Ti(II) and Rh(I) Complexes as Reagents toward a Thapsigargin Core

Article abstract of DOI:10.1021/acs.joc.8b03249

A novel approach toward the [5 - 7]fused bicyclic core of thapsigargin, a subnanomolar inhibitor of the endo/sarcoplasmic calcium ATPase (SERCA), is presented. The synthetic route includes an original Ti(II)-mediated hydroxy-directed reductive coupling of

Full text of DOI:10.1021/acs.joc.8b03249

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Note
Ti(II) and Rh(I) Complexes as Reagents towards Thapsigargin Core
Youssouf Sanogo, Raja Ben Othman, Sabrina Dhambri, Mohamed Selkti, Alan Jeuken, Joëlle
Prunet, Jean-Pierre Férézou, Janick Ardisson, Marie-Isabelle Lannou, and Geoffroy Sorin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03249 • Publication Date (Web): 09 Apr 2019
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Page 1 of 13
The Journal of Organic Chemistry
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Ti(II) and Rh(I) Complexes as Reagents towards Thapsigargin
Core
Youssouf Sanogo,† Raja Ben Othman,† Sabrina Dhambri,† Mohamed Selkti,# Alan Jeuken,§
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§
†,*
†,*
∥
Joëlle Prunet, Jean-Pierre Férézou, Janick Ardisson, Marie-Isabelle Lannou and Geof-
froy Sorin†,*
† Unité CNRS UMR 8638 Université Paris Descartes, Faculté de Pharmacie, Sorbonne Paris Cité, 4 avenue de l’Observatoire, 75270 PARIS cedex
06, France
# Unité CNRS UMR 8015, Université Paris Descartes, Faculté de Pharmacie, Sorbonne Paris Cité, 4 avenue de l’Observatoire, 75270 PARIS cedex
06, France
§ WestCHEM, School of Chemistry, University of Glasgow, Joseph Black Building, University Avenue, Glasgow G12 8QQ, UK
∥
Méthodologie, Synthèse et Molécules Thérapeutiques, ICMMO (CNRS UMR 8182), Université Paris-Sud, Université Paris-Saclay, Bâtiment 410,
F-91405 Orsay, France
Natural products • Multi–step synthesis • Thapsigargin • Titanium(II) complexes • Rhodium(I) complexes.
ABSTRACT: A novel approach towards the [5–7] fused bicyclic core of thapsigargin, a subnanomolar inhibitor of the
endo/sarcoplasmic calcium ATPase (SERCA), is presented. The synthetic route includes an original Ti(II)–mediated
hydroxy–directed reductive coupling of an enantiomerically enriched propargylic alcohol and an intramolecular Rh(I)–
catalyzed cyclocarbonylation reaction as key steps. Interestingly, through first experiments of titanocene-mediated re-
ductive cyclization of a 1,8–enyne, a seven–membered cycle was isolated as a unique product with a total diastereose-
lectivity.
7b,e
Sesquiterpene lactones of the guaianolide type are
widespread in natural products and have recently at-
tracted much interest from the synthetic community.1
Among them, the guaianolide thapsigargin (Tg) 1, isolat-
ed from the Mediterranean plant species Thapsia
(Apiaceae),2 is a very potent inhibitor of the en-
do/sarcoplasmic calcium ATPase (SERCA), related to a
subnanomolar affinity for this enzyme.3 Remarkably,
thapsigargin prodrugs are currently evaluated in patients
with various cancer types.4 Structurally, Tg 1 presents a
challenging complex chemical structure, including a
polyoxygenated [5–7–5] fused tricyclic core possessing
eight stereogenic centres and functionalized with five
different ester groups.5
sequence
tion.7f,h
or allenic Pauson–Khand type annela-
Scheme 1: Ley’s, Baran’s and Evans’ total synthesis of
Tg 1.
O
14
OAc
O
6
H
O
10
2
1
O
O
OH
O
Thapsigargin Tg 1
3
7
5
OH
13
11
O
15
12
O
Ley 2007, 42 steps, 0.61%
OMOM
OMOM
H
H
H
Ring Closing
Metathesis
TBDPSO
TBDPSO
H
TESO
H
TESO
OEt
O
OEt
(S)-
(+)-
Carvone
Baran 2017, 11 steps, 0.14%
The promising therapeutic potential associated to the
unique structure of Tg have attracted many efforts aimed
at the achievement of its total synthesis. Remarkably,
Ley et al. succeeded in the first total synthesis of Tg 1
from (S)–carvone by means of a key ring–closing diene
metathesis step (2).6a-c Very recently, two elegant, scal-
able and concise total syntheses were reported by Baran
and Evans groups through, respectively, a photochemi-
cal rearrangement (3) and a pinacol cyclization (4) also
from carvone derivatives (Scheme 1).6d,e A few other
efforts have led to alternative interesting approaches,7
through either ring–closing metathesis,7c,i photochemical
rearrangement,7a,d,g cycloaddition [2+2] / ring expansion
2
O
C3H7
OAc
O
H
H
O
Photochemical
rearrangement
C3H7
OH
O
O
O
OH
O
OTBS
TBSO
(+)-
Dihydrocarvone
3
Evans 2017, 12 steps, 5.8%
H
H
H
Pinacol
cyclization
TBSO
OBn
HO
TBSO
OBn
O
OTMS
OTMS
O
O
O
MeO2C
O
(R)-(-)-Carvone
4
In our laboratories, a combined program towards the
elaboration of Tg 1 and analogues aimed at developing
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The Journal of Organic Chemistry
Page 2 of 13
two synthetic approaches. In this context, a diastereose- This reaction was related to that performed by Yang et
al. 10a in 2010. It is interesting to note that, in 1995, pio-
neering works were achieved by Sato et al. who estab-
lished that low–valent titanium alkoxide Ti(OiPr)2, pre-
pared by combining of Ti(OiPr)4 / 2 iPrMgCl, regioselec-
tively incorporates silylacetylenes to provide titanacyclo-
propene complexes which act as versatile vicinal vinylic
dianions.10b-e Sequential reactions with two different
electrophiles were validated with high regio– and (E)/(Z)
stereoselectivity. More particularly, Sato described the
reductive coupling of silylalkyne with a ketone to provide
an allylic alcohol in high yield and regioselectivity. Later,
Yang reported that, when this reaction involved a pro-
pargylic alcohol and an aldehyde as starting materials,
an hydroxy–directed reductive coupling could occur
providing syn–1,3–diols with good to high yields and
diastereoselectivities. However, only a limited range of
ketones was tested and reactions revealed sometimes
less effective, with moderate yields and diastereoselec-
tivity, although no rationalization was provided (Scheme
3).
1
2
3
4
5
6
7
8
lective route from commercial 2–methyl–cyclopentane–
1,3–dione and involving a ring–closing enyne metathesis
for the formation of the bicyclic system has been very
recently reported.7i We envisioned an alternative strategy
towards Tg 1 framework comprising two key steps, in-
stallation of the chains on either side of the C7 tertiary
alcohol and formation of the bicyclic system through
allene–yne Rh(I)–catalyzed Pauson–Khand annelation
(APKR).7f More recently, we have successfully per-
9
formed
intramolecular
alkoxyallene–ynes
Rh(I)–
10
11
12
13
14
15
16
17
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catalyzed Pauson–Khand reactions, to access [5–7]
fused ring systems bearing an enol ether moiety.8
Herein, we report a new route towards the bicyclic
core of Tg 1 including a diastereoselective titanium–
mediated reductive coupling of a propargylic alcohol and
an intramolecular cyclocarbonylation reaction as key
steps.
To address the challenges in forming the bicyclic sys-
tem of Tg 1 and ensuring the installation of the range of
functional groups throughout the cyclic system, we
planned to develop a new sequence involving the stere-
oselective construction of the key C4–C10 (E)–enyne
subunit 9. Indeed, this segment could be considered as
a critical precursor for the elaboration of the bicyclic
dienone 5 or trienone 7 from respectively 1,8–enyne 6 or
allene–yne 8 by intramolecular carbocyclisation (Scheme
2).
Scheme 3. Yang’s reductive coupling reactions.
1. iPrMgCl (3.2 equiv.)
R
R
2. Ti(OiPr)4 (1.6 equiv.)
Et2O, 78 to 40 °C, 5 h
TMS
OH
OH
OH
-
-
3. Electrophile (3.5 equiv.)
RS
RL
TMS
Et2O,
-
78 to
O
-
50 °C, 18 h
RL
RS Yield (%) dr
R
Cy
H
78
62
26
20:1
11:1
4:1
nPr
Et
RL
RS
nBu Me
17-77%, dr < 20:1
vinyl Me
iPr
Scheme 2. Retrosynthetic analysis.
Therefore, inspired by these works,10 we have envi-
sioned the synthesis of (E)–enyne 9 by diastereoselec-
tive titanium reductive coupling reaction between pro-
pargylic alcohol (S)–12 and methyl pyruvate 11a, as this
sequence would represent a highly concise route to the
key C4–C10 segment (Scheme 2).
1
10
OH
OH
OH
H
4
10
Ene-yne
1
7
OH
OH
3
O
7
5
cyclo
-
OH
12
carbonylation
O
MeO2C
Late
functionalization
OMe
6
5
1
Tg 1
9
•
The synthesis of (E)–enyne 9b began with the prepa-
ration of enantiomerically enriched propargylic alcohol
(S)–12, which was readily achieved in 93% yield and
90% ee by means of Noyori reduction 11 of known ynone
13 (derived from propanediol in 66% yield over four
steps) (Scheme 4).12,13,14
10
4
1
5
10
Allene-yne
OH
OH
7
OH
OH
3
O
7
6
cyclo
-
12
carbonylation
O
MeO2C
OMe
7
8
PO
10
PO
P = protecting group
[Pd] Cross
PO
10
10
4
[Ti] Reductive
coupling
coupling
R3Si
8
8
OP
OH
OH
8
OH
Scheme 4. Synthesis of enyne 9b.
6
O
6
11
11
OP
O
MeO2C
OMe
R3Si
OMe
10
O
9
11a
12
The major milestone of our strategy was to efficiently
synthesize the C4–C10 fragment 9. The latter comprises
a tertiary and a secondary alcohol at respectively C11
and C8 in a syn relationship linked to a (E) double bond
at C6–C7. Such fragment is frequently encountered in
the skeleton of natural products 9 or synthetic intermedi-
ates 6d and a general method for its elaboration could be
very useful.
Enyne 9 would derive from (E)–vinylic silane 10 by
palladium–catalyzed cross–coupling reaction. The dia-
stereoselective construction of the syn–1,3–diol moiety
at C8–C11 in the segment 9 was designed to be imple-
mented using a Ti(II) mediated hydroxy–directed reduc-
tive coupling of propargylic alcohol 12 with methyl py-
ruvate 11a (Scheme 2).
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The Journal of Organic Chemistry
Noyori's catalyst (7 mol %)
O
carried out on a 33 mmol scale of propargylic alcohol
iPrOH, RT, 2 h
10
6
HO
OH
8
(S)–12 in a reproducible manner.15 Unfortunately, when
implementing optimized conditions to ketones 11a–c, no
significant improvement was observed.
TBDPSO
1
2
66%
propane-1,3-diol over 4 steps
93%, ee 90%
TMS
13
Ts
N
Noyori's
catalyst
3
Ru
N
H
4
5
6
7
8
9
1. iPrMgCl (1.1 equiv.)
0 °C, 15 min
2. Ti(OiPr)4 (4 equiv.)
iPrMgCl (8.2 equiv.)
Scheme 5. Optimization of the titanium reductive cou-
pling reaction.
TBDPSO
TBDPSO
2,2-DMP
PPTS
DCM, RT, 16 h
10
10
-
35 °C, 2 h
TBDPSO
TBDPSO
TBDPSO
TMS
8
OH
OH
8
OH
10
10
10
97%, dr 95:5
3. 11d (10 equiv.)
Toluene (0.1 M),
Yang's or
6
6
11
8
laboratory's conditions
OH
TMS
8
OH
OH
TMS
8
OH
+
TMS
-
50 °C, 16 h
6
6
6
(S)
-
12
11
42%, 53% (brsm)
syn/anti 87:13
Z/E 0:100
Ketone
14d
TMS
R
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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R = CO2Me
R = CH2OBn
R = CH OTBS
2
R = CH=CH2
11a
11b
11c
11d
14a
14b
14c
14d
(S)
-
12
18
O
1. O3, DCM/MeOH,
-78 °C, 4 h
then NaBH4, 78 °C to RT
-
R
TBDPSO
TBDPSO
2. DMP, NaHCO3, DCM, RT, 1 h
3. NaClO2, NaH2PO4
2-methyl-2-butene
10
a Yang's conditions: 1. iPrMgCl (3.2 equiv.), Ti(OiPr)4 (1.6 equiv.), Et2O,
2. Ketone 11a d (3.5 equiv.), Et2O, 78 to 50 °C, 18 h
b Laboratory's conditions: 1. iPrMgCl (1.1 equiv.), 0 °C, 15 min;
-
78 to
-
40 °C, 5 h;
TMS
O
O
TMS
8
O
O
8
tBuOH/H2O, RT, 2 h
-
-
-
6
6
11
4. TMSCHN2
PhH/MeOH, RT, 20 min
a
nOe
H6-H13
O
12
2. Ti(OiPr)4 (4 equiv.), iPrMgCl 1.35 M in Et2O (8.2 equiv.) 2 h,
-
35 °C, solvent (0.1 M);
13
nOe
H6-Ha
OMe
15
3. Ketone 11a-d (10 equiv.).
16
47% over 4 steps
dr 95:5
Ketone
SnBu3
Entry
Conditions
Conv. %
Ratio 14/18
14 dr Isolated Yield
syn/anti
TBDPSO
RO
10
%
-
10
PdCl2(PPh3)2 (20 mol %)
CuI (20 mol %)
THF, 50 °C, 2 h
NIS, MeCN
120 °C, 72 h
4
a
11a-c
1
2
0
-
I
O
O
8
O
5
6
6
b 11d, Et2O
65
(14d)
87:13
-
11d
O
70%, dr 95:5
77%, dr 95:5
12
O
2h,
-
50 °C
45:55
12
O
OMe
17
OMe
b 11d, Tol.
16h, 50 °C
62
(14d)
87:13
(14d) 42
53 brsm
11d
3
9a R = TBDPS
TBAF, THF
RT, 16 h
-
82:18
70%, dr > 95:5
9b R = H
Crystal structure
At this stage, protection of the 1,3–diol 14d as a cyclic
ketal 15 (97% yield, dr 95:5), followed by classical trans-
formation of the terminal double bond into an ester func-
tion in four steps (reductive ozonolysis, Dess–Martin
periodinane oxidation, Pinnick oxidation 16 and esterifica-
tion), delivered 16 in 47% yield (dr 95:5).17 The relative
configuration of cyclic ketal 15 was established by nOe
NMR experiments. Finally, a three step sequence involv-
of (±)
-9b
by ORTEP diagram
Subsequent reductive coupling reaction of propargylic
alcohol (S)–12 turned out to be more challenging than
expected. The results are summarized in Scheme 5.
Despite several attempts, the coupling reaction between
(S)–12 and methyl pyruvate 11a under Yang’s conditions
failed to give 14a (Entry 1). A methodologic survey of the
coupling reaction between (S)–12 and several ketones
(11b–d) was thus realized. The reactivity of a–
oxygenated methylketones 11b and 11c was examined
under Yang’s conditions, however, starting material was
systematically recovered in both cases (Entry 1). Methyl
vinyl ketone 11d was next considered, since resulting
diol (14d) would be a relevant intermediate in the elabo-
ration of key enyne 9. For the purpose of improving
Yang’s results (Scheme 3), the reaction was performed
after initial formation of the corresponding alkoxide with
one equivalent of iPrMgCl and generation of the titani-
um(II) / acetylene complex [produced in situ in the pres-
ence of iPrMgCl (8 equivalents) and Ti(OiPr)4 (4 equiva-
lents), for 2 h at –35 °C]. In diethyl ether as solvent, the
formation of diol 14d appeared rather sluggish, since
65% conversion was observed along with a 45:55 ratio
18
ing iododesilation (17) followed by Stille coupling (9a)
and cleavage of silyl ether at C10 afforded alcohol 9b (dr
> 95:5). The structure of 9b was unambiguously con-
firmed by X–ray crystallography (Scheme 4).19
With enyne 9b in hands, we focused on the intramo-
lecular cyclocarbonylation step for the elaboration of
bicycles 5 and 7 (Scheme 2). At this stage, the sequence
was studied in racemic series from easy accessible (±)–
9b.15,20
Towards bicyclic (±)–dienone 5 comprising the tertiary
alcohol at C10 of Tg 1, 1,8–enyne (±)–20 was prepared
in a classical four step sequence, via alcohol (±)–19, as
a separable mixture of diastereomers [(±)–20a,b dr
55:45]. To our knowledge, elaboration of [5–7] fused
bicyclic pentenones by Pauson–Khand reactions from
1,8–enynes is scarcely reported.21 First attempts in the
presence of Co(CO)8 and CO were not conclusive de-
spite the use of different additives. Therefore, we turned
our attention towards a similar reaction mediated by low–
valent titanium alkoxide reagent (η2-propene)-Ti(OiPr)2,
mainly reported by Buchwald and Sato.22,23 Notably, the
elaboration of [5–5] and [5–6] fused cores was described
through the formation of a titanabicyclic intermediate,
which could be intercepted by CO.
1
diol 14d / (Z)–alkene 18 (Entry 2, H NMR estimation).
Finally, toluene was found to be the most suitable sol-
vent for this transformation; when extending the reaction
time to 16 h at -50 °C, propargylic alcohol (S)–12 dis-
played a conversion of 62% (ratio diol 14d / 18: 82:18)
and, after purification, 1,3–diol 14d was isolated in 42%
yield (53% brsm), with syn/anti dr 87:13 and (E)/(Z) dr >
95:5 (Entry 3, 1H NMR estimation). Remarkably, no regi-
oisomer was detected in the crude NMR spectra. Finally,
through optimized conditions, this reaction could be
Scheme 6. First attempts towards the preparation of
bicyclic dienone (±)–21.
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1. DMP, NaHCO3,
DCM, RT, 0.5 h
2. MeLi, THF,
1. DMP, NaHCO3,
DCM, RT, 2 h
2. CH2CHMgCl, THF
0 °C to RT, 4.5 h
HO
2
10
10
OH
O
4
OH
O
1
1. DMP, NaHCO3,
DCM, RT, 0.5 h
2. Ohira-Bestmann reagent
K2CO3, MeOH, RT, 3.5 h
4
1
2
LiHMDS, (CH2O)n
10
-
78 °C to RT, 1 h
4
THF,
-
78 °C to RT,
24 h
(±)-9b
4
O
O
O
O
82% (2 steps)
dr 55:45
66% (2 steps)
dr 55:45
MeO2C
MeO2C
(±)
(±)-9b
3
4
53% (2 steps)
O
60% (brsm)
O
(±)-
20a,b
-
19
MeO2C
MeO2C
(±)
(±)
-
24
-
23
OH
2
5
6
7
8
1. MsCl, Et3N
DCM, 0 °C to RT, 0.5 h
2. MeLi (4 equiv.), CuCN (4 equiv.)
1. iPrMgCl (1 equiv.),
3. CO (1 atm),
0 °C to reflux
iPrO
•
1
O
0 °C, 15 min
Ti
(±)-20a
iPrO
10
5
4
O
2. iPrMgCl (4 equiv.)
Ti(OiPr)4 (2 equiv.)
Toluene, 0 °C to RT, 16 h
LiCl (4 equiv.), THF,
-78 °C, 0.5 h
O
O
MeO2C
45% (2 steps)
I
14
MeO2C
Me
OH
H
9
OH
OH
H
(±)-25
14
2
Me
1
Me
Me
8
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
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36
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1
O
1
O
4
6
O
Me
[Rh(CO)2Cl]2 (10 mol %)
10
2
+
5
O
2
dppp (50 mol %)
CO (1 atm)
5
Me
15
O
H
O
10
Me
MeO2C
O
O
MeO2C
13
MeO2C
(±)-25
4
4
5
5
7
7
O
Toluene, 90 °C, 24 h
71%
Me
(±)
-
21
0%
(±)
-22
nOe (±)-22
MeO2C Me
33% (non optimized)
(±)-26
Crystal structure of (±)
-
26
In our case, the reaction was performed after initial
formation of the corresponding alkoxide with one equiva-
lent of iPrMgCl, generation of the titanabicyclic complex I
in the presence of iPrMgCl (4 equivalents) and Ti(OiPr)4
(2 equivalents), in toluene for 16 h from 0 °C to RT and
final CO trapping under atmospheric pressure. Under
these conditions, a unique product was isolated corre-
sponding to the seven–membered cycle (±)–22, in a
non–optimized 33% yield and a total diastereoselectivity
[the relative configuration of (±)–22 was established by
nOe NMR experiments, thus also evidencing the config-
uration of (±)–20a at C10]. The formation of this seven–
membered cycle through titanocene-mediated reductive
cyclization of 1,8–enyne (±)–20 is very promising but
demonstrates that the insertion of CO to afford the bicy-
clic system (±)–21 is more challenging than expected
and should deserve further studies (Scheme 6).24
by ORTEP diagram
In summary, an advanced [5–7] fused bicyclic inter-
mediate of Tg 1, has been synthesized in a 15 step se-
quence starting from known propargylic alcohol 12. The
synthetic route relies upon the elaboration of key (E)–
enyne 9b, through a low–valent titanium–mediated dia-
stereoselective reductive coupling involving enantioen-
riched propargylic alcohol (S)–12 and methyl vinyl ke-
tone 11d. This transformation allows the control of the
stereochemistry of both tertiary alcohol at C11 and al-
kene at C6–C7 using inexpensive and eco–friendly tita-
nium isopropoxide and can be conducted on a 33 mmol
scale (and even on a 65.7 mmol scale in cheaper race-
mic series). Interestingly, through first experiments of
titanocene-mediated reductive cyclization of 1,8–enyne
(±)–20, a seven–membered cycle (±)–22 is isolated as a
unique product with a total diastereoselectivity. Further
studies would permit the insertion of CO towards the
formation of bicyclic pentenone (±)–21. Finally, a Rh(I)–
catalyzed intramolecular allene–yne Pauson–Khand
reaction, conducted in racemic series, enables the elab-
oration of the [5–7] fused bicyclic trienone (±)–26 in 71%
yield, from allene–yne (±)–25. The structure of key com-
pounds was confirmed by X–ray crystallography. The
present study demonstrates the possibility of elaborating
a highly functionalized scaffold necessary for the further
synthesis of complex guaianolides such as thapsigargin
by using the previously described APKR strategy. The
enantioselective synthesis of intermediate 26 as well as
its further transformation into Tg 1 is currently under
investigation in our laboratories.
An alternative sequence was also investigated involv-
ing an intramolecular Rh(I)–catalyzed Pauson–Khand
reaction of allene–yne 8 to access the bicyclic core 7 of
Tg 1, in accordance with our previous studies.7f Methyl–
allene (±)–25 was easily prepared in five steps from
alcohol (±)–9b. Dess–Martin oxidation followed by Ohi-
ra–Bestmann reaction
Further homologation in the presence of LiHMDS and
paraformaldehyde furnished primary alcohol (±)–24 in
60% yield (brsm). Finally, mesylation and SN2’ reaction
completed the synthesis of expected methyl–allene (±)–
25 in 45% yield over two steps.7f,26a We next addressed
the formation of the [5–7] bicyclic trienone (±)–26 by
intramolecular allene–yne PKR from allene–yne (±)–25.
Hence, Mukai,26 Brummond 27 and our group 7f,8 reported
that Rh(I)–catalyzed intramolecular APKR was an effi-
cient method for the construction of bicyclo[5.3.0] ring
systems.28 Exposure of (±)–25 to [Rh(CO)2Cl]2 (10 mol
25
afforded the alkyne (±)–23.
Experimental section
General Remarks: All reactions sensitive to moisture
and/or air were carried out under argon atmosphere in
dry, freshly distilled solvents under anhydrous conditions
using oven–dried glassware, unless otherwise noted.
THF and toluene were distilled over sodi-
um/benzophenone system, DCM, DMSO and DMF were
distilled over calcium hydride, MeOH and EtOH were
distilled over magnesium turnings. Reactions were moni-
tored by TLC (silica gel 60 F254plates) and visualization
was accomplished with UV light (254 nm & 366 nm) and
subsequent use of phosphomolybdic acid solution in
EtOH (5%), KMnO4 solution or vanillin/sulphuric acid
solution in EtOH, followed by heating at 100–110 °C.
Flash chromatography was performed with silica gel 60
%)
in
the
presence
of
1,3–
bis(diphenylphosphino)propane (dppp) (50 mol %) in
toluene at 90 °C, under 1 atm of CO, cleanly afforded
the desired bicyclic trienone (±)–26 in 71% yield. Finally,
the structure of trienone (±)–26, comporting the bicyclic
core of Tg 1 was readily confirmed by X–ray crystallog-
raphy (Scheme 7).29
Scheme 7. Synthesis of bicyclic trienone (±)–26.
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The Journal of Organic Chemistry
(particle size 40–63 μm). Yield refers to chromatograph-
3.66-3.57 (m, 1H), 3.49-3.40 (m, 1H), 3.40 (s, 3H), 1.99-
1.84 (m, 2H), 1.00 (s, 9H), 0.14 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3) 169.6, 136.2, 135.6(4C), 133.7 (2C),
129.7 (2C), 128.8 (2C), 128.7 (2C), 127.8 (4C), 127.4,
102.1, 91.1, 82.6, 62.4, 59.4, 57.5, 37.7, 26.9 (3C), 19.3,
–0.1 (3C).
1
2
3
4
5
6
7
8
ically and spectroscopically pure compounds, unless
1
otherwise noted. H NMR spectra were recorded at 300
and 400 MHz. Chemical shifts are expressed in ppm,
relative to the residual 1H solvent signal (CDCl3: δ = 7.26
ppm) as the internal reference. Coupling constants (J)
are reported in hertz (Hz). The following abbreviations
are used to designate the multiplicities: s = singlet; d =
doublet; t = triplet; q = quartet; quint. = quintet, sext. =
sextet, sept. = septet, m = multiplet; br = broad. 1H NMR
assignments were confirmed by 2D COSY spectra. The
given multiplicities reflect apparent signal patterns. Dia-
(S)-5-((tert-butyldiphenylsilyl)oxy)-1-
(trimethylsilyl)pent-1-yn-3-yl
(S)-2-methoxy-2-
phenylacetate. Propargylic alcohol 12 (70 mg, 0.17
mmol, 1.0 equiv.) was dissolved in anhydrous dichloro-
methane (0.05 M, 3 mL) and (S)-methoxyphenylacetic
acid (72 mg, 0.43 mmol, 2.5 equiv.), DMAP (21 mg, 0.17
mmol, 1.0 equiv.) and DCC (43 mg, 0.43 mmol, 2.5
equiv.) were successively added. The mixture was
stirred at room temperature for 30 min before addition of
diethyl ether (10 mL).The crude mixture was filtered
through a pad of Celite®, which was rinsed with diethyl
ether. The filtrate was concentrated in vacuo and the
residue was purified by flash chromatography over silica
gel (cyclohexane/ EtOAc, 90:10) to furnish correspond-
ing (S)-MPA ester (90 mg, 0.16 mmol, 95% yield) as a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
stereomer ratio (dr) was estimated by H NMR spectro-
scopic analysis (300 or 400 MHz), unless otherwise
noted. 13C{1H} NMR spectra were recorded at 75 and
100 MHz. Chemical shifts are given in ppm relative to
the residual 13C solvent signal (CDCl3: δ = 77.16 ppm,
CD3OD: δ = 49.00 ppm). 13C NMR assignments were
confirmed by 2D HSQC and HMBC spectra. IR spectra
were recorded with
a FT-IR spectrometer. High-
resolution mass spectra (HRMS) were measured on a
mass spectrometer equipped with a TOF system and an
electrospray ionization (ESI) ion source.
1
colourless oil. RN: 1477482-31-7. H NMR (300 MHz,
CDCl3) δ 7.77-7.58 (m, 4H), 7.51-7.29 (m, 11H), 5.73 (t,
J = 6.9 Hz, 1H), 4.77 (s, 1H), 3.82-3.64 (m, 2H), 3.44 (s,
3H), 2.14-1.95 (m, 2H), 1.05 (s, 9H), 0.09 (s, 9H);
13C{1H} NMR (75 MHz, CDCl3) δ 169.6, 135.9, 135.6
(4C), 133.6 (2C), 129.6 (2C), 128.8 (2C), 128.6 (2C),
127.8 (4C), 127.4, 101.7, 91.0, 82.6, 62.6, 59.7, 57.4,
37.6, 27.0 (3C), 19.3, –0.2 (3C). Analytical data are in
agreement with those reported in the literature.12
(S)-5-((tert-butyldiphenylsilyl)oxy)-1-
(trimethylsilyl)pent-1-yn-3-ol 12. To a solution of di-
chloro(p-cymene)ruthenium(II) dimer (0.042 g, 0.069
mmol, 0.056 equiv.) in dry DCM (0.034 M, 2 mL) was
added
(1S,
2S)-(+)-N-para-toluolsulfonyl-1,2-
diphenylethylendiamine (0.050 g, 0.137 mmol, 0.11
equiv.) and KOH (0.055 g, 0.991 mmol, 0.82 equiv.) at
RT. The purple mixture was stirred for 20 min before
being quenched by water. After 10 min of vigorous stir-
ring, the mixture was extracted with DCM (3x). The com-
bined organic extracts were dried over CaH2, filtered and
concentrated under reduced pressure to give a purple
solid. To the freshly prepared catalyst dissolved in iPrOH
(3R,5S,E)-7-((tert-butyldiphenylsilyl)oxy)-3-methyl-
4-((trimethylsilyl)methylene)hept-1-ene-3,5-diol 14d.
To a solution of propargylic alcohol (S)–12 (13.68 g,
33.30 mmol, 1.0 equiv.) in dry toluene (0.11 M, 300 mL)
was added iPrMgCl (1.35 M in Et2O, 27 mL, 36.64 mmol,
1.1 equiv.) at 0 °C. After 15 min, freshly distilled Ti(OiPr)4
(39.4 mL, 133.2 mmol, 4 equiv.) was added. The mixture
was cooled to –35 °C and iPrMgCl (1.35 M in Et2O, 200
mL, 273.1 mmol, 8.2 equiv.) was added dropwise by
means of dropping funnel. The black mixture was stirred
for 2 h at –35 °C and 3-buten-2-one (27 mL, 333 mmol,
10 equiv.) was added dropwise. The mixture was stirred
for 16 h at –50 °C before being quenched with HCl 4 M
and warmed to RT. The mixture was vigorously stirred
then extracted with Et2O (3x). The combined organic
extracts were washed with brine and dried over MgSO4.
The solvent was evaporated under reduced pressure
and the crude residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/Et2O, 90:10 to 85:15)
to afford diol 14d (6.75 g, 14.0 mmol, 42%, 53% brsm,
Z/E = 0:100) as an inseparable mixture of diastereomers
at C11 (dr 87:13).15 Major diastereomer: FTIR (neat)
(mixture of diastereomers 3315, 2957, 2930, 2856,
1472, 1427, 1389, 1318, 1248, 1105, 1080, 852, 841,
12
(0.013 M, 5 mL) was added a solution of ketone 13
(0.500 g, 1.22 mmol, 1.0 equiv.) in iPrOH (0.493 M, 5
mL) at RT.13 After 30 min stirring, the solvent was evapo-
rated and the crude product was purified by flash chro-
matography over silica gel (cyclohexane/EtOAc, 90:10)
to afford alcohol (S)–12 (0.465 g, 1.13 mmol, 93%, ee =
90%) as a yellow oil. Analytical data were in agreement
with those reported in the literature.12 RN: 225114-87-4.
(S)-5-((tert-butyldiphenylsilyl)oxy)-1-
(trimethylsilyl)pent-1-yn-3-yl
(R)-2-methoxy-2-
phenylacetate. Propargylic alcohol 12 (70 mg, 0.17
mmol, 1.0 equiv.) was dissolved in anhydrous dichloro-
methane (0.05 M, 3 mL) and (R)-methoxyphenylacetic
acid (72 mg, 0.43 mmol, 2.5 equiv.), DMAP (21 mg, 0.17
mmol, 1.0 equiv.) and DCC (43 mg, 0.43 mmol, 2.5
equiv.) were successively added. The mixture was
stirred at room temperature for 30 min before addition of
diethyl ether (10 mL).The crude mixture was filtered
through a pad of Celite®, which was rinsed with diethyl
ether. The filtrate was concentrated in vacuo and the
residue was purified by flash chromatography over silica
gel (cyclohexane/EtOAc, 90:10) to furnish corresponding
(R)-MPA ester (87 mg, 0.156 mmol, 92% yield) as a
colourless oil. FTIR (neat) 2956, 2876, 1462, 1428,
1372, 1251, 1087, 1096, 1006, 953, 821, 737, 699 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.63-7.52 (m, 4H), 7.44-
7.27 (m, 11H), 5.71 (t, J = 6.4 Hz, 1H), 4.78 (s, 1H),
1
736, 698 cm-1; H NMR (400 MHz, CDCl3) δ 7.76-7.63
(m, 4H), 7.50-7.35 (m, 6H), 5.97 (dd, J = 17.2, 10.6 Hz,
1H), 5.50 (s, 1H), 5.30 (dd, J = 17.2, 1.2 Hz, 1H), 5.04
(dd, J = 10.6, 1.2 Hz, 1H), 4.89 (dd, J = 10.4, 1.8 Hz,
1H), 4.29 (br s, 2H), 3.81 (m, 2H), 2.53-2.40 (m, 1H),
1.67-1.57 (m, 1H), 1.48 (s, 3H), 1.06 (s, 9H), 0.13 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.9, 145.8,
135.7 (4C), 132.9 (2C), 130.0 (2C), 128.0 (4C), 126.3,
111.4, 78.5, 77.4, 64.3, 38.8, 31.1, 26.9 (3C), 19.1, 0.8
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The Journal of Organic Chemistry
Page 6 of 13
(3C); HRMS (ESI) calcd for C28H42O3Si2Na+ [(M+Na)+]
reduced pressure. The crude product was purified by
1
2
3
4
5
6
7
8
505.2570, found (mixture of diastereomers) 505.2583.
flash chromatography over silica gel (cyclohex-
ane/EtOAc, 85:15) to afford alcohol (2.15 g, 4.08 mmol,
68%, dr 95:5) as a white solid. FTIR (neat) 3475, 3071,
2956, 2933, 2858, 1473, 1428, 1379, 1250, 1204, 1112,
1075, 864, 846, 739, 702 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.77-7.65 (m, 4H), 7.46-7.33 (m, 6H), 5.61 (d, J
= 2.0 Hz, 1H), 4.93 (dt, J = 10.4, 2.0 Hz, 1H), 3.98-3.86
(td, J = 10.0, 4.8 Hz, 1H), 3.76-3.71 (ddd, J = 10.0, 6.4,
3.2 Hz 1H), 3.68-3.64 (dd, J = 10.4, 6.0 Hz, 1H), 3.48-
3.35 (dd, J = 10.4, 7.2 Hz, 1H), 2.00-1.87 (m, 2H), 1.46
(s, 3H), 1.38 (s, 6H), 1.06 (s, 9H), 0.22 (s, 9H); 13C{1H}
NMR (75 MHz, CDCl3) δ 157.6, 135.7 (4C), 133.7 (2C),
129.6 (2C), 127.6 (4C), 125.4, 98.3, 79.4, 70.3, 69.2,
60.2, 40.8, 30.5, 26.9 (3C), 25.5, 25.4, 19.3, 0.4 (3C);
HRMS (ESI) m/z calcd for C30H46O4Si2Na+ [(M+Na)+]
549.2832, found 549.2820.
1
Minor diastereomer: H NMR (400 MHz, CDCl3) δ 7.76-
7.63 (m, 4H), 7.50-7.35 (m, 6H), 6.06 (dd, J = 17.2, 10.6
Hz, 1H), 5.47 (s, 1H), 5.22 (dd, J = 17.2, 1.0 Hz, 1H),
5.04 (dd, J = 10.6, 1.0 Hz, 1H), 4.89 (dd, J = 10.4, 1.8
Hz, 1H), 4.18 (br s, 2H), 3.94-3.81 (m, 2H), 2.59-2.51 (m,
1H), 1.77-1.69 (m, 1H), 1.46 (s, 3H), 1.06 (s, 9H), 0.13
(s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ 162.6, 147.3,
135.7 (4C), 132.8 (2C), 130.0 (2C), 128.0 (4C), 126.2,
110.8, 78.5, 77.4, 64.0, 39.1, 29.8, 26.9 (3C), 19.1, 0.8
(3C).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(S,Z)-5-((tert-butyldiphenylsilyl)oxy)-1-
(trimethylsilyl)pent-1-en-3-ol (±)-18. FTIR (neat) 3435,
3072, 3050, 2931, 2895, 2858, 1428, 1248, 1106, 1079,
1
836, 765 cm-1; H NMR (300 MHz, CDCl3) δ 7.74-7.67
(m, 4H), 7.48-7.38 (m, 6H), 6.32 (dd, J = 8.3, 14.5 Hz,
1H), 5.65 (d, J = 14.5 Hz, 1H), 4.57 (td, J = 8.3, 3.6 Hz,
1H), 3.95-3.80 (m, 2H), 2.92 (br.s, 1H), 1.90-1.68 (m,
2H), 1.08 (s, 9H), 0.15 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 150.0, 135.7 (4C), 133.3, 133.2, 131.1, 129.9
(2C), 127.9 (4C), 71.6, 62.6, 39.1, 27.0 (3C), 19.2, 0.6
(3C). HRMS (ESI) m/z calcd for C24H36O2Si2Na+
[(M+Na)+] 435.2152, found 435.2164.
To a cooled solution of previous alcohol (3.90 g, 7.40
mmol, 1.0 equiv.) in DCM (0.093 M, 80 mL) was succes-
sively added NaHCO3 (1.86 g, 22.20 mmol, 3 equiv.) and
Dess-Martin Periodinane (3.76 g, 8.88 mmol, 1.2 equiv.)
at RT. After 30 min, the mixture was quenched by a
saturated aqueous Na2S2O3 solution and extracted with
DCM (3x). The combined organic extracts were washed
with brine, dried over MgSO4 and concentrated under
reduced pressure.
tert-butyldiphenyl(2-((4S,6R,E)-2,2,6-trimethyl-5-
((trimethylsilyl)methylene)-6-vinyl-1,3-dioxan-4-
yl)ethoxy)silane 15. 2,2-dimethoxypropane (7.5 mL,
60.8 mmol, 10 equiv.) and PPTS (0.152 g, 0.61 mmol,
0.1 equiv.) were successively added to a solution of diol
14d (2.93 g, 6.08 mmol, 1.0 equiv.) in DCM (0.62 M, 10
mL) and the reaction was stirred for 16 h. A saturated
solution of NaHCO3 was added and the mixture was
extracted with DCM (3x). The combined organic extracts
were dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/EtOAc, 95:5) to afford
acetonide 15 (3.08 g, 5.89 mmol, 97%, dr 95:5) as a
colorless oil. FTIR (neat) 2956, 2933, 2858, 1472, 1428,
1368, 1250, 1202, 1074, 951, 863, 843, 736, 699 cm-1;
1H NMR (400 MHz, CDCl3) δ 7.80-7.63 (m, 4H), 7.47-
7.32 (m, 6H), 5.95 (dd, J = 17.1, 10.5 Hz, 1H), 5.60 (s,
1H), 5.24 (d, J = 17.1 Hz, 1H), 5.00-4.87 (m, 2H), 3.88
(td, J = 9.9, 4.2 Hz, 1H), 3.72-3.63 (m, 1H), 2.05 (tt, J =
14.1, 4.2 Hz, 1H), 1.96-1.83 (m, 1H), 1.45 (s, 6H), 1.37
(s, 3H), 1.05 (s, 9H), 0.21 (s, 9H); 13C{1H} NMR (100
MHz, CDCl3) δ 159.4, 145.9, 135.8 (4C), 134.0 (2C),
129.6 (2C), 127.6 (4C), 122.1, 112.0, 98.5, 78.8, 69.8,
60.5, 41.1 , 30.5, 28.8, 26.9 (3C), 26.1, 19.4, 0.4 (3C);
HRMS (ESI) m/z calcd for C31H46O3Si2Na+ [(M+Na)+]
545.2883, found 545.2872.
The crude aldehyde was dissolved in a mixture of
tBuOH (0.016 M, 445 mL) and 2-methyl-2-butene (0.073
M, 100 mL). To this mixture was added a solution of
NaClO2 (1.0 g, 11.1 mmol, 1.5 equiv.) and NaH2PO4
(1.33 g, 11.1 mmol, 1.5 equiv.) in water (38 mL) at RT.
After 1 h, an additional solution of NaClO2 (1.0 g, 11.1
mmol, 1.5 equiv.) and NaH2PO4 (1.33 g, 11.1 mmol, 1.5
equiv.) in water (38 mL) was added. The reaction was
quenched after 1 h with a 0.1 M HCl solution and ex-
tracted with DCM (3x). The combined organic extracts
were washed with brine, dried over MgSO4 and concen-
trated under reduced pressure.
To the carboxylic acid dissolved in a mixture of dry
benzene (0.025 M, 296 mL) and MeOH (0.09 M, 82 mL)
was added dropwise a solution of trimethylsilyldiazome-
thane (2.0 M in hexane, 4.07 mL, 8.14 mmol, 1.1 equiv.)
at RT. After 30 min, the solvent were evaporated under
reduced pressure. The residue was purified by flash
chromatography over silica gel (cyclohexane/EtOAc,
88:12) to afford ester 16 (3.14 g, 5.65 mmol, 69% over 3
steps,17 dr 95:5) as a white solid. FTIR (neat) 2952,
2858, 1757, 1732, 1462, 1428, 1379, 1250, 1111, 1074,
1
847, 701 cm-1; H NMR (400 MHz, CDCl3) δ 7.43-7.41
(m, 4H), 7.14-7.10 (m, 6H), 5.49 (d, J = 2.0 Hz, 1H), 4.73
(dt, J = 11.2, 2.0 Hz, 1H), 3.60 (td, J = 10.4, 3.6 Hz, 1H),
3.42 (m, 4H), 1.76-1.68 (m, 1H), 1.58-1.50 (m, 1H), 1.27
(s, 3H), 1.22 (s, 3H), 1.16 (s, 3H), 0.79 (s, 9H), -0.01 (s,
9H); 13C{1H} NMR (100 MHz, CDCl3) δ 175.6, 156.2,
135.7 (4C), 133.9, 133.8, 129.8, 129.7, 127.8 (2C),
127.7 (2C), 123.8, 100.4, 77.8, 69.5, 60.2, 52.0, 39.6,
29.2, 26.9 (3C), 25.7, 24.0, 19.3, 0.3 (3C); HRMS (ESI)
m/z calcd for C31H46O5Si2Na+ [(M+Na)+] 577.2782, found
577.2773.
Methyl
(4S,6S,E)-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)-2,2,4-trimethyl-5-
((trimethylsilyl)methylene)-1,3-dioxane-4-carboxylate
16. To a solution of acetonide 15 (3.13 g, 6.00 mmol, 1.0
equiv.) in a 1:1 DCM/ MeOH mixture (0.1 M, 60 mL) was
bubbled O3 at –78 °C until completion of the reaction
(monitored by TLC) then NaBH4 (1.59 g, 42 mmol, 7
equiv.) was added. The mixture was warmed to RT,
stirred for 30 min and subsequently quenched with a
saturated solution of NH4Cl. The aqueous layer was
extracted with DCM (3x) then the combined organic ex-
tracts were dried over MgSO4 and concentrated under
Methyl
(4S,6S,E)-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)-5-(iodomethylene)-
2,2,4-trimethyl-1,3-dioxane-4-carboxylate 17. A flame
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The Journal of Organic Chemistry
1
dried Schlenk was charged with 16 (4.63 g, 8.35 mmol,
1171, 1126, 1046, 971 cm-1; H NMR (400 MHz, CDCl3)
δ 5.63 (quint, J = 2.4 Hz, 1H), 4.91 (dt, J = 10.1, 2.4 Hz,
1H), 3.81-3.75 (m, 2H), 3.73 (s, 3H), 2.22 (dddd, J =
14.4, 6.3, 4.3, 2.4 Hz, 1H), 2.15 (dd, J = 7.5, 3.4 Hz, 1H),
2.00 (d, J = 2.4 Hz, 3H), 1.85 (dddd, J = 14.4, 10.1, 7.5,
4.3 Hz, 1H), 1.50 (s, 3H), 1.46 (s, 3H), 1.38 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 174.6, 150.5, 106.1,
100.8, 95.9, 75.9, 75.3, 72.7, 61.6, 52.4, 36.4, 29.1,
25.5, 23.3, 4.7; HRMS (ESI) m/z calcd for C15H22O5Na+
[(M+Na)+] 305.1365, found 305.1375.
1
2
3
4
5
6
7
8
1.0 equiv.), N-iodosuccinimide (5.64 g, 25.07 mmol, 3
equiv.) and freeze-pump-thaw degassed CH3CN (0.5 M,
15 mL), and the mixture was stirred at 120 °C in the dark
for 72 h. It was then poured on a saturated aqueous
NaHCO3/Na2S2O3 (1:1) solution and subsequently ex-
tracted with Et2O (3x). The combined organic extracts
were washed with brine, dried over MgSO4 and concen-
trated under reduced pressure. The crude product was
purified by flash chromatography over silica gel (cyclo-
hexane/Et2O, 85:15) to afford vinyl iodide 17 (3.90 g,
6.42 mmol, 77%, dr 95:5) as a colorless oil. FTIR (neat)
2988, 2938, 2857, 1757, 1733, 1462, 1428, 1372, 1227,
1109, 1080, 738, 702 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.74-7.68 (m, 4H), 7.45-7.34 (m, 6H), 6.56 (d, J = 1.8
Hz, 1H), 4.83 (dt, J = 8.8, 1.8 Hz, 1H), 3.91 (td, J = 10.4,
4.4 Hz, 1H), 3.77-3.71 (m, 1H), 3.70 (s, 3H), 2.44-2.35
(m, 1H), 1.68-1.59 (m, 1H), 1.52 (s, 3H), 1.51 (s, 3H),
1.35 (s, 3H), 1.07 (s, 9H); 13C{1H} NMR (100 MHz,
CDCl3) δ 174.1, 149.4, 135.8 (4C), 134.0 (2C), 130.0
(2C), 127.8 (4C), 101.1, 77.0, 76.8, 72.8, 60.0, 52.3,
35.4, 29.0, 27.0 (3C), 25.1, 23.5, 19.4; HRMS (ESI) m/z
calcd for C28H37IO5SiNa+ [(M+Na)+] 631.1353, found
631.1348.
9
Methyl
(4S,6S,E)-5-(but-2-yn-1-ylidene)-6-(2-
hydroxypropyl)-2,2,4-trimethyl-1,3-dioxane-4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
carboxylate (±)–19. NaHCO3 (261 mg, 3.11 mmol, 3
equiv.) and Dess-Martin Periodinane (528 mg, 1.24
mmol, 1.2 equiv.) were successively added to alcohol
(±)–9b (292 mg, 1.04 mmol, 1.0 equiv.) dissolved in
DCM (0.093 M, 11 mL). The mixture was stirred for 30
min at RT then quenched with a saturated aqueous
NaHCO3/Na2S2O3 (1:1) solution and extracted with DCM
(3x). The combined organic extracts were washed with
brine, dried over MgSO4 and concentrated under redu-
ced pressure. The crude aldehyde was directly used in
the next step without further purification. FTIR (neat)
2952, 2857, 1733, 1378, 1252, 1112, 1126, 1046, 971
cm-1; 1H NMR (400 MHz, CDCl3) δ 9.78 (dd, J = 2.4, 1.2
Hz, 1H), 5.64 (app. quint, J = 2.4 Hz, 1H), 5.31 (dt, J =
10.0, 2.4 Hz, 1H), 3.73 (s, 3H), 3.05-2.97 (ddd, J = 17.2,
2.4, 1.2 Hz 1H), 2.74 (ddd, J = 17.2, 10.0, 2.4 Hz, 1H),
2.00 (d, J = 2.4 Hz, 3H), 1.47 (s, 3H), 1.46 (s, 3H), 1.41
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 200.3, 174.6,
150.0, 106.2, 101.1, 96.9, 75.8, 75.0, 67.6, 52.4, 47.8,
28.9, 25.3, 22.9, 4.6.
Methyl (4S,6S,E)-5-(but-2-yn-1-ylidene)-6-(2-((tert-
butyldiphenylsilyl)oxy)ethyl)-2,2,4-trimethyl-1,3-
dioxane-4-carboxylate 9a.
A
flame-dried round-
bottomed flask was charged with 17 (4.12 g, 6.76 mmol,
1.0 equiv.), PdCl2(PPh3)2 (0.474 g, 0.67 mmol, 0.10
equiv.), CuI (0.257 g, 1.35 mmol, 0.20 equiv.), THF (0.13
M, 52 mL) and tributyl(1-propynyl)tin.18 Argon was bub-
bled until the yellow mixture turned black and the reac-
tion was stirred at 60 °C for 1 h. The solvent was re-
moved under pressure and the crude product was puri-
fied by flash chromatography over silica gel (cyclohex-
ane/Et2O, 85:15) to afford enyne 9a (2.46 g, 4.73 mmol,
70%, dr 95:5) as a yellow oil. FTIR (neat) 3072, 2991,
2933, 2857, 1756, 1734, 1473, 1458, 1258, 1209, 1111,
1082, 738, 703 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72-
7.63 (m, 4H), 7.44-7.33 (m, 6H), 5.64 (quint, J = 2.0 Hz,
1H), 5.16-5.10 (dt, J = 10.8, 2.0 Hz, 1H), 3.89 (td, J =
10.0, 4.0 Hz, 1H), 3.76-3.68 (m, 1H), 3.69 (s, 3H), 2.48-
2.37 (m, 1H), 1.92 (d, J = 2.0 Hz, 3H), 1.71-1.62 (m, 1H),
1.50 (s, 3H), 1.47 (s, 3H), 1.38 (s, 3H), 1.06 (s, 9H);
13C{1H} NMR (100 MHz, CDCl3) δ 174.9, 151.6, 135.7
(4C), 134.2 (2C), 129.6 (2C), 127.7 (4C), 105.5, 100.8,
95.4, 75.9, 75.4, 68.9, 60.1, 52.2, 36.6, 29.2, 26.9 (3C),
25.4, 23.3, 19.4, 4.7; HRMS (ESI) m/z calcd for
C31H40O5SiNa+ [(M+Na)+] 543.2543, found 543.2547.
The crude aldehyde (1.04 mmol, 1.0 equiv.) was dis-
solved in dry THF (0.11 M, 9 mL) and methyllithium (1.6
M in Et2O, 0.7 mL, 1.14 mmol, 1.1 equiv.) was added
dropwise at –78 °C. The mixture was slowly warmed up
to RT then stirred for 1 h. A solution of saturated aque-
ous NH4Cl was added and the aqueous layer was ex-
tracted with EtOAc (3x). The combined organic extracts
were washed with brine, dried over MgSO4 and concen-
trated under reduced pressure. The crude product was
purified by flash chromatography over silica gel (cyclo-
hexane/EtOAc, 75:25 to 60:40) to afford alcohol (±)–19
(253 mg, 0.85 mmol, 82% over 2 steps) as a mixture of
two unseparable diastereomers (dr 55:45). 1H NMR (300
MHz, CDCl3) δ 5.59-5.54 (m, 1H), 5.00 and 4.86 (dt, J =
9.9, 2.4 Hz, 1H), 3.97-3.96 (m, 1H), 3.70 and 3.68 (s,
3H), 2.11-2.00 (m, 1H), 1.97-1.96 (m, 3H), 1.78-1.55 (m,
1H), 1.45-1.34 (m, 9H), 1.20-1.13 (m, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 174.6 and 174.4, 151.1 and 150.2,
106.0 and 105.6, 100.7, 95.9 and 95.9, 75.9 and 75.8,
75.3 and 75.2, 73.6 and 69.9, 67.9 and 65.4, 52.3 and
52.2, 42.4 and 42.1, 29.0, 25.4, 23.4, 23.2 and 23.1, 4.6
and 4.5; HRMS (ESI) m/z calcd for C16H24O5Na+
[(M+Na)+] 319.1516, found 319.1510.
Methyl
(4S,6S,E)-5-(but-2-yn-1-ylidene)-6-(2-
hydroxyethyl)-2,2,4-trimethyl-1,3-dioxane-4-
carboxylate 9b. Tetrabutylammonium fluoride (1 M in
THF, 3 mL, 2.98 mmol, 2 equiv.) was added dropwise to
a solution of 9a (780 mg, 1.49 mmol, 1.0 equiv.) in dry
THF (0.2 M, 8 mL) at 0 °C. After stirring for 12 h at RT,
the mixture was quenched with water and extracted with
EtOAc (3x). The combined organic extracts were
washed with brine, dried over MgSO4 and concentrated
under reduced pressure. The crude residue was purified
by flash chromatography over silica gel (cyclohex-
ane/EtOAc, 60:40) to afford alcohol 9b (0.292 g, 1.03
Methyl
(4S,6S,E)-5-(but-2-yn-1-ylidene)-6-(2-
hydroxy-2-methylbut-3-en-1-yl)-2,2,4-trimethyl-1,3-
dioxane-4-carboxylate (±)–20. NaHCO3 (930 mg, 11.09
mmol, 3 equiv.) and Dess-Martin Periodinane (1.9 g,
4.43 mmol, 1.2 equiv.) were successively added to alco-
hol (±)–19 (mixture of two diastereoisomers, dr 55:45)
(1.1 g, 3.70 mmol, 1.0 equiv.) dissolved in DCM (0.093
20
mmol, 70%, dr > 95:5) as a brown solid. [α]D +23.4 (c
1.02, CHCl3); FTIR (neat) 3399, 2952, 2858, 1771,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 13
M, 39 mL). The mixture was stirred for 2 h at RT then was warmed up to RT and stirred for 6 h. A CO atmos-
1
2
3
4
5
6
7
8
quenched with a saturated aqueous NaHCO3/Na2S2O3
(1:1) solution. The aqueous layer is extracted with DCM
(3x) and the combined organic extracts were washed
with brine, dried over MgSO4 and concentrated under
reduced pressure. The crude ketone was engaged in the
next step without further purification. FTIR (neat) 2991,
2945, 1753, 1725, 1435, 1374, 1256, 1127, 1112, 1074,
908, 730 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.64 (quint,
J = 2.4 Hz, 1H), 5.26 (td, , J = 9.4, 2.4 Hz, 1H), 3.77 (s,
3H), 2.99 (dd, J = 16.8, 2.4 Hz, 1H), 2.75 (dd, J = 16.8,
9.4 Hz, 1H), 2.17 (s, 3H), 1.98 (d, J = 2.4 Hz, 3H), 1.47
(s, 3H), 1.46 (s, 3H), 1.40 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 206.1, 174.9, 151.0, 105.9, 101.1, 96.6,
75.8, 75.1, 68.8, 52.4, 47.8, 30.6, 28.9, 25.4, 22.9, 4.7.
phere was then installed at 0 °C, the mixture was
warmed up from 0 °C to reflux over 16 h and subse-
quently quenched with a 0.1 M HCl solution. The aque-
ous layer was extracted with Et2O (3x), the combined
organic extracts were washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The
crude product was purified by flash chromatography over
silica gel (cyclohexane/EtOAc, 75:25 to 60:40) to afford
cycloheptene (±)–22 (8.5 mg, 0.026 mmol, 33%, dr >
98:2): FTIR (neat) 3470, 2987, 1751, 1736, 1456, 1372,
9
1
1252, 1210, 1134, 1106, 1051, 997 cm-1; H NMR (400
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3) δ 6.16 (s, 1H), 5.52 (qd, J = 6.8, 1.8 Hz,
1H), 4.24 (dt, J = 11.8, 1.8 Hz, 1H), 3.75 (s, 3H), 2.35 (q,
J = 6.8 Hz, 1H), 2.06 (t, J = 11.8 Hz, 1H), 1.67-1.60 (m,
4H), 1.56 (s, 3H), 1.48 (s, 3H), 1.39 (s, 3H), 1.33 (s, 3H),
1.10 (dd, J = 6.8 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 175.1, 141.3, 138.1, 125.8, 122.3, 100.9, 76.5,
72.7, 68.1, 52.3, 51.3, 41.8, 28.8, 27.7, 25.2, 24.1, 14.3,
13.9; HRMS (ESI) m/z calcd for C18H28O5Na+ [(M+Na)+]
347.1834, found 347.1822.
The crude ketone (3.70 mmol, 1.0 equiv.) was dissol-
ved in dry THF (0.11 M, 33 mL) and vinylmagnesium
chloride (1.6 M in Et2O, 4.6 mL, 7.39 mmol, 2 equiv.)
was added dropwise at 0 °C. The mixture was stirred for
4.5 h at RT then a solution of saturated aqueous NH4Cl
was added. The aqueous phase was extracted with
EtOAc (3x), the combined organic extracts were washed
with brine, dried over MgSO4, filtered and concentrated
under reduced pressure. The crude residue was purified
by flash chromatography over silica gel (cyclohexa-
ne/EtOAc, 75:25 to 60:40) to afford alcohol (±)–20a and
(±)–20b (0.52 g, 0.80 mmol, 66% over 2 steps) as a
separable mixture of two diastereoisomers (dr 55:45).
Major diastereoisomer (±)–20a: FTIR (neat) 3542, 2989,
2941, 1755, 1733, 1455, 1373, 1248, 1208, 1110, 995,
Methyl (4S,6S,E)-5-(but-2-yn-1-ylidene)- 2,2,4-
trimethyl-6-(prop-2-yn-1-yl)-1,3-dioxane-4-
carboxylate (±)–23.
Alcohol (±)–9b (107 mg, 0.38 mmol, 1.0 equiv.) was
oxidized in corresponding aldehyde as previously des-
cribed for the synthesis of (±)–19. The crude aldehyde
was directly used in the next step without further purifica-
tion.
25
Ohira-Bestmann reagent (0.087 g, 0.453 mmol, 1.2
1
730 cm-1; H NMR (400 MHz, CDCl3) δ 5.91 (dd, J =
equiv.) in dry MeOH (0.46 M, 1 mL) and K2CO3 (0.104 g,
0.756 mmol, 2 equiv.) were successively added to the
crude aldehyde (0.38 mmol, 1.0 equiv.) dissolved in dry
MeOH (0.156 M, 2.4 mL). The mixture was stirred for 3.5
h at RT then a solution of saturated aqueous NaHCO3
was added. The aqueous phase was extracted with Et2O
(3x), the combined organic extracts were washed with
brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was purified by
flash chromatography over silica gel (cyclohex-
ane/EtOAc, 60:40) to afford alkyne (±)–23 (0.055 g,
0.198 mmol, 53% over 2 steps) as a colorless oil. FTIR
(neat) 3289, 2991, 2942, 1756, 1732, 1451, 1373, 1258,
1209, 1112, 999, 714 cm-1; 1H NMR (400 MHz, CDCl3) δ
5.64 (quint, J = 2.4 Hz, 1H), 4.87 (dt, J = 10.2, 2.4 Hz,
1H), 3.73 (s, 3H), 2.93 (dt, J = 17.2, 2.4 Hz, 1H), 2.45
(ddd, J = 17.2, 10.2, 2.4 Hz, 1H), 2.04 (d, J = 2.4 Hz,
3H), 1.99 (t, J = 2.4 Hz, 1H), 1.52 (s, 3H), 1.45 (s, 3H),
1.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 174.5,
149.8, 107.0, 101.2, 96.7, 82.1, 75.7, 75.0, 72.0, 69.0,
52.4, 29.0, 25.4, 24.2, 23.0, 4.7; HRMS (ESI) m/z calcd
for C16H20O4Na+ [(M+Na)+] 299.1259, found 299.1256.
17.2, 10.8 Hz, 1H), 5.61 (qd, J = 2.8, 1.2 Hz, 1H), 5.26
(dt, J = 10.8, 1.2 Hz, 1H), 5.24 (dd, J = 17.2, 1.6 Hz, 1H),
5.00 (dd, J = 10.4, 1.6 Hz, 1H), 3.74 (s, 3H), 2.20 (dd, J
= 14.8, 2.0 Hz, 1H), 2.00 (d, J = 2.8 Hz, 3H), 1.81 (dd, J
= 14.8, 10.8 Hz, 1H), 1.51 (s, 3H), 1.47 (s, 3H), 1.41 (s,
3H), 1.37 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
174.0, 150.7, 145.5, 111.3, 105.9, 100.9, 96.2, 76.0,
75.4, 72.7, 70.8, 52.4, 44.4, 29.1, 26.5, 25.4, 23.2, 4.7;
HRMS (ESI) m/z calcd for C18H26O5Na+ [(M+Na)+]
345.1678, found 345.1682. Minor diastereoisomer (±)–
20b: FTIR (neat) 3537, 2988, 2940, 1755, 1732, 1453,
1
1374, 1249, 1208, 1110, 995, 730 cm-1; H NMR (400
MHz, CDCl3) δ 5.92 (dd, J = 17.2, 10.8 Hz, 1H), 5.59
(qd, J = 2.4, 1.8 Hz, 1H), 5.37 (dd, J = 17.2, 1.6 Hz, 1H),
5.15 (dd, J = 10.8, 1.6 Hz, 1H), 4.98 (dt, J = 10.8, 1.8 Hz,
1H), 3.78 (s, 3H), 2.22 (dd, J = 14.8, 1.8 Hz, 1H), 2.03
(d, J = 2.4 Hz, 3H), 1.87 (dd, J = 14.8, 10.8 Hz, 1H), 1.50
(s, 3H), 1.46 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ 174.4, 150.7, 144.2, 112.6,
105.8, 100.9, 95.9, 76.0, 75.4, 73.8, 71.9, 52.5, 43.7,
29.6, 29.1, 25.4, 23.1, 4.7; HRMS (ESI) m/z calcd for
C18H26O5Na+ [(M+Na)+] 345.1678, found 345.1682.
Methyl
(4S,6S,E)-5-(but-2-yn-1-ylidene)-
6-(4-
Methyl
(4S,6S,E)-5-(but-2-yn-1-ylidene)-6-(2-
hydroxybut-2-yn-1-yl)-2,2,4-trimethyl-1,3-dioxane-4-
carboxylate (±)–24. Freshly prepared LiHMDS (1 M,
1.62 mL, 1.62 mmol, 3 equiv.) was added dropwise to a
solution of alkyne (±)–23 (150 mg, 0.54 mmol, 1.0
equiv.) in THF (0.05 M, 10 mL) at –78 °C. The reaction
mixture was stirred for 1 h at –78 °C then paraformalde-
hyde (100 mg, 3.33 mmol, 6 equiv.) was added in one
portion. The mixture was allowed to warm up to RT,
stirring was maintained 3 h and the reaction was
hydroxy-2-methylbut-3-en-1-yl)-2,2,4-trimethyl-1,3-
dioxane-4-carboxylate (±)–22. A solution of iPrMgCl
(1.35 M in Et2O, 0.06 mL, 0.08 mmol, 1.0 equiv.) was
added dropwise to a solution of allylic alcohol (±)–20a
(22 mg, 0.07 mmol, 1.0 equiv.) in dry toluene (0.1 M, 0.7
mL) at 0 °C in a flame dried Schlenk. After 15 min,
Ti(OiPr)4 (0.04 mL, 0.14 mmol, 2 equiv.) and iPrMgCl
(1.35 M in Et2O, 0.21 mL, 0.28 mmol, 4 equiv.), were
successively added dropwise over 5 min. The mixture
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Page 9 of 13
The Journal of Organic Chemistry
4-carboxylate (±)–26. Allene (±)–25 (13 mg, 0.042
quenched by addition of a solution of saturated aqueous
1
2
3
4
5
6
7
8
NH4Cl. The aqueous phase was extracted with Et2O
(3x), the combined organic extracts were washed with
brine, dried over MgSO4, filtered and concentrated under
reduced pressure. The crude residue was purified by
flash chromatography over silica gel (cyclohex-
ane/EtOAc, 80:20) to afford propargylic alcohol (±)–24
(64 mg, 0.209 mmol, 60% brsm) as a colorless oil. FTIR
(neat) 3411, 2989, 2919, 2219, 1785, 1756, 1434, 1373,
mmol, 1.0 equiv.) was dissolved in freshly distilled tolu-
ene (0.1 M, 0.42 mL). The reaction mixture was de-
gassed by bubbling with argon for 5 min then a CO at-
mosphere was installed. Dppp (8.6 mg, 0.021 mmol, 0.5
equiv.) and [Rh(CO)2Cl]2 (1.5 mg, 0.004 mmol, 0.1
equiv.) were successively added and CO was bubbled
again for 2 min. The mixture was then heated at 90 °C
for 24 h, then the mixture was cooled to RT and the
solvent was removed. The crude residue was purified by
flash chromatography over silica gel (cyclohex-
ane/EtOAc, 80:20) to afford cyclopentenone (±)–26 (9.6
mg, 0.029 mmol, 71%) as a white solid. FTIR (neat)
2989, 2925, 2854, 1753, 1690, 1380, 1252, 1213, 1110,
998, 864 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.43 (d, J =
2.4 Hz, 1H), 4.76 (dt, J = 11.6, 2.4 Hz, 1H), 3.77 (s, 3H),
3.04 (d, AB syst J = 11.3 Hz, 1H), 2.98 (d, AB syst J =
11.3 Hz, 1H), 2.90 (dd, J = 16.8, 11.6, 1H), 2.37 (dd, J =
16.8, 2.4 Hz, 1H), 1.91 (s, 3H), 1.88 (s, 3H), 1.63 (s, 3H),
1.51 (s, 3H), 1.41 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 204.5, 174.3, 157.2, 150.0, 140.8, 131.6,
129.7, 116.2, 101.4, 76.5, 69.4, 52.6, 40.4, 40.2, 28.7,
25.1, 24.3, 23.3, 8.7; HRMS (ESI) m/z calcd for
C19H24O5Na+ [(M+Na)+] 345.1624, found 345.1700.
1258, 1210, 1113, 1019, 954 cm-1; H NMR (400 MHz,
1
9
CDCl3) δ 5.65 (quint, J = 2.4 Hz, 1H), 4.85 (dt, J = 9.8,
2.4 Hz, 1H), 4.26 (t, J = 2.4 Hz, 2H), 3.73 (s, 3H), 2.93
(dq, J = 17.2, 2.4 Hz, 1H), 2.50 (ddt, J = 17.2, 9.8, 2.4
Hz, 1H), 2.04 (d, J = 2.4 Hz, 3H), 1.52 (s, 3H), 1.45 (s,
3H), 1.38 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
174.7, 149.5, 107.2, 101.2, 96.7, 83.7, 79.3, 75.8, 75.0,
71.9, 52.5, 51.6, 29.0, 25.4, 24.5, 23.1, 4.8; HRMS (ESI)
m/z calcd for C17H22O5Na+ [(M+Na)+] 329.1365, found
329.1372.
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13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
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44
45
46
47
48
49
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51
52
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60
Methyl
(4S,6S,E)-
5-(but-2-yn-1-ylidene)-2,2,4-
trimethyl-6-(2-methylbuta-2,3-dien-1-yl)-1,3-dioxane-
4-carboxylate (±)–25. To a solution of primary alcohol
(±)–24 (0.029 g, 0.094 mmol, 1.0 equiv.) in dry DCM
(0.15 M, 0.6 mL) at 0 °C, were added Et3N (14 μL, 0.103
mmol, 1.1 equiv.) and MsCl (8 μL, 0.103 mmol, 1.1
equiv.). The mixture was stirred for 0.5 h at RT then a
solution of saturated aqueous NH4Cl was added. The
aqueous phase was extracted with DCM (3x), the com-
bined organic extracts were washed with brine, dried
over MgSO4, filtered and concentrated under reduced
pressure. The residue was filtered through a short pad of
silica gel to furnish crude intermediate mesylate.
ASSOCIATED CONTENT
Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
Copies of H and 13C{1H} NMR spectra, X-ray crystallog-
raphy data and CIF files are available in the Supporting
Information.
CuCN (34 mg g, 0.378 mmol, 4 equiv.) and LiCl (32
mg, 0.759 mmol, 8 equiv.) were heated under vacuum at
130 °C for 2 h. After cooling to RT, THF (0.37 mL) was
added. To the resulting solution at –78 °C, was added
dropwise MeLi (1.6 M, 0.24 mL, 0.378 mmol, 4 equiv.),
the mixture was warmed up to –20 °C. After cooling
again to –78 °C, the crude mesylate (0.094 mmol) in
THF (0.6 mL) was added. The reaction was stirred for
0.5 h at the same temperature and quenched by addition
of a solution of saturated aqueous NH4Cl. The aqueous
phase was extracted with Et2O (3x), the combined or-
ganic extracts were washed with brine, dried over
MgSO4, filtered and concentrated under reduced pres-
sure. The crude residue was purified by flash chromatog-
raphy over silica gel (cyclohexane/EtOAc, 80:20) to af-
ford allene (±)–25 (13 mg, 0.042 mmol, 45% over 2
steps) as a colorless oil. FTIR (neat) 2988, 2941, 2918,
1960, 1757, 1732, 1435, 1371, 1257, 1242, 1210, 1112,
AUTHOR INFORMATION
Corresponding Author
* E-mail
janick.ardisson@parisdescartes.fr
marie-isabelle.lannou@parisdescartes.fr
geoffroy.sorin@parisdescartes.fr
Funding Sources
The authors declare no competing financial interest.
Author Contributions
The manuscript was written through contributions of all
authors. / All authors have given approval to the final ver-
sion of the manuscript.
ACKNOWLEDGMENT
Financial support by CNRS and Paris Descartes University
is gratefully acknowledged.
1
997 cm-1; H NMR (400 MHz, CDCl3) δ 5.60 (quint, J =
2.4 Hz, 1H), 4.85 (dt, J = 10.0, 2.4 Hz, 1H), 4.62 (sext, J
= 3.1 Hz, 2H), 3.73 (s, 3H), 2.66 (dtd, J = 17.2, 3.1, 2.4
Hz, 1H), 2.10 (ddt, J = 17.2, 10.0, 3.1 Hz, 1H), 2.00 (d, J
= 2.4 Hz, 3H), 1.73 (t, J = 3.1 Hz, 3H), 1.49 (s, 3H), 1.46
(s, 3H), 1.35 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ
206.7, 174.8, 152.0, 105.6, 100.9, 96.6, 95.9, 75.8, 75.4,
74.3, 72.1, 52.3, 38.2, 29.1, 25.4, 22.9, 19.1, 4.7; HRMS
(ESI) m/z calcd for C18H24O4Na+ [(M+Na)+] 327.1572,
found 327.1563.
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Pauson−Khand−Type Reaction. J. Org. Chem. 2008, 73,
1061−1066 and references therein.
(29) Crystallographic data are available from Cambridge
Crystallographic Data Centre, reference: CCDC 1856837.
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(27) (a) Brummond, K. M.; Chen, H.; Fisher, K. D.;
Kerekes, A. D.; Rickards, B.; Sill, P. C.; Geib, S. J. An Allenic
Pauson−Khand−Type Reaction:ꢀ A Reversal in π-Bond Se-
lectivity and the Formation of Seven−Membered Rings. Org.
Lett. 2002, 4, 1931−1934. (b) Grillet, F.; Huang, C.; Brum-
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The Journal of Organic Chemistry
SYNOPSIS TOC.
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TBDPSO
•
TBDPSO
Me
Me
Ti(II)-
Reductive
coupling
Rh(I)-
APKR
O
O
O
Me3Si
OH
OH
OH
O
O
Me
71%
O
MeO2C Me
O
O
Me3Si
42%,
53% (brsm)
dr 87:13
OMe
61%, 5 steps,
ee >90%
Bicyclic core of
thapsigargin
Z/E 0:100
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