[*E)-4-methyl-
6-tri¯uoroacetamidohex-3-en-1-yl]-3-[*1E,3E)-5-chloro-
penta-1,3-dien-1-yl]cyclopentanone *18). The procedure
for the synthesis of 13 was followed 1on 27 mg of 17).
Puri®cation by ¯ash chromatography 1hexanes:EtOAc 7:3)
gave chloride 18 126 mg, 93%) as a yellowish oil. 1H NMR
1300 MHz, CDCl3) d 6.54 11H, s), 6.25±6.08 12H, m), 5.75
11H, q, Jˆ7.5Hz), 5.63 11H, dd, Jˆ8.0, 14.5Hz), 5.16 11H,
t, Jˆ6.5Hz), 4.08 12H, d, Jˆ7.0 Hz), 3.64 13H, s), 3.40 12H,
q, Jˆ6.0 Hz), 2.86 11H, q, Jˆ8.0 Hz), 2.65±2.52 11H, m),
2.21 12H, t, Jˆ7.0 Hz), 2.29±1.62 17H, m), 1.60 13H, s). 13C
NMR 175MHz, CDCl 3) d 214.8, 170.1, 157.0 1q), 133.5,
133.2, 131,8, 131.1, 128.1, 127.0, 116.0 1q), 63.0, 52.0,
48.3, 44.8, 38.2, 37.4, 31.6, 26.9, 25.9, 22.6, 15.5. IR
1®lm) n 3344, 3102, 2953, 1749, 1722, 1556, 1436, 1283,
1211, 1177, 1064. MS 1m/e): 418 1M-OMe)1, 413
1M-HCl)1. HRMS 1M-OMe)1 calc. for C20H24ClF3NO3:
418.1397; found: 418.1406.
1
ketal 23 as a clear oil 11.61 g, 57%). H NMR 1300 MHz,
CDCl3) d 6.60 11H, dd, Jˆ11.0, 15.0 Hz), 5.96 11H, t,
Jˆ11.0 Hz), 5.62±5.49 11H, m), 5.35 11H, t, Jˆ10.0 Hz),
5.25 11H, d, Jˆ7.5Hz), 4.66±4.52 11H, m), 4.22±3.96 12H,
m), 3.67 13H, s), 3.28, 3.21 16H, 2s), 3.69±3.31 14H, m),
2.73 12H, d, Jˆ8.5Hz), 2.63±2.40 11H, m), 2.29±2.15 11H,
m), 2.10±1.84 13H, m), 1.80 13H, s), 1.60±1.42 11H, m),
1.06 121H, s). 13C NMR 175MHz, CDCl 3) d 171.8, 156.4
1q, Jˆ20.0 Hz), 135.8, 134.5, 130.0, 129.2, 126.9, 116.4 1q,
Jˆ280.5 Hz), 111.6, 69.4, 57.9, 51.8, 50.1, 48.9, 48.4, 45.7,
40.8, 36.4, 32.0, 30.3, 30.0, 23.2, 17.9, 12.3. IR 1®lm) n
2946, 2867, 1739, 1694, 1462, 1436, 1360, 1316, 1256,
1201, 1143, 1086, 1050. MS 1EI): 624 1M-C3H7)1. HRMS
1M-C3H7)1 calc. for C29H46ClF3NO6Si: 624.2735; found:
624.2730.
3.1.8. *Z)-6-Azido-1-chloro-4-methyl-2-triisopropylsiloxy-
hex-3-ene *19). The procedure for the synthesis of 14 was
followed 1on 3.0 g of 6). Puri®cation by ¯ash chroma-
tography 1hexanes:ethyl acetate 9:1), gave azide 19 as a
1
clear oil 12.23 g, 91%). H NMR 1300 MHz, CDCl3) d
5.29 11H, d, Jˆ7.5Hz), 4.63 11H, dt, Jˆ6.0, 8.5Hz),
3.57±3.37 14H, m), 2.52±2.42 11H, m), 2.32±2.22 11H,
m), 1.78 13H,s), 1.08 121H, s). 13C NMR 175MHz,
CDCl3) d 134.1, 129.6, 69.5, 49.5, 49.0, 32.0, 23.0, 17.9,
12.3. IR 1®lm) n 2933, 2865, 2095, 1461, 1380, 1255, 1066.
MS: 302 1M-C3H7)1, 274 1M-N2-C3H7)1. HRMS 1M-C3H7)1
calc. for C13H25ClN3OSi: 302.1455; found: 302.1466.
3.1.11. *^)-*3Z,9E,11Z)-7-Aza-1-chloro-4-methyl-12-*2-
methoxycarbonyl-3-oxo)cyclopentyl-7-tri¯uoroacetyl-2-
triisopropylsiloxydodeca-3,9,11-triene *24). To a solution
of ketal 23 1296 mg, 444 mmol) in CH2Cl2 13 mL) at 08C,
was added a solution of TFA 1400 mL) in water 1400 mL).
The mixture was stirred for 45min at 0 8C, treated with
NaHCO3 then water and extracted three times with
CH2Cl2. The combined organic layers were dried on
MgSO4 and the solvent was removed in vacuo. The product
was puri®ed by ¯ash chromatography 1hexanes:EtOAc 8:2),
3.1.9. *Z)-1-Chloro-4-methyl-6-tri¯uoroacetamido-2-tri-
isopropylsiloxyhex-3-ene *21). To a solution of azide 19

4174
D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
1
to give ketone 24 as a clear oil 1256 mg, 93%). H NMR
1300 MHz, CDCl3) d 6.59 11H, dd, Jˆ11.0, 15.0 Hz), 6.08
11H, t, Jˆ11.0 Hz), 5.73±5.43 11H, m), 5.38 11H, q,
Jˆ10.0 Hz), 5.26 11H, d, Jˆ4.5Hz), 4.66±4.52 11H, m),
4.25±3.95 12H, m), 3.73 13H, s), 3.77±3.21 14H, m), 3.00
12H, d, Jˆ11.5Hz), 2.62±2.18 15H, m), 1.81 13H, s), 1.75±
1.61 11H, m), 1.06 121H, s). 13C NMR 175MHz, CDCl 3) d
210.2, 168.7, 156.6 1q, Jˆ20.0 Hz), 134.5, 133.7, 133.5,
133.2, 129.3, 128.1, 116.4 1q, Jˆ280.5Hz), 69.5, 61.3,
52.5, 48.9, 45.9, 39.6, 38.0, 32.0, 29.8, 28.0, 23.2, 17.9,
12.3. IR 1®lm) n 2946, 2867, 1760, 1732, 1694, 1620,
1516, 1462, 1382, 1353, 1326, 1271, 1201, 1144, 1114,
1066. MS 1EI) 578 1M-C3H7)1. HRMS 1M-C3H7)1 calc.
for C27H40ClF3NO5Si: 578.2316; found: 578.2321.
3.1.14. *^)-*4Z,10E,12Z)*1R,14S)-8-Aza-5-methyl-1-meth-
oxycarbonyl-3,17-dioxo-8-tri¯uoroacetylbicyclo[12.3.0]-
heptadeca-4,10,12-triene *27). To a solution of cesium
carbonate 11.61 g, 4.99 mmol) in CH3CN 1345mL) at
408C, was added, over a period of 7 h via syringe pump, a
solution of chloroketone 26 1330 mg, 0.71 mmol) in CH3CN
110 mL). The mixture was stirred for an additional 2.5h,
cooled down to rt, ®ltered on Celite, rinsed several times
with CH2Cl2 and concentrated in vacuo. The product was
puri®ed by ¯ash chromatography 1hexanes:EtOAc 7:3), to
give macrocycle 27 as a white solid, mp 139±1418C 190 mg,
1
30%). H NMR 1300 MHz, CDCl3) d 6.64±6.52 11H, m),
6.30±6.20 11H, q, Jˆ10.5Hz), 6.03 11H, d, Jˆ7.0 Hz),
5.61±5.48 11H, m), 5.44±5.31 11H, q, Jˆ10.5Hz), 5.02
11H, m), 4.55±4.35 12H, m), 3.71 13H, s), 3.96±3.56 12H,
m), 3.47±3.29 11H, m), 3.21 11H, d, Jˆ20.0 Hz), 3.16±3.05
12H, m), 2.90 11H, d, Jˆ20.0 Hz), 2.87±2.50 12H, m), 2.16±
2.00 12H, m), 1.87 13H, d, Jˆ11.5Hz). 13C NMR 175MHz,
CDCl3) d 212.7, 201.1, 169.3, 156.5 1q, Jˆ24.0 Hz), 145.6,
133.5, 132.0, 130.3, 128.3, 125.5, 116.5 1q, Jˆ280.0 Hz),
52.4, 43.9, 43.7, 42.2, 40.8, 37.5, 30.2, 28.9, 26.1, 23.7. IR
1®lm) n 2955, 1752, 1728, 1691, 1640, 1457, 1370, 1300.
MS 1EI): 427 1M1). HRMS 1M1) calc. for C21H24F3NO5:
427.1606; found: 427.1599.
3.1.12.
*^)-*3Z,9E,11Z)-7-Aza-1-chloro-2-hydroxy-4-
methyl-12-*2-methoxycarbonyl-3-oxo)cyclopentyl-7-tri-
¯uoroacetyldodeca-3,9,11-triene *25). To a solution of
protected chlorohydrine 24 1644 mg, 1.04 mmol) in THF
111 mL) at 2208C was added TBAF 11.0 M in THF,
2.1 mL, 2.1 mmol). The mixture was stirred for 5h at rt,
treated with NH4Cl sat. 110 mL), heated up to rt and
extracted with CH2Cl2 13£15mL). The combined organic
layers were dried on MgSO4 and the solvent was removed in
vacuo. The product was puri®ed by ¯ash chromatography
1hexanes:ethyl acetate 6:4) to give chlorohydrine 25 as a
3.1.15. *^)-N-*6-chloro-3-methyl-5-triisopropylsiloxy-
hex-3-ene)-N-t-butoxycarbonyl-N-tosylamide *29). To a
solution of alcohol 28 1298 mg, 0.928 mmol) in THF
110 mL) at 08C, was added TsNHBOC 1504 mg,
1.86 mmol) and triphenylphosphine 1488 mg, 1.86 mmol).
DEAD was then slowly added at 08C, and the mixture was
stirred for 24 h at rt. The solvent was removed and the crude
directly puri®ed by ¯ash chromatography 1hexanes:ethyl
acetate 8:2) to give tosylamide 29 as a yellowish oil
1
clear oil 1434 mg, 90%). H NMR 1300 MHz, CDCl3) d
6.58 11H, m), 6.04 11H, t, Jˆ11.0 Hz), 5.65±5.54 11H,
m), 5.38±5.27 12H, m), 4.51±4.40 11H, m), 4.12±3.90
12H, m), 3.66 13H, s), 3.83±3.30 14H, m), 2.9512H, d, Jˆ
11.5 Hz), 2.52±2.12 15H, m), 1.75 13H, s), 1.67±1.59 11H,
m). 13C NMR 175MHz, CDCl 3) d 210.1, 169.1, 156.8 1q,
Jˆ20.0 Hz), 138.5, 137.4, 133.3, 129.7, 127.9, 126.4, 116.5
1q, Jˆ280.5 Hz), 68.1, 61.3, 52.6, 49.4, 45.8, 39.5, 38.0,
32.0, 27.8, 23.9, 20.4. IR 1®lm) n 3480, 2957, 1728, 1687,
1443, 1356, 1276, 1202, 1147, 1065. MS 1EI) 447 1M-
H2O)1. HRMS 1M-H2O)1 calc. for C21H25ClF3NO4:
447.1424; found: 447.1417.
1
1506 mg, 95%). H NMR 1300 MHz, CDCl3) d 7.77 12H,
d, Jˆ8.4 Hz); 7.29 12H, d, Jˆ8.0 Hz); 5.28 11H, dd, Jˆ8.6,
1.1 Hz); 4.72 11H, ddd, Jˆ8.7, 5.8); 3.83 12H, m); 3.53 11H,
dd, Jˆ10.8, 5.9 Hz); 3.44 11H, dd, Jˆ10.8, 5.6 Hz); 2.68±
2.59 11H, m); 2.42 13H, s); 2.42±2.33 11H, m); 1.81 13H, s);
1.3519H, s); 1.01 121H, s). 13C NMR 175MHz, CDCl 3) d
150.7, 144.2, 137.3, 134.4, 129.2, 127.8, 84.3, 69.3, 49.5,
45.6, 33.7, 27.9, 23.3, 21.6, 18.0, 17.9, 12.3. IR 1®lm) n
2943, 2866, 1730, 1670, 1598, 1460, 1366, 1289, 1260,
1157. SM 1m/e): 530 1M-C3H7)1. HRMS 1M-C3H7)1 calc.
for C25H41O5ClNSSi: 530.2163; found: 530.2175^0.0016.
3.1.13. *^)-*3Z,9E,11Z)-7-Aza-1-chloro-4-methyl-12-*2-
methoxycarbonyl-3-oxo)cyclopentyl-2-oxo-7-tri¯uoro-
acetyldodeca-3,9,11-triene *26). To a solution of chloro-
hydrine 25 1119 mg, 0.26 mmol) in CH2Cl2 12.5mL) at 0 8C,
was added Dess±Martin periodinane 1141 mg, 0.33 mmol).
The mixture was stirred for 2.5h, treated with 1 M sodium
thiosulfate and extracted with CH2Cl2 13£5mL). The
combined organic layers were dried on MgSO4 and the
solvent removed in vacuo. The product was puri®ed by
¯ash chromatography 1hexanes:ethyl acetate 7:3), to give
chloroketone 26 as a clear oil 154 mg, 74% corrected
3.1.16. *^)-N-*6-chloro-3-methyl-5-triisopropylsiloxy-
hex-3-ene)-N-tosylamide *30). A solution of sulfonamide
29 152 mg, 0.09 mmol) in DMSO 11 mL) was heated up to
170±1808C for 20 min. The mixture was poured into water
and extracted four times with a 1:1 mixture of hexanes and
diethyl ether. The organic layers were dried on sodium
sulphate, ®ltered and the solvents removed in vacuo. The
product was puri®ed by ¯ash chromatography 1hexanes±
ethyl acetate 8:2), to give sulfonamide 30 as a yellow oil
1
yield). H NMR 1300 MHz, CDCl3) d 6.78±6.63 11H, m),
6.27 11H, d, Jˆ11.5Hz), 6.08±6.00 11H, t, Jˆ11.0 Hz),
5.73±5.56 11H, m), 5.38±5.28 11H, m), 4.32±4.05 14H,
m), 3.66 13H, s), 3.75±3.34 13H, m), 2.94 12H, d, Jˆ
11.5Hz), 3.00±2.72 11H, m), 2.52±2.12 13H, m), 1.99
13H, d, Jˆ13.0 Hz), 1.72±1.56 11H, m). 13C NMR
175MHz, CDCl 3) d 210.7, 190.9, 168.8, 159.7, 157.9,
156.4 1q, Jˆ20.0 Hz), 133.1, 130.0, 127.9, 121.3, 116.5
1q, Jˆ280.5Hz), 61.4, 52.3, 49.7, 43.9, 39.7, 38.0, 34.0,
31.5, 27.9, 26.3. IR 1®lm) n 2951, 1756, 1727, 1691,
1620, 1515, 1443, 1361, 1271, 1201, 1146. MS 1EI): 463
1M1). HRMS 1M1) calc. for C21H25ClF3NO5: 463.1373;
found 463.1360.
1
134 mg, 81%). H NMR 1300 MHz, CDCl3) d 7.73 12H, d,
Jˆ8.3 Hz), 7.30 12H, d, Jˆ8.3 Hz), 5.21 11H, d, Jˆ8.8 Hz),
4.70 11H, t, Jˆ5.9 Hz), 4.50 11H, ddd, Jˆ12.5, 8.7, 0.8 Hz),
3.50 11H, dd, Jˆ10.7, 5.5 Hz), 3.15 11H, dd, Jˆ10.7,
6.9 Hz), 3.12±2.91 12H, m), 2.42 13H, s), 2.39±2.31 11H,
m), 2.17±2.09 11H, m), 1.62 13H, s), 1.01 121H, s). 13C
NMR 175MHz, CDCl 3) d 143.4, 136.8, 134.3, 129.9,
129.7, 127.1, 69.2, 48.8, 40.9, 32.5, 22.7, 21.5, 17.8, 12.3.

D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
4175
IR 1®lm) n 3282, 2944, 2888, 1668, 1599, 1463, 1382, 1159,
1094, 1015. SM 1m/e): 430 1M-C3H7)1. HRMS 1M-C3H7)1
calc. for C20H33O3ClNSSi: 430.1639; found: 430.1629^
0.0013.
1300 MHz, CDCl3) d 7.67 12H, d, Jˆ8.1 Hz), 7.29 12H, d,
Jˆ8.0 Hz), 6.49 11H, dd, Jˆ14.3, 11.5Hz), 5.99 11H, td,
Jˆ11.0, 3.2 Hz), 5.57±5.20 13H, m), 4.50±4.38 11H, m),
3.94±3.40 14H, m), 3.68 13H, s), 3.20±3.00 11H, m),
3.20±1.90 17H, m), 2.9511H, d, Jˆ11.5Hz), 2.40 13H, s),
1.71 13H, s), 1.70±1.50 11H, m). 13C NMR 175MHz,
CDCl3) d 210.2, 169.1, 143.4, 138.2, 136.7, 132.4, 131.2,
129.8, 129.7, 129.1, 127.1, 126.2, 68.0, 61.3, 52.5, 50.5,
49.4, 46.0, 39.6, 38.0, 32.5, 27.7, 23.6, 21.5. IR 1®lm) n
3502, 2973, 2932, 2872, 1756, 1729, 1439, 1336, 1285,
1157, 1118. SM 1m/e): 491 1M - CH4O)1. HRMS1M-
CH4O)1 calc. for C25H50O5ClNS: 491.1533; found:
491.1542^0.0014.
3.1.17. *^)-*3Z,9E,11Z)-7-Aza-1-chloro-4-methyl-12-*2-
methoxycarbonyl-3,3-dimethoxy)cyclopentyl-7-p-toluene-
sulfonyl-2-triisopropylsiloxydodeca-3,9,11-triene *32).
To a solution of sulfonamide 30 12.8 g, 5.9 mmol) and
triphenylphosphine 13.2 g, 12.2 mmol) in THF 158 mL) at
08C, was added via canula alcohol 31 11.1 g, 4.1 mmol),
followed by DIAD 12.0 mL, 10.2 mmol). The mixture was
stirred at rt for 3 h, and the solvent removed in vacuo. The
product was puri®ed by ¯ash chromatography 1hexanes±
ethyl acetate 9:1), to give the desired product as a yellowish
oil contaminated with the starting tosylamide, which was
3.1.20. *^)-*3Z,9E,11Z)-7-Aza-1-chloro-4-methyl-12-*2-
methoxycarbonyl-3-oxo)cyclopentyl-2-oxo-7-p-toluene-
sulfonyldodeca-3,9,11-triene *35). The procedure for the
synthesis of 26 was followed 1starting on 1.02 g of 34).
Puri®cation by ¯ash chromatography 1hexanes±ethyl
acetate, 7:3) gave chloroketone 35 as a clear oil 1810 mg,
1
removed during the subsequent step. H NMR 1300 MHz,
CDCl3) d 7.68 12H, d, Jˆ8.1 Hz), 7.30 12H, d, Jˆ8.1 Hz),
6.50 11H, dd, Jˆ13.7, 12.2 Hz), 5.88 11H, td, Jˆ10.9,
2.3 Hz), 5.49 11H, td, Jˆ14.6, 7.5Hz), 5.26 11H, t, Jˆ
10.3 Hz), 5.18 11H, d, Jˆ9.0 Hz), 4.62±4.52 11H, m),
3.97±2.70 12H, m), 3.6513H, s), 3.58±3.40 12H, m), 3.35
11H, ddd, Jˆ10.7, 6.2, 2.0 Hz), 3.26 13H, s), 3.19 13H, s),
3.19±2.9512H, m), 2.69 11H, d, Jˆ8.6 Hz), 2.52±2.35 11H,
m), 2.43 13H, s), 2.28±2.08 11H, m), 2.08±1.3514H, m),
1.68 13H, s), 1.05121H, s). 13C NMR 175MHz, CDCl 3) d
171.9, 143.2, 134.9, 129.7, 129.0, 128.3, 127.2, 127.1,
111.5, 69.4, 69.2, 57.9, 51.8, 51.0, 50.8, 50.0, 49.2, 48.9,
45.9, 40.8, 36.3, 32.7, 30.0, 23.2, 22.6, 21.5, 17.9, 12.3. IR
1®lm) n 2945, 2866, 1738, 1461, 1437, 1348, 1255, 1159,
1119, 1093, 1050. SM 1m/e): 682 1M - C3H7)1. HRMS 1M -
C3H7)1 caqlc. For C37H60O7ClNSSi: 682.3000; found:
682.2991^0.0020.
1
79%). H NMR 1300 MHz, CDCl3) d 7.62 12H, d, Jˆ
8.2 Hz), 7.23 12H, d, Jˆ8.1 Hz), 6.52 11H, dd, Jˆ14.8,
11.5Hz), 6.18 11H, s), 5.91 11H, t, Jˆ10.9 Hz), 5.45 11H,
dt, Jˆ15.2, 6.8 Hz), 5.24 11H, t, Jˆ10.0 Hz), 4.07±4.00
12H, m), 3.97±3.79 12H, m), 3.67±3.51 12H, m), 3.62
13H, s), 3.29±3.11 13H, m), 2.89 11H, d, Jˆ11.5Hz),
2.80±2.69 12H, m), 2.44±2.04 11H, m), 2.3513H, s), 1.92
13H, s), 1.65±1.53 11H, m). 13C NMR 175MHz, CDCl 3) d
210.6, 190.7, 168.9, 159.8, 143.2, 137.0, 132.2, 129.6,
129.4, 129.3, 127.1, 127.0, 121.2, 61.5, 52.3, 49.5, 49.3,
45.4, 39.7, 38.0, 33.4, 27.9, 26.4, 21.4. IR 1®lm) n 2974,
2935, 2874, 1756, 1729, 1702, 1618, 1439, 1336, 1284,
1157, 1117, 1092. MS 1m/e): 521 1M1). HRMS 1M1) calc.
for C26H52O6ClNS: 521.1639; found: 521.1644^0.0016.
3.1.18. *^)-*3Z,9E,11Z)-7-Aza-1-chloro-4-methyl-12-*2-
methoxycarbonyl-3-oxo)cyclopentyl-7-p-toluenesulfonyl-
2-triisopropylsilyloxydodeca-3,9,11-triene *33). The pro-
cedure for the synthesis of 24 was followed 1starting on
2.9 g of impure 32). Puri®cation by ¯ash chromatography
1hexanes±ethyl acetate 8:2) gave ketone 33 as a colorless oil
3.1.21. *^)-*4Z,10E,12Z)*1R*,14S*)-8-Aza-5-methyl-1-
methoxycarbonyl-3,17-dioxo-8-p-toluenesulfonylbicyclo-
[12.3.0]heptadeca-4,10,12-triene *36). To a solution of
cesium carbonate 11.4 g, 4.3 mmol) and sodium iodide
10.65g, 4.3 mmol) in acetonitrile 1800 mL) at 45 8C, was
added over 1.5h, with a syringe pump, a solution of chloro-
ketone 35 10.45g, 0.86 mmol) in acetonitrile 110 mL). The
mixture was stirred for 4 h at the same temperature, cooled
down to rt, ®ltered on Celite, rinsed with methylene chloride
and the solvent was removed in vacuo. The product was
puri®ed by ¯ash chromatography 1hexanes:ethyl acetate,
8:2), to give macrocycle 36 as a white solid 1250 mg,
1
11.8 g, 65% 12 steps).) H NMR 1300 MHz, CDCl3) d 7.68
12H, d, Jˆ8.0 Hz), 7.30 12H, d, Jˆ8.0 Hz), 6.49 11H, dd,
Jˆ14.0, 12.0 Hz), 6.01 11H, td, Jˆ11.0, 3.0 Hz), 5.61±5.52
11H, m), 5.30 11H, t, Jˆ10.0 Hz), 5.18 11H, d, Jˆ8.5Hz),
4.55 11H, ddd, Jˆ11.0, 8.5, 6.0 Hz), 3.93±3.53 13H, m),
3.69 13H, s), 3.50 11H, ddd, Jˆ11.0, 6.0, 1.5Hz), 3.33
11H, ddd, Jˆ11.0, 6.0, 3.5Hz), 3.18±2.96 12H, m), 2.95
11H, d, Jˆ11.5 Hz), 2.51±2.10 15H, m), 2.42 13H, s),
1.72±1.59 11H, m), 1.68 13H, s), 1.03 121H, s). 13C NMR
175MHz, CDCl 3) d 210.3, 168.8, 143.3, 134.7, 132.3,
129.7, 128.9, 127.2, 69.5, 61.4, 52.5, 50.9, 50.6, 49.1,
46.7, 46.1, 45.8, 39.7, 38.0, 32.8, 32.6, 28.0, 23.2, 21.5,
17.9, 12.3. IR 1®lm) n 3029, 2946, 2867, 1758, 1729,
1462, 1438, 1339, 1220, 1210, 1158, 1091. SM 1m/e): 636
1M-C3H7)1. HRMS 1M-C3H7)1 calc. for C32H47O6ClNSSi:
636.2582; found: 636.2589^0.0019.
1
60%). H NMR 1300 MHz, CDCl3) d 7.66 12H, d, Jˆ
8.2 Hz), 7.29 12H, d, Jˆ8.0 Hz), 6.3511H, dd, Jˆ14.9,
10.7 Hz), 6.12 11H, t, Jˆ10.6 Hz), 5.97 11H, s), 5.42 11H,
ddd, Jˆ15.0, 9.9, 4.5 Hz), 5.25 11H, t, Jˆ10.8 Hz), 4.27
11H, dt, Jˆ10.5, 8.4 Hz), 4.14 11H, dd, Jˆ14.6, 4.4 Hz),
3.66 13H, s), 3.46±3.30 11H, m), 3.32 11H, dd, Jˆ14.6,
10.0 Hz), 3.21±3.07 11H, m), 3.13 11H, d, Jˆ19.6 Hz),
2.84 11H, d, Jˆ19.6 Hz), 2.85±2.73 11H, m), 2.67±2.46
12H, m), 2.41 13H, s), 2.09±1.99 12H, m,), 1.82 13H, s),
1.82±1.70 11H, m). 13C NMR 175MHz, CDCl 3) d 212.7,
200.5, 169.4, 147.6, 143.6, 136.3, 130.7, 129.9, 129.7,
127.8, 127.4, 127.1, 61.6, 52.4, 49.0, 45.3, 42.3, 40.9,
37.5, 29.5, 26.0, 23.4, 21.5. IR 1®lm), n 3020, 2955, 1754,
1732, 1688, 1627, 1599, 1455, 1392, 1338, 1224, 1159,
1093. MS 1m/e): 4851M 1). HRMS 1M1) calc. for
C26H31O6NS: 485.1872; found: 485.1882 ^0.0014.
3.1.19.
*^)-*3Z,9E,11Z)-7-Aza-1-chloro-2-hydroxy-4-
methyl-12-*2-methoxycarbonyl-3-oxo)cyclopentyl-7-p-
toluenesulfonyldodeca-3,9,11-triene *34). The procedure
for the synthesis of 25 was followed 1starting with 1.74 g
of 33). Puri®cation by ¯ash chromatography 1hexanes±ethyl
1
acetate, 6:4) gave 34 as a clear oil 11.26 g, 92%). H NMR

4176
D. Fortin et al. / Tetrahedron 57 $2001) 4167±4177
3.1.22.
*^)-3-Aza-6,7-dehydro-18-methoxy-18-oxo-3-
1739, 1692, 1460, 1388,1375, 1352. MS 1EI): 427 1M1).
HRMS 1M1) calc. for C21H24F3NO5: 427.1606; found:
427.1602.
toluenesulfonylandrosterone *37b). To a solution of
cesium carbonate 11.25g, 3.84 mmol) in CH 3CN
1750 mL) at 828C, was added with a syringe pump over
12 h a solution of chloride 13 131 mg, 0.0611 mmol) in
CH3CN. After 12 h additional stirring, the mixture was
cooled down and ®ltered on Celite. The product was puri®ed
by ¯ash chromatography 1hexanes:EtOAc 6:4) to give an
inseparable mixture of diastereomers 1CATAT:TACST
3.1.25.
*^)-2b6a7a10a14b-3-methyl-6-tosylamido-
methyltricyclo[4.9.010,14]pentadeca-3,8-dien-1,13-dione
*40). A solution of macrocycle 36 158 mg, 0.12 mmol) and
triethylamine 150 mL, 0.36 mmol) in toluene 12 mL) was
introduced in a pyrex tube, previously washed with ammo-
nium hydroxide, water then acetone. The solution was
degassed, the tube was sealed in vacuo then heated up for
12 h in an oven at 2358C. The tube was cooled down to rt,
opened and the solvent removed in vacuo. The product was
puri®ed by ¯ash chromatography 1hexanes±ethyl acetate,
9:1) to give tricycle 40 125mg, 49%) as a clear oil, which
was crystallized from methanol:hexanes 1mp 199±2028C).
1H NMR 1300 MHz, CDCl3) d 7.72 12H, d, Jˆ8.3 Hz), 7.32
12H, d, Jˆ7.9 Hz), 5.64 11H, dd, Jˆ10.5, 6.5 Hz), 5.55 11H,
m), 5.47 11H, td, Jˆ10.1, 1.5Hz), 4.31 11H, t, Jˆ6.8 Hz),
3.06 11H, ddd, Jˆ13.1, 6.8, 3.9 Hz), 2.96±2,87 11H, m),
2.87±2.67 13H, m), 2.58 11H, dd, Jˆ11.8, 3.0 Hz), 2.44
13H, s), 2.32±2.10 13H, m), 2.08±1.87 12H, m), 1.82±1.60
12H, m), 1.60±1.50 15H, m). 13C NMR 175MHz, CDCl 3) d
212.5, 143.6, 133.9, 133.4, 129.8, 129.2, 127.0, 127.0,
123.7, 77.2, 65.2, 54.2, 46.7, 42.0, 38.9, 36.8, 36.3, 29.8,
27.1, 21.5, 21.0. IR 1®lm) n 3285, 2922, 2853, 2357, 1733,
1454, 1378, 1322, 1158, 1085. MS 1m/e): 427 HRMS 1M1)
calc. for C24H29O4NS: 427.1817; found: 427.1820^0.0013.
1
4.5:1) 117 mg, 59%). Major adduct: H NMR 1300 MHz,
CDCl3) d 7.69±7.63 12H, m), 7.34±7.28 12H, m), 5.69
11H, d, Jˆ10.0 Hz), 5.56 11H, dt, Jˆ3.0, 10.0 Hz), 3.69
13H, s), 3.59±3.53 11H, m), 2.70±1.95 112H, m), 1.91±
1.10 18H, m), 0.89 13H, s). 13C NMR 1300 MHz, CDCl3)
d 212.2, 169.7, 143.4, 133.6, 129.7, 129.7, 128.7, 128.5,
127.6, 127.5, 60.9, 52.3, 51.6, 47.8, 43.4, 41.8, 39.0, 37.8,
37.3, 34.51, 32.5, 29.6, 22.5, 22.3, 21.6, 21.2. IR 1®lm) n
2953, 2870, 1748, 1723, 1648, 1599, 1456, 1340. MS 1EI)
471 1M1). HRMS 1M1) calc. for C26H33O5NS: 471.2079;
found: 471.2074.
3.1.23. *^)-3-Aza-6,7-dehydro-18-methoxy-18-oxo-3-tri-
¯uoroacetylandrosterone *38b). To a solution of cesium
carbonate 14.60 g, 14.1 mmol) in CH3CN 11100 mL) at
828C, was added over 12 h, with a syringe pump, a solution
of chloride 18 1456 mg, 1.02 mmol) in CH3CN 19 mL).
After stirring for 7 h at the same temperature, the mixture
was cooled down, ®ltered on Celite and the solvent removed
in vacuo. The product was puri®ed by ¯ash chromatography
1hexanes:EtOAc 6:4) to give a mixture of diastereomers
1CATAT:TACST 5.2:1) 1271 mg, 63%). The major adduct
38b 1CATAT) was crystallized from EtOAc:hexanes 1mp
150±1528C), to give a crystal on which X-ray analysis was
Acknowledgements
A basic research chair from Biochem Pharma Inc. is grate-
fully acknowledged, as well as ®nancial support from
NSERC Canada. We wish to thank Mr Marc Drouin for
X-ray analyses, as well as Mr Gaston Boulay for MS analyses.
1
performed. H NMR 1300 MHz, CDCl3) d 5.79 11H, t,
Jˆ9.5 Hz), 5.61±5.52 11H, m), 3.70 13H, s), 3.30±2.80
12H, m), 2.75±2.45 14H, m), 2.35±1.80 15H, m), 1.70±
1.2517H, m), 0.92 13H, s). 13C NMR 175MHz, CDCl 3) d
211.9, 169.7, 157.0 1q), 129 1, 126.7, 116.5 1q, Jˆ
288.0 Hz), 60.9, 52.3, 51.7, 45.0, 43.2, 40.6, 39.3, 37.5,
37.2, 35.6, 34.4, 29.8, 22.3, 21.9, 21.5. IR 1®lm) n 3019,
2954, 2874, 1753, 1724, 1692, 1464, 1194, 1147. MS 1EI):
413 1M1). HRMS 1M1) calc. for C21H26F3NO4: 413.1814;
found: 413.1821.
References
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3.1.24. *^)-3-Aza-6,7-dehydro-4,5a-dihydro-18-meth-
oxy-18-oxo-3-tri¯uoroacetyl-9b-adrenosterone
*39).
Macrocycle 27 17 mg, 16.4 mmol) in solution in degassed
toluene 11.0 mL) was heated up in a pyrex tube in vacuo at
1958C for 12 h. The solvent was removed in vacuo and the
product puri®ed by ¯ash chromatography 1hexanes:EtOAc
7:3) to give tetracycle 39 having the TSCAT stereo-
chemistry as a thick oil 14 mg, 78% corrected yield). To
be noted, the restricted rotation around the amide bond
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appearance of which was temperature dependent. 1H
NMR 1300 MHz CDCl3) d 5.94 11H, dq, Jˆ2.5, 12.0 Hz),
5.46 11H, dt, Jˆ2.5, 12.0 Hz), 4.3±3.6 15H, m), 3.20 11H,
m), 3.057±2.70 14H, m), 2.65±2.10 15H, m), 1.98 11H, dd,
Jˆ2.5, 13.0 Hz), 1.86 13H, s), 1.60 12H,s), 1.4±1.2 11H, m),
0.92 13H,s). 13C NMR 175MHz, CDCl 3) d 211.3, 178.0,
173.0, 140.1 1q), 132.4, 128.7, 124.6, 116.1 1q, Jˆ
288.5 Hz), 59.6, 51.2, 50.6, 50.1, 49.4, 47.8, 45.4, 43.7,
40.3, 37.7, 29.7, 24.7, 22.6. IR 1®lm) n 2927, 2856, 1766,
Â
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Â
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17. Iodide 6 was synthesized in 8 steps from but-3-yn-1-ol, see: