Enantioselective Synthesis of the Tricyclic Core of FR901483 Featuring a Rhodium-Catalyzed [2+2+2] Cycloaddition

Article abstract of DOI:10.1055/s-0032-1316786

An efficient approach to the tricyclic framework of FR901483 is described. The sequence features a [3,3]-sigmatropic rearrangement of a cyanate to an isocyanate, followed by its subsequent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a terminal

Full text of DOI:10.1055/s-0032-1316786

FEATURE ARTICLE
▌719
fEeanturae nartticiloe selective Synthesis of the Tricyclic Core of FR901483 Featuring a
Rhodium-Catalyzed [2+2+2] Cycloaddition
Enantioselective Synthesis of the Tricyclic Core of FR901483
Stéphane Perreault, Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
E-mail: rovis@lamar.colostate.edu
Received: 27.07.2012; Accepted: 04.09.2012
from an oxidative spiroannulation of a tyrosine dimer.
The unique structure of FR901483 has generated tremen-
dous interest from the synthetic community, an interest
that has resulted in a number a total syntheses and several
Abstract: An efficient approach to the tricyclic framework of
FR901483 is described. The sequence features a [3,3]-sigmatropic
rearrangement of a cyanate to an isocyanate, followed by its subse-
quent asymmetric rhodium-catalyzed [2+2+2] cycloaddition with a
terminal alkyne for the synthesis of the indolizidine core. The aza- synthetic studies.4,5 All reported nonracemic syntheses to
tricyclic core is completed using an intramolecular benzoin reaction
to close the last ring of the natural product. Through a model study
of the key cycloaddition, we evaluated the impact of different sub-
date involve one or two tyrosine derivatives as the source
of chirality.6
Recent work from our group has demonstrated that indol-
izidine-based natural products can be assembled efficient-
ly using a rhodium-catalyzed asymmetric [2+2+2]
cycloaddition between alkenyl isocyanates 2 and exoge-
nous alkynes 3 (Scheme 1).7–9 Extensive phosphoramidite
ligand (L*) optimizations have led to a broader scope of
heterocycles since one can control the selective formation
of bicyclic lactams 4 or vinylogous amides 5, the latter
arising from a CO migration. With terminal alkynes I and
II7 and unsymmetrical internal alkynes III and IV,8a sin-
gle regioisomeric products are obtained in good yields and
excellent enantioselectivities.
stituents on the tether of the alkenyl isocyanate.
Key words: [3,3]-sigmatropic rearrangement, isocyanate, [2+2+2]
cycloaddition, indolizidine, FR901483
Indolizidine alkaloids are ubiquitous natural products iso-
lated from a myriad of sources with wide diversity in their
substitution pattern and stereochemistry (Figure 1).1
FR901483 (1) is a fungal metabolite with immunosup-
pressive activity isolated from the fermentation broth of
the fungus Cladobotryum sp. No. 11231.2,3 Its unprece-
dented and rigid molecular structure was ascertained by
X-ray crystallographic analysis. In its crystal structure,
the C-ring exists in a boat conformation and the indoli-
zidine nitrogen lone pair is equatorial resulting in a cis fu-
sion for the 6,5-bicycle. There is no data about the
preferred conformation in solution.
O
R2
R3
O
R3
R2
R3
C
Rh(I), L*
N
2
N
N
+
+
*
R1
*
R1
O
R2
R1
3
4
R
1 = H or alkyl
5
5
3
6
7
N
2
alkyne scope
9
1
MeO
R3
R2
H
H
EWG
RS
Aryl
8
OMe
indolizidine
OH
H
Me
N
Me
H
Aryl
Alkyl
EDG
RL
Aryl
N
N
A
B
C
N
HO
I
II
III
IV
V
H
OH
OH
OPO(OH)2
P
Scheme 1 Scope of the rhodium-catalyzed enantioselective [2+2+2]
O
cycloadditions of alkenyl isocyanates and exogenous alkynes
(–)-FR901483 (1)
conformation observed
by X-ray in solid state
One of the main synthetic challenges associated with
FR901483 is the stereoselective formation of the quater-
nary aza-stereocenter. A potential approach to this prob-
lem would rely on the development of a vinylogous amide
selective [2+2+2] cycloaddition between a functionalized
alkenyl isocyanate 6 and 4-methoxybenzylacetylene (7)
(Scheme 2). To date, the effect of substitution on the iso-
cyanate tether had been largely unexplored. In the partic-
ular case of FR901483, a carbonyl/alcohol precursor at C2
is desired in order to introduce the secondary methyl-
amine functionality at a later stage in the synthesis.
Figure 1 Structure and conformation of (–)-FR901483
Biosynthetically, the tricyclic core of FR901483 is most
likely derived from an aldol reaction between C6 and C7.3
The azaspiro[4.5]decane (A and C rings) may be accessed
SYNTHESIS 2013, 45, 0719–0728
Advanced online publication: 26.02.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316786; Art ID: SS-2012-M0507-FA
© Georg Thieme Verlag Stuttgart · New York

720
S. Perreault, T. Rovis
FEATURE ARTICLE
play to our advantage. To identify the ideal functional
group on the tether for our synthetic plan, we first investi-
gated the cycloaddition of several model 1,1-disubstituted
alkenyl isocyanates (Table 1).
O
PMP
PMP
C
N
N
(–)-FR901483 (1)
X
2
7
2
X
O
R
As expected with GuiPhos (L1) as ligand, the vinylogous
amide products 11a–e are slightly favored with ratios
10/11 around 1:2 (entries 1, 3, 5, 7, and 9). Product selec-
tivities may be sometimes improved using phosphorami-
dite L2 (entries 2, 4, 6, 8, and 10). As previously observed,
GuiPhos (L1) leads to higher enantioselectivities in com-
parison to L2.7d,e However, the only substrate that affords
a cycloadduct with a useful enantioselectivity (94% ee) is
isocyanate 9b with a gem-dimethyl substituent at C2 (en-
try 3). Alkenyl isocyanates 9c–e, bearing C2 substituents
that could potentially lead to the needed carbonyl/alcohol
for the synthesis of FR901483, generate vinylogous amide
products with moderate enantioselectivities (54–65% ee).
6
8
R
Scheme 2 General approach to FR901483; PMP = 4-MeOC6H4
Inherently, terminal alkynes such as 710 preferentially af-
ford the lactam products (cf. Scheme 1, 4). To overcome
this preference, we have developed phosphoramidite li-
gands L1 (GuiPhos) and L2 (Figure 2) as a solution to the
selective formation of vinylogous amide adducts with al-
kyl-substituted acetylenes.7d,e Unfortunately, to date these
two ligands have proven inefficient for the synthesis of in-
dolizidines with aza-quaternary stereocenters, delivering
the vinylogous amide adducts with moderate product- and
enantioselectivities. However, the impact of substitution
on the tether was unknown and we speculated that it might
At this point, we turned our attention to alkenes as carbon-
yl precursor on the tether (Table 2). Surprisingly, cycload-
SiMe3
t-Bu
Ar
Ar
O
P
O
Me
O
Me
P N
O
O
O
O
N
P
N
O
Me
Me
Ar
Ar
SiMe3
t-Bu
(R)-L2
Ar = C6F5
(R)-L1 (GuiPhos)
(–)-L3 (CKPhos)
Figure 2 Ligands L1, L2, and L3
Biographical Sketches█
Stéphane Perreault was 2007 under the direction of at Colorado State University
born and raised in Thetford Professor Claude Spino with Professor Tomislav
Mines (Quebec, Canada) from the same institution. Rovis. In 2010, he joined
and received his B.Sc. in He was the recipient of the Gilead Sciences where he is
chemistry in 2002 from Uni- Governor General’s Aca- currently working as a re-
versité de Sherbrooke. He demic Gold Medal. From search scientist in medicinal
earned his Ph.D. degree 2008 to 2010, he was a chemistry.
(NSERC scholarship) in FQRNT postdoctoral fellow
Tomislav Rovis was born in NSERC postdoctoral fellow CAREER and a Roche Ex-
Zagreb in the former Yugo- at Harvard University with cellence
in
Chemistry
slavia but was largely raised Professor David A. Evans. award. He has been named a
in Southern Ontario, Cana- In 2000, he began his inde- GlaxoSmithKline Scholar,
da. Following his under- pendent career at Colorado Amgen Young Investigator,
graduate studies at the State University and was Eli Lilly Grantee, Alfred P.
University of Toronto, he promoted in 2005 to Associ- Sloan Fellow, a Monfort
earned his Ph.D. degree at ate Professor and in 2008 to Professor at Colorado State
the same institution in 1998 Professor. His group’s ac- University. He currently
under the direction of Pro- complishments have been holds the John K. Stille
fessor Mark Lautens. From recognized by a number of Chair in Chemistry.
1998 to 2000, he was an awards including an NSF
Synthesis 2013, 45, 719–728
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of the Tricyclic Core of FR901483
721
Table 1 Model Study Examining Tether Substituentsa
MeO
O
OMe
O
C
OMe
X
X
a
N
N
X
X
X
X
+
N
+
O
7
9a–e
10a–e
11a–e
Entry
Isocyanate
Ligand
Ratio (10/11)
Compound 11
Yieldb,c (%)
eed (%)
1
2
L1
L2
1:2.5
1:3
50
52
65
14
NCO
NCO
9a
3
4
L1
L2
1:2
1:4
44 (70)
62 (70)
94
82
9b
O
O
S
5
6
L1
L2
1:1.5
1:1.5
42
42
55
8
NCO
9c
7
8
L1
L2
1:1.5
1:7.5
8 (15)e
64
63
S
NCO
NCO
45 (85)e
9d
OTBS
1:1.5
(dr 11e 3:2)
1:1.5
24
15
29
24
58
54
12
8
9
10
L1
L2
9e
(dr 11e 1:1)
a Reaction conditions: (a) [Rh(C2H4)Cl]2 (3 mol%), phosphoramidite ligand (6 mol%), 7 (1.3 equiv), toluene (0.04 M), 110 °C, 16 h.
b Isolated yield of 11.
c 100% conversion of 9 unless specified in parentheses.
d Enantiomeric excess determined by HPLC analysis on a chiral stationary phase.
e Reaction performed at 140 °C in xylene.
ditions of isocyanate 12a in the presence of L1 or L2 as Having established a vinylogous amide selective cycload-
ligand slightly favor the lactam product with very low en- dition for the synthesis of models of the indolizidine core
antioselectivities for the desired vinylogous amide prod- of FR901483, a more functionalized isocyanate was re-
uct 14b (entries 1 and 2). Fortunately, this selectivity is quired. We identified two possible dienyl isocyanates 15a
reversed using tetrasubstituted alkene substituents 12b–e and 15b that could lead to the tricyclic core and ultimately
in combination with L1 or L2. More importantly, these di- to FR901483 (Scheme 3). These isocyanates would be de-
enyl isocyanates offer moderate to good enantioselectivi- rived from cyanates 16a and 16b, respectively, via a [3,3]-
ties (entries 4, 5, 7, 8, 10, 11, 13, and 14). The real sigmatropic rearrangement. Cyanates 16a and 16b would
breakthrough came with the advent of CKPhos (L3), be rapidly assembled from methallyl alcohol (17) and al-
which improves upon L1 and L2 in both product- and en- kylating agents 18a and 18b, respectively.
antioselectivity.7f This electron-deficient TADDOL phos-
phoramidite ligand greatly overcomes the inherent
preference of alkyl-substituted acetylenes to form lactam
indolizinones and mainly provides vinylogous amide
Treatment of methallyl alcohol (17) with butyllithium (2
equiv) followed by subsequent C-alkylation with either
propargyl bromide 18a or alkyl iodide 18b yields allylic
alcohols 19a,b (Scheme 4).11 The latter are then converted
products 14 with excellent control of product- (up to
into the corresponding allylic bromides 20a,b. Alkylation
1:14), regio- (single isomer), and enantioselectivities (up
of ethyl benzoylacetate with the respective allylic bro-
to 99% ee). In this series of dienyl isocyanates, 12b (entry
mide 20a or 20b (neat, 50 °C) gives keto esters 21a,b,
6) affords the best combination of results (product selec-
which are not isolated.12 Addition of tetrahydrofuran,
tivity, yield and enantioselectivity).
paraformaldehyde, and potassium carbonate triggers a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 719–728

722
S. Perreault, T. Rovis
FEATURE ARTICLE
Table 2 Model Study Using Allylic Isocyanatesa
MeO
O
OMe
O
C
R1
R2
R1
R2
OMe
R1
R2
N
N
N
a
+
+
O
7
12a–f
13a–f
14a–f
Entry
Isocyanate
R1
Ligand
Ratio (13/14)
Compound 14
R2
H
Yieldb,c (%)
eed (%)
1
2
3
H
12a
12b
12c
12d
L1
L2
L3
1.3:1
1.1:1
1:13
27
31
57
5
46
94
4
5
6
Me
Et
Me
Et
L1
L2
L3
1:1.3
1:2
1:7.5
44
52
85
89
71
98
7
8
9
L1
L2
L3
1:1.8
1:3
1:5.5
48
53
80
92
79
98
10
11
12
Bu
Bu
L1
L2
L3
1:2
1:3.7
1:5
51
67
64
92
81
99
13
14
(CH2)5
H
12e
L1
L2
1:1.5
1:2.5
51
60
91
71
15
16
17
i-Pr
12fe
L1
L2
L3
1:1.3
1:1.7
1:14
31
35
66
54
9
99
a Reaction conditions: (a) [Rh(C2H4)Cl]2 (3 mol%), phosphoramidite ligand (6 mol%), 7 (1.3 equiv), toluene (0.04 M), 110 °C, 16 h.
b Isolated yield of 14.
c 100% conversion of 12 unless specified in parentheses.
d Enantiomeric excess determined by HPLC analysis on a chiral stationary phase.
e Ratio E/Z 10:1 (confirmed by NOE).
cascade of transformations starting with an aldol reaction
followed by a benzoyl transfer and a E1cb elimination to
O
N
C
N
[3,3]
afford α,β-unsaturated esters 22a,b. Double 1,2-addition
of methyllithium on the esters leads to allylic alcohols
23a,b, which are converted into the corresponding carba-
mates 24a,b using trichloroacetyl isocyanate and a basic
workup.13 Dehydration with trifluoroacetic anhydride14f
generates cyanates 16a,b, which immediately undergo a
[3,3]-sigmatropic rearrangement.14 This completes the
synthesis of dienyl isocyanates 15a,b, which are isolated
in very good yields upon distillation.
O
TMS
16a
TMS
alkylation
15a
18a
I
TMS
OH
TBSO
Br
18a
18b
17
In a very convergent manner, all atoms of the FR901483
skeleton are brought together using a rhodium-catalyzed
asymmetric [2+2+2] cycloaddition (Scheme 5). In the
presence of CKPhos (L3), the enantioselective cycloaddi-
tions of dienyl isocyanates 15a and 15b afford the desired
indolizinones 25 and 26, respectively, with excellent con-
trol of product- and enantioselectivities.
18b
O
C
N
O
N
[3,3]
TBSO
alkylation
TBSO
15b
16b
Scheme 3 Retrosynthesis of dienyl isocyanates 15a,b
Synthesis 2013, 45, 719–728
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of the Tricyclic Core of FR901483
723
(TiCp2Cl) is known to homolyze epoxide C–O bonds. The
subsequent radical trapping with alkenes or alkynes
(intra- or intermolecular) represents a valuable tool for or-
ganic synthesis. In our case, generation of a secondary
radical 28 should trigger the ring-closing reaction on the
alkyne. Unfortunately, all attempts to access epoxide 27
from cycloadduct 25 failed.
b,c
a
OH
Br
OH
R
R
18a or 18b
19a R =
TMS 23%
17
20a 81%
20b 83%
19b R = CH2OTBS 72%
d
O
Ph
OEt
O
OEt
R
R
O
22a 89%
22b 75%
21a,b
PMP
N
PMP
N
OTi(IV)
PMP
N
O
e
O
O
OH
O
O
O
NH2
TiCp2Cl
OH
f
R
R
23a,b
24a 96%
24b 67%
27
28
29
g
Equation 1
[3,3]
N
En route to epoxide 27, we observed something very in-
teresting in one of our approaches (Scheme 6). Chlorina-
tion of cycloadduct 25 with N-chlorosuccinimide to give
30 followed by a 1,4-reduction mediated by Red-Al af-
fords a single diastereomer of chloro ketone 31. Treat-
ment of chloro ketone 31 with sodium borohydride in
dichloromethane and methanol (1:1) leads to the forma-
tion of secondary alcohol 32 where the chlorine atom has
been substituted by a methoxy group. Interestingly, this
substitution occurs with retention of configuration at C6.
The use of different solvent systems, different alcohol nu-
cleophiles or stronger reducing agents only affords the
over-reduced product (C6 = CH2).
NCO
O
R
R
15a R =
15b R = CH2OTBS 92%
TMS 85%
16a,b
Scheme 4 Reagents and conditions: (a) (i) BuLi, TMEDA, Et2O,
–78 °C; (ii) 18a or 18b, –78 °C to 23 °C; (b) MsCl, Et3N, CH2Cl2, 0
°C; (c) LiBr, THF, 0 °C to 23 °C; (d) (i) ethyl benzoylacetate, K2CO3,
NaI (cat.), neat, 50 °C; (ii) K2CO3, (CH2O)n, THF, 65 °C; (e) MeLi,
CeCl3, Et2O, 0 °C; (f) (i) trichloroacetyl isocyanate, CH2Cl2, 0 °C; (ii)
K2CO3, MeOH, H2O, –78 °C to 23 °C; (g) TFAA, Me2NEt, CH2Cl2,
0 °C.
MeO
OMe
PMP
N
PMP
N
O
C
Cl
O
a
b
a
N
N
+
L3
7
O
O
25
30
TMS
TMS
TMS
15a
6.0 g scale
25
product selectivity = 1:17
73%, 98% ee
PMP
N
PMP
N
TMS
OMe
OH
Cl
O
6
c
7
MeO
OMe
32
(single diast.)
31
(single diast.)
TMS
TMS
O
C
a
N
N
Scheme 6 Reagents and conditions: (a) NCS, CH2Cl2, –78 °C; (b)
Red-Al, THF, –78 °C; (c) NaBH4, MeOH, CH2Cl2, –78 °C to 23 °C
(77%, 3 steps).
+
L3
7
O
OTBS
OTBS
15b
26
The stereochemistry of the C7-hydroxy can be easily ra-
tionalized from conformer trans-31 (Scheme 7).16 Hy-
dride delivery is clearly favored from the top face, away
from the axial substituent at C9. To explain the retention
of stereochemistry at C6, we invoke an anchimeric effect
(neighboring group participation) from the nitrogen lone
pair allowing the formation of aziridinium 34, which can
be opened with methanol to generate the observed product
32 (relative stereochemistry determined by NOE).17
product selectivity = 1:19
70%, 98% ee
6.0 g scale
Scheme 5 Reagents and conditions: (a) [Rh(C2H4)2Cl]2 (2 mol%),
L3 (4 mol%), toluene (0.08 M), 110 °C, 36–48 h.
With the entire carbon scaffold of the target in place, we
turned our attention at closing the last ring. Our first strat-
egy was based on a 6-exo-dig radical cyclization of ep-
oxyalkyne 27 (Equation 1).15 Titanocene chloride
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 719–728

724
S. Perreault, T. Rovis
FEATURE ARTICLE
PMP
N
PMP
H
PMP
PMP
Cl
d
a,b,c
N
6
N
N
Cl
Cl
TMS
TMS
O
O
9
7
OH
O
OTBS
OH
35
(single diast.)
26
trans-31
33
MeO
4.0%
PMP
Cl
PMP
H
PMP
N
H
N
N
OMe
Cl
H
Cl
TMS
TMS
N
e, 39
H
OH
OH
OH
O
O
O
5.9%
32
34
37
36
Scheme 7 Rationale for the stereochemistry of 32
BF4
Cl
At this point, we envisaged closing the last ring via an in-
tramolecular benzoin reaction.18 To test this strategy, we
synthesized ketoaldehyde 36 (Scheme 8). The four-step
sequence starts with chlorination of cycloadduct 26 fol-
lowed by 1,4-reduction. We planned to use the C6-chlo-
rine as a synthetic handle to introduce the secondary
alcohol (cf. Schemes 6 and 7). Deprotection of the prima-
ry alcohol followed by Swern oxidation affords the ben-
zoin precursor 36.
N
N
Cl
O
N
O
Cl
O
Cl
39
PMP
N
Cl
HO
N
PMP
38
Scheme 8 Reagents and conditions: (a) NCS, CH2Cl2, –78 °C; (b)
Red-Al, THF, –78 °C (85%, 2 steps); (c) 1% HCl–MeOH, 0 °C
(90%); (d) (i) (COCl)2, DMSO, CH2Cl2, –78 °C; (ii) Et3N, –78 °C to
23 °C (87%); (e) (i) 39 (50 mol%), KHMDS (45 mol%), toluene; (ii)
high vacuum; (iii) 36, toluene (0.05 M), 70 °C (41%).
It has long been known that thiazolylidene carbenes cata-
lyze benzoin reactions of aldehydes via the mechanism
proposed by Breslow in 1957.19 Recently developed, bi-
cyclic triazolylidene carbenes, generated from the corre-
sponding triazolium salts, typically out-perform other
carbene precursors in this transformation.20 When ketoal-
dehyde 36 is submitted to pre-catalyst 3921 in the presence
of Hünig’s base, no benzoin products, intra- or intermo-
lecular 37 or 38, are observed (Scheme 8). Fortunately,
using free carbene conditions previously developed by
our group,21a we were pleased to observe a full conversion
tral alumina. Toluene was degassed with argon and passed through
one column of neutral alumina and one column of Q5 reactant.
Et3N, DIPEA, and MeOH were distilled from CaH2. Column chro-
matography was performed on SiliCycle®SilicaFlash® P60, 40–63
1
μm 60A. H NMR spectra were recorded on a Varian 300 or 400
MHz spectrometers at r.t., from CDCl3 or acetone-d6. 13C NMR
spectra were recorded a Varian 300 or 400 MHz spectrometers (at
of 36 and the formation of the desired benzoin product 37 75 or 100 MHz) at r.t., from CDCl3 (δ = 77.0). LR-MS and HRMS
were recorded on a Fisons VG Autospec spectrometer. HPLC spec-
tra were obtained on an Angilent 1100 series system. Optical rota-
tion was obtained with an Autopol-III automatic polarimeter.
(41% yield) along with a small amount of benzoin dimer
38.22,23 The structure of 37 was supported by extensive
NMR analysis, including COSY, APT, HMQC, and
NOESY techniques.
2-(ω-Silylalkyl)allyl Bromides 20a,b; General Procedure
To a 0.1 M soln of allylic alcohol 19a,b (1.0 equiv) in CH2Cl2 at
–78 °C were added Et3N (2.2 equiv) and MsCl (2.0 equiv). The mix-
ture was allowed to warm to 0 °C over a period of 3 h and quenched
with sat. aq NaHCO3. CH2Cl2 was added, the phases were separat-
ed, and the aqueous phase was extracted with CH2Cl2 (2 ×) The or-
ganic layers were combined, dried (anhyd MgSO4), and evaporated
under reduced pressure. To a 0.2 M soln of the crude mesylate in
THF at 0 °C was added LiBr (4.0 equiv). The mixture was stirred at
23 °C for 3–6 h and quenched with brine. The phases were separated
and the aqueous phase was extracted with Et2O (2 ×). The organic
layers were combined, dried (anhyd MgSO4), and evaporated under
reduced pressure. The crude product was purified by flash column
chromatography (pentane).
In closing, we have assembled the entire scaffold of the
immunosuppressive agent FR901483 with appropriate
functionality in place to complete the synthesis. We have
successfully developed a highly selective rhodium-
catalyzed [2+2+2] cycloaddition of two functionalized al-
kenyl isocyanates and 4-methoxybenzylacetylene for the
enantioselective construction of the indolizidine core of
FR901483. The complete sequence to the aza-tricyclic
core also stars a [3,3]-sigmatropic rearrangement of a cy-
anate into an isocyanate and an intramolecular benzoin re-
action to close the last ring of the natural product.
1-(Bromomethyl)-6-(trimethylsilyl)hex-1-en-5-yne (20a)
Colorless oil; yield: 9.20 g (81%).
1H NMR (300 MHz, CDCl3): δ = 5.23 (s, 1 H), 5.02 (s, 1 H), 4.0 (s,
2 H), 2.45–2.41 (m, 4 H), 0.14 (s, 9 H).
All reactions were carried out under an atmosphere of argon in
flame-dried glassware with magnetic stirring. THF and CH2Cl2
were degassed with argon and passed through two columns of neu-
Synthesis 2013, 45, 719–728
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of the Tricyclic Core of FR901483
725
1-(Bromomethyl)-5-(tert-butyldimethylsiloxy)pent-1-ene (20b)
der reduced pressure. MeOH–H2O (2:1, 0.1 M) was then added to
Colorless oil; yield: 13.2 g (82%).
the resulting precipitate. The suspension was cooled to 0 °C and
CH2Cl2 was added until completely soluble. K2CO3 (3.0 equiv) was
added. The mixture was allowed to warm slowly to 23 °C and
stirred for 16 h (for 23a, the mixture was kept at 0 °C for 8 h to min-
imize the desilylation reaction). MeOH was evaporated under re-
duced pressure and the aqueous phase was extracted with CH2Cl2 (3
×). The organic layers were combined, washed with brine, dried
(MgSO4), and concentrated under reduced pressure. The crude
product was purified by flash chromatography (hexane–EtOAc,
4:1).
1H NMR (300 MHz, CDCl3): δ = 5.17 (s, 1 H), 4.98–4.97 (m, 1 H),
3.98 (s, 2 H), 3.63 (t, J = 6.2 Hz, 2 H), 2.27 (t, J = 7.7 Hz, 2 H), 1.74–
1.64 (m, 2 H), 0.89 (s, 9 H), 0.05 (s, 6 H).
Ethyl 2-(2,4-Dimethylenealkyl)acrylates 22a,b;
General Procedure
To a mixture of ethyl benzoylacetate (90% from Aldrich, 1.1 equiv)
and allylic bromide 20a,b (1.0 equiv) was added K2CO3 (1.5 equiv)
and NaI (0.15 equiv). The flask was sealed with a septum and the
mixture was stirred at 50 °C for 24–48 h (the disappearance of the
allylic bromide and the in situ generated allylic iodide were fol-
lowed by NMR aliquot). THF (0.7 M), K2CO3(1.0 equiv), and para-
formaldehyde (2.0 equiv) were then added. The mixture was stirred
at 65 °C for 24–48 h (the disappearance of the intermediate was fol-
lowed by TLC). After cooling, the mixture was quenched with H2O.
Et2O was added, the phases were separated, and the aqueous phase
was extracted with Et2O (2 ×). The organic layers were combined,
washed with brine (1 ×), dried (anhyd MgSO4), and evaporated un-
der reduced pressure. The crude product was purified by flash col-
umn chromatography (hexane–Et2O, 20:1).
2-Methyl-3,5-dimethylene-9-(trimethylsilyl)non-8-yn-2-yl
Carbamate (24a)
Yellowish oil; yield: 7.94 g (96%, 2 steps).
1H NMR (300 MHz, CDCl3): δ = 5.10 (s, 1 H), 4.95 (s, 1 H), 4.90
(s, 1 H), 4.89 (s, 1 H), 4.56 (br s, 2 H), 2.83 (s, 2 H), 2.36 (t, J = 6.9
Hz, 2 H), 2.22 (t, J = 6.9 Hz, 2 H), 1.56 (s, 6 H), 0.13 (s, 9 H).
8-(tert-Butyldimethylsiloxy)-2-methyl-3,5-dimethyleneoctan-2-
yl Carbamate (24b)
Yellowish oil; yield: 7.72 g (67%, 2 steps).
1H NMR (300 MHz, CDCl3): δ = 5.10 (s, 1 H), 4.89 (s, 1 H), 4.88
(s, 1 H), 4.84 (s, 1 H), 4.48 (br s, 2 H), 3.61 (t, J = 6.6 Hz, 2 H), 2.82
(s, 2 H), 2.04 (t, J = 7.7 Hz, 2 H), 1.71–1.64 (m, 2 H), 1.56 (s, 6 H),
0.89 (s, 9 H), 0.04 (s, 6 H).
Ethyl 2,4-Dimethylene-8-(trimethylsilyl)oct-7-ynoate (22a)
Colorless oil; yield: 8.84 g (89%).
1H NMR (300 MHz, CDCl3): δ = 6.24 (s, 1 H), 5.57 (s, 1 H), 4.88
(s, 1 H), 4.82 (s, 1 H), 4.19 (q, J = 7.3 Hz, 2 H), 3.03 (s, 2 H), 2.37
(t, J = 7.7 Hz, 2 H), 2.24 (t, J = 7.7 Hz, 2 H), 1.29 (t, J = 7.3 Hz, 3
H), 0.13 (s, 9 H).
2-Isopropylidene-4-methylenealkyl Isocyanate 15a,b;
General Procedure
To a cold soln (0 °C) of allyl carbamate 24a,b (1.0 equiv) in CH2Cl2
(0.2 M) was added Me2NEt (2.6 equiv). Then, TFAA (1.2 equiv,
freshly distilled over P2O5) was added dropwise to the soln at 0 °C.
After stirring at 0 °C for 30 min, the mixture was concentrated under
reduced pressure. Hexane was then added to the residual oil. The bi-
phasic mixture was stirred for 10 min and allowed to decant. After
decantation, the same process was repeated one more time with the
residual oil before removing the hexane under reduced pressure.
The crude isocyanate was then purified by short path distillation.
Ethyl 7-(tert-Butyldimethylsiloxy)-2,4-dimethyleneheptanoate
(22b)
Colorless oil; yield: 10.5 g (75%).
1H NMR (300 MHz, CDCl3): δ = 6.22 (s, 1 H), 5.55–5.54 (m, 1 H),
4.84 (s, 1 H), 4.75 (s, 1 H), 4.19 (q, J = 7.3 Hz, 2 H), 3.61 (t, J = 6.3
Hz, 2 H), 3.02 (s, 2 H), 2.07 (t, J = 7.7 Hz, 2 H), 1.71–1.62 (m, 2 H),
1.29 (t, J = 7.3 Hz, 3 H), 0.89 (s, 9 H), 0.05 (s, 6 H).
2-Methyl-3,5-dimethylenealkan-2-ols 23a,b;
2-Isopropylidene-4-methylene-8-(trimethylsilyl)oct-7-ynyl
Isocyanate (15a)
General Procedure
A flame-dried round bottom flask was charged with anhyd CeCl3
(2.0 equiv) in an inert atmosphere (N2) glove box. Upon removal
from the glove box, THF (0.1 M based on α,β-unsaturated ester)
was added and the suspension was stirred for 1 h at 23 °C. After
cooling to 0 °C, the α,β-unsaturated ester 22a,b (1.0 equiv) was add-
ed and the mixture was stirred 1 h at 0 °C. After cooling to –40 °C,
MeLi (1.6 M in Et2O, 2.0 equiv) was added over 30 min with a sy-
ringe pump. The mixture was stirred for 5 min and quenched with
H2O. Et2O was added, the phases were separated, and the aqueous
phase was extracted with Et2O (2 ×). The organic layers were com-
bined, washed with brine (1 ×), dried (anhyd MgSO4), and evapo-
rated under reduced pressure. The crude product was used without
further purification.
Yellowish oil; yield: 6.35 g (85%); bp 100 °C/4 mbar.
1H NMR (300 MHz, CDCl3): δ = 4.83 (s, 1 H), 4.73 (s, 1 H), 3.82
(s, 2 H), 2.86 (s, 2 H), 2.38 (t, J = 7.3 Hz, 2 H), 2.20 (t, J = 7.3 Hz,
2 H), 1.80 (s, 3 H), 1.71 (s, 3 H), 0.14 (s, 9 H).
7-(tert-Butyldimethylsiloxy)-2-isopropylidene-4-methylenehep-
tyl Isocyanate (15b)
Yellowish oil; yield: 6.75 g (92%); bp 120 °C/2 mbar.
1H NMR (300 MHz, CDCl3): δ = 4.79 (s, 1 H), 4.68 (s, 1 H), 3.81
(s, 2 H), 3.62 (t, J = 6.6 Hz, 2 H), 2.86 (s, 2 H), 2.02 (t, J = 7.8 Hz,
2 H), 1.80 (s, 3 H), 1.71 (s, 3 H), 1.71–1.62 (m, 2 H), 0.90 (s, 9 H),
0.04 (s, 6 H).
2-Methyl-3,5-dimethylene-9-(trimethylsilyl)non-8-yn-2-ol (23a)
1H NMR (300 MHz, CDCl3): δ = 5.18 (s, 1 H), 4.93 (s, 1 H), 4.90
(s, 1 H), 4.82 (s, 1 H), 2.87 (s, 2 H), 2.38 (t, J = 7.7 Hz, 2 H), 2.24
(t, J = 7.7 Hz, 2 H), 1.36 (s, 6 H), 0.13 (s, 9 H).
Rhodium-Catalyzed Enantioselective [2+2+2] Cycloaddition;
General Procedures
Method A (less than 0.4 mmol of isocyanate): A flame-dried round
bottom flask was charged with [Rh(C2H4)2Cl]2 (3 mol%) and the
phosphoramidite ligand (6 mol%), and was fitted with a flame-dried
reflux condenser in an inert atmosphere (N2) glove box. Upon re-
moval from the glove box, a soln of alkyne (1.3 equiv) and isocya-
nate (1.0 equiv) in toluene was added via syringe followed by an
additional rinse of toluene to wash down the remaining residue and
reach the final concentration (0.04 M based on isocyanate). The re-
sulting soln was heated to 110 °C in an oil bath for 16–48 h. The
mixture was cooled to r.t., concentrated in vacuo, and purified by
flash column chromatography (gradient elution typically hexane–
EtOAc, 40:60 for the lactam adduct followed by 100% EtOAc or
EtOAc–MeOH, 20:1 for the vinylogous amide adduct).
8-(tert-Butyldimethylsiloxy)-2-methyl-3,5-dimethyleneoctan-2-
ol (23b)
1H NMR (300 MHz, CDCl3): δ = 5.17 (s, 1 H), 4.89–4.88 (m, 1 H),
4.84 (s, 1 H), 4.81 (s, 1 H), 3.61 (t, J = 6.2 Hz, 2 H), 2.07 (t, J = 7.4
Hz, 2 H), 1.71–1.61 (m, 2 H), 1.35 (s, 6 H), 0.88 (s, 9 H), 0.04 (s, 6
H).
2-Methyl-3,5-dimethylenealkan-2-yl Carbamates 24a,b;
General Procedure
To a 0.2 M soln of allylic alcohol 23a,b (1.0 equiv) in CH2Cl2 at 0
°C was added trichloroacetyl isocyanate (1.05 equiv) dropwise. The
soln was stirred 0 °C for 45 min and the solvent was evaporated un-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 719–728

726
S. Perreault, T. Rovis
FEATURE ARTICLE
Method B (0.4 to 12 mmol of isocyanate): A flame-dried round bot-
tom flask was charged with [Rh(C2H4)2Cl]2 (2 mol%) and the phos-
phoramidite ligand (4 mol%), and was fitted with a flame-dried
reflux condenser in an inert atmosphere (N2) glove box. Upon re-
moval from the glove box, toluene was added (90% of the amount
needed to reach 0.08 M). A soln of alkyne (1.3 equiv) and isocya-
nate (1.0 equiv) in toluene was added via syringe followed by an ad-
ditional rinse of toluene to wash down the remaining residue and
reach the final concentration (0.08 M based on isocyanate). The re-
sulting solution was heated to 110 °C in an oil bath for 24–48 h (the
disappearance of the isocyanate is followed by NMR of aliquots).
(R)-6-Chloro-2-isopropylidene-5-(4-methoxybenzyl)-2,3,8,8a-
tetrahydroindolizin-7(1H)-ones; General Procedure
To a 0.1 M soln of vinylogous amide cycloadduct 25 or 26 (1.0
equiv) in CH2Cl2 at –78 °C was added NCS (recrystallized from
benzene, 1.3 equiv) in one portion. The mixture was stirred at –78
°C for 15 min and quenched with sat. aq Na2S2O3. The phases were
separated and the aqueous phase was extracted with CH2Cl2 (2 ×).
The organic layers were combined, dried (anhyd MgSO4), and
evaporated under reduced pressure. The crude product can be puri-
fied by flash column chromatography (hexane–EtOAc, 1:1) but was
usually used without further purification for the next step.
Method C (more than 12 mmol of isocyanate): A vial was charged
with [Rh(C2H4)2Cl]2 (2 mol%) and the phosphoramidite ligand (4
mol%) in an inert atmosphere (N2) glove box. Upon removal from
the glove box, the contents of the vial were rapidly transferred into
a flame-dried round-bottom flask fitted with a reflux condenser.
Toluene (90% of the amount needed to reach 0.08 M) was then add-
ed using a funnel and the system was evacuated and refilled with ar-
gon (2 ×). A soln of alkyne (1.3 equiv) and isocyanate (1.0 equiv)
in toluene was added via syringe followed by an additional rinse of
toluene to wash down the remaining residue and reach the final con-
centration (0.08 M based on isocyanate). The resulting soln was
heated to 110 °C in an oil bath for 36–48 h (the disappearance of the
isocyanate is followed by NMR of aliquots).
(R)-6-Chloro-2-isopropylidene-5-(4-methoxybenzyl)-8a-[4-(tri-
methylsilyl)but-3-ynyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one
(30)
1H NMR (300 MHz, CDCl3): δ = 7.16 (d, J = 8.7 Hz, 2 H), 6.87 (d,
J = 8.7 Hz, 2 H), 4.13–4.04 (m, 2 H), 3.95 (d, J = 16.1 Hz, 1 H), 3.85
(d, J = 15.4 Hz, 1 H), 3.80 (s, 3 H), 2.90 (d, J = 16.5 Hz, 1 H), 2.72
(s, 2 H), 2.39–2.26 (m, 1 H), 2.24– 2.12 (m, 1 H), 2.00–1.80 (m, 3
H), 1.63 (s, 3 H), 1.54 (s, 3 H), 0.14 (s, 9 H).
(R)-8a-[3-(tert-Butyldimethylsiloxy)propyl)-6-chloro-2-isopro-
pylidene-5-(4-methoxybenzyl)-2,3,8,8a-tetrahydroindolizin-
7(1H)-one
1H NMR (300 MHz, CDCl3): δ = 7.15 (d, J = 8.8 Hz, 2 H), 6.85 (d,
J = 8.8 Hz, 2 H), 5.30 (s, 1 H), 4.15–4.05 (m, 2 H), 3.93 (d, J = 13.9
Hz, 1 H), 3.83 (d, J = 11.0 Hz, 1 H), 3.79 (s, 3 H), 3.58–3.42 (m, 2
H), 2.77 (s, 1 H), 2.71 (s, 1 H), 2.70 (s, 1 H), 2.34–2.22 (m, 1 H),
1.70–1.43 (m, 3 H), 1.62 (s, 3 H), 1.53 (s, 3 H), 0.84 (s, 9 H), 0.01
(s, 6 H).
(R)-2-Isopropylidene-5-(4-methoxybenzyl)-8a-[4-(trimethylsi-
lyl)but-3-ynyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one (25)
Following the general procedure, method C; yellow solid; yield:
6.81 g (73%); 98% ee by HPLC (Chiracel ADH, hexane–i-PrOH,
90:10, 1 mL/min).
(6S,8aR)-6-Chloro-2-isopropylidene-5-(4-methoxybenzyl)hexa-
hydroindolizin-7(1H)-ones; General Procedure
[α]D20 +40.0 (c 0.010, CHCl3).
To a 0.08 M soln of chlorinated vinylogous amide cycloadduct
(from the previous general procedure) in THF at –78 °C was added
Red-Al (65% wt in toluene, 2.0 equiv) dropwise. The mixture was
stirred at –78 °C for 6 h and quenched slowly with H2O. CH2Cl2 was
added and the biphasic mixture was allowed to warm to 23 °C and
stirred for 30 min. The phases were separated and the aqueous phase
was extracted with CH2Cl2 (2 ×). The organic layers were com-
bined, dried (anhyd MgSO4), and evaporated under reduced pres-
sure. The crude product can be purified by flash column
chromatography (hexane–EtOAc, 4:1) or can be used without fur-
ther purification for the next step.
1H NMR (300 MHz, CDCl3): δ = 7.00 (d, J = 8.6 Hz, 2 H), 6.73 (d,
J = 8.6 Hz, 2 H), 4.83 (s, 1 H), 3.89 (d, J = 14.9 Hz, 1 H), 3.76 (d,
J = 14.9 Hz, 1 H), 3.66 (s, 3 H), 3.43–3.34 (ABq, 2 H), 2.73 (d, J =
15.7 Hz, 1 H), 2.46 (d, J = 16.4 Hz, 1 H), 2.36 (d, J = 16.4 Hz, 1 H),
2.18 (d, J = 15.7 Hz, 1 H), 2.11–2.03 (m, 1 H), 1.89–1.61 (m, 3 H),
1.51 (s, 3 H), 1.42 (s, 3 H), 0.01 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 190.5, 161.1, 158.7, 129.7, 127.0,
126.0, 125.3, 114.2, 106.0, 98.6, 85.0. 66.3, 55.2, 50.0, 45.7, 41.6,
39.6, 31.5, 20.8, 15.2, 0.0.
MS (EI): m/z (%) = 422 (100).
HRMS (ESI): m/z [M + H]+ calcd for C26H36NO2Si: 422.2510;
found: 422.2510.
(5S,6S,8aR)-6-Chloro-2-isopropylidene-5-(4-methoxybenzyl)-
8a-[4-(trimethylsilyl)but-3-ynyl)-hexahydroindolizin-7(1H)-
one (31)
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.8 Hz, 2 H), 6.85 (d,
J = 8.8 Hz, 2 H), 4.52 (d, J = 10.2 Hz, 1 H), 3.81–3.74 (m, 1 H), 3.80
(s, 3 H), 3.65– 3.56 (m, 1 H), 3.49–3.29 (m, 2 H), 2.74 (dd, J = 14.6,
11.0 Hz, 1 H), 2.56 (d, J = 13.4 Hz, 1 H), 2.47–2.40 (m, 1 H), 2.43
(d, J = 13.4 Hz, 1 H), 2.12 (dm, J = 15.4 Hz, 1 H), 2.01–1.78 (m, 2
H), 1.68–1.52 (m, 2 H), 1.63 (s, 3 H), 1.59 (s, 3 H), 0.13 (s, 9 H).
(R)-8a-[3-(tert-Butyldimethylsiloxy)propyl)-2-isopropylidene-
5-(4-methoxybenzyl)-2,3,8,8a-tetrahydroindolizin-7(1H)-one
(26)
Following the general procedure, method C; yellow oil; yield: 5.89
g (70%); 98% ee by HPLC (Chiracel ADH, hexane–i-PrOH, 90:10,
1 mL/min).
[α]D20 +34.4 (c 0.010, CHCl3).
(5S,6S,8aR)-8a-[3-(tert-Butyldimethylsiloxy)propyl)-6-chloro-
2-isopropylidene-5-(4-methoxybenzyl)-hexahydroindolizin-
7(1H)-one
1H NMR (300 MHz, CDCl3): δ = 7.11 (d, J = 8.6 Hz, 2 H), 6.85 (d,
J = 8.6 Hz, 2 H), 4.96 (s, 1 H), 4.04 (d, J = 15.3 Hz, 1 H), 3.87 (d,
J = 15.3 Hz, 1 H), 3.79 (s, 3 H), 3.58–3.44 (m, 4 H), 2.74 (d, J = 15.7
Hz, 1 H), 2.58 (d, J = 16.0 Hz, 1 H), 2.51 (d, J = 16.0 Hz, 1 H), 2.28
(d, J = 15.7 Hz, 1 H), 1.72–1.44 (m, 3 H), 1.64 (s, 3 H), 1.55 (s, 3
H), 1.26–1.17 (m, 1 H), 0.85 (s, 9 H), 0.01 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 196.0, 166.4, 164.0, 135.0, 132.6,
131.8, 130.4, 119.6, 103.8, 103.7, 72.3, 68.1, 60.6, 55.3, 51.0, 47.0,
45.0, 33.7, 32.9, 31.2, 26.3, 26.2, 23.6, 0.1. 0.0.
Colorless oil; yield: 1.37 g (85%, 2 steps).
1H NMR (300 MHz, CDCl3): δ = 7.21 (d, J = 8.8 Hz, 2 H), 6.81 (d,
J = 8.8 Hz, 2 H), 4.50 (d, J = 9.9 Hz, 1 H), 3.80–3.70 (m, 1 H), 3.78
(s, 3 H), 3.65–3.60 (m, 1 H), 3.52–3.38 (m, 4 H), 2.77 (dd, J = 15.4,
11.4 Hz, 1 H), 2.55 (d, J = 13.1 Hz, 1 H), 2.44 (d, J = 13.1 Hz, 1 H),
2.41–2.34 (m, 1 H), 2.12 (dm, J = 15.0 Hz, 1 H), 1.62 (s, 3 H), 1.60
(s, 3 H), 1.55–1.33 (m, 4 H), 0.87 (s, 9 H), 0.01 (s, 6 H).
MS (EI): m/z (%) = 470 (100), 356 (85).
HRMS (ESI): m/z [M + H]+ calcd for C28H44NO3Si: 470.3085;
found: 470.3083.
(5S,6S,7R,8aR)-2-Isopropylidene-6-methoxy-5-(4-methoxyben-
zyl)-8a-[4-(trimethylsilyl)but-3-ynyl)-hexahydroindolizin-7-ol
(32)
To a 0.1 M soln of α-chloro ketone 31 in CH2Cl2–MeOH (1:1) at
–78 °C was added NaBH4 (1.8 equiv) in 1 portion. The mixture was
stirred at –78 °C to 23 °C for 16 h and quenched with H2O. CH2Cl2
Synthesis 2013, 45, 719–728
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Enantioselective Synthesis of the Tricyclic Core of FR901483
727
was added and the biphasic mixture was stirred for 30 min. The
phases were separated and the aqueous phase was extracted with
CH2Cl2 (2 ×). The organic layers were combined, dried (anhyd
MgSO4), and evaporated under reduced pressure. The crude product
was purified by flash column chromatography (hexane–EtOAc,
3:1) to give alcohol 32 (416 mg, 77%, 3 steps) as a colorless gum.
1H NMR (300 MHz, CDCl3): δ = 7.21 (d, J = 8.6 Hz, 2 H), 6.82 (d,
J = 8.6 Hz, 2 H), 4.26–4.23 (m, 1 H), 3.79 (s, 3 H), 3.46 (br s, 2 H),
3.40 (s, 3 H), 3.35–3.21 (m, 2 H), 3.11 (dd, J = 14.6, 2.9 Hz, 1 H),
2.54 (dd, J = 14.7, 4.4 Hz, 1 H), 2.43 (s, 1 H), 2.22 (dm, J = 15.7 Hz,
1 H), 2.15–2.05 (m, 2 H), 2.04–1.94 (m, 3 H), 1.82 (dd, J = 15.0, 3.0
Hz, 1 H), 1.56 (s, 6 H), 1.55–1.48 (m, 1 H), 0.13 (s, 9 H).
EtOAc, 3:1) to give the aza-tricycle 37 (33 mg, 41%) as a colorless
gum.
1H NMR (300 MHz, CDCl3): δ = 7.15 (d, J = 8.6 Hz, 2 H), 6.76 (d,
J = 8.6 Hz, 2 H), 4.30 (s, OH), 3.85 (d, J = 12.9 Hz, 1 H), 3.75 (s, 3
H), 3.69 (d, J = 10.2 Hz, 1 H), 3.47–3.41 (m, 1 H), 3.20–3.10 (m, 2
H), 2.80 (dd, J = 15.3, 5.5 Hz, 1 H), 2.66 (dd, J = 17.6, 8.2 Hz, 1 H),
2.59–2.41 (m, 1 H), 2.29–2.22 (m, 1 H), 2.18 (d, J = 14.4 Hz, 1 H),
2.09 (d, J = 14.4 Hz, 1 H), 1.97 (d, J = 12.9 Hz, 1 H), 1.86 (dd, J =
12.9, 3,6 Hz, 1 H), 1.58–1.47 (m, 1 H), 1.54 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 208.5, 158.3, 130.7, 129.0, 128.1,
123.5, 113.7, 78.2, 65.0, 63.6, 61.7, 55.2, 51.9, 45.1, 43.7, 37.8,
35.5, 29.9, 20.7, 20.6.
(5S,6S,8aR)-6-Chloro-8a-[3-hydroxypropyl)-2-isopropylidene-
5-(4-methoxybenzyl)-hexahydroindolizin-7(1H)-one (35)
A cold soln of 1% HCl in MeOH (0.29 M, 24 mL, 2.5 equiv) was
added to (6S,8aR)-8a-[3-(tert-butyldimethylsiloxy)propyl)-6-chlo-
ro-2-isopropylidene-5-(4-methoxybenzyl)-hexahydroindolizin-7(1H)-
one (1.4 g, 2.76 mmol). The mixture was stirred at 0 °C for 15 min
and concentrated to dryness. CH2Cl2 and sat. aq NaHCO3 were add-
ed. The phases were separated and the aqueous phase was extracted
with CH2Cl2 (2 ×). The organic layers were combined, dried (anhyd
MgSO4), and evaporated under reduced pressure. The crude product
was purified by flash column chromatography (hexane–EtOAc,
3:2) to give 35 (974 mg, 90%) as a yellowish oil.
MS (EI): m/z (%) = 470 (100), 356 (85).
HRMS (ESI): m/z [M + H]+ calcd for C22H29ClNO3: 390.1830;
found: 390.1827.
Acknowledgment
We thank NIGMS (GM80442) for support. S.P. thanks the FQRNT
for a postdoctoral fellowship. We thank Johnson Matthey for a ge-
nerous loan of rhodium salts.
Supporting Information for this article is available online at
1H NMR (300 MHz, CDCl3): δ = 7.21 (d, J = 8.8 Hz, 2 H), 6.83 (d,
J = 8.8 Hz, 2 H), 4.52 (d, J = 10.6 Hz, 1 H), 3.86–3.78 (m, 2 H), 3.78
(s, 3 H), 3.67–3.61 (m, 1 H), 3.52–3.33 (m, 4 H), 2.77 (dd, J = 15.4,
11.4 Hz, 1 H), 2.57 (d, J = 13.1 Hz, 1 H), 2.45 (d, J = 13.1 Hz, 1 H),
2.46–2.37 (m, 1 H), 2.15 (dm, J = 15.0 Hz, 1 H), 1.64 (s, 3 H), 1.61
(s, 3 H), 1.55–1.35 (m, 3 H).
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References
(1) For reviews see refs 1a,b and for reviews of recent syntheses,
see refs 1c–g: (a) Daly, J. W. J. Med. Chem. 2003, 46, 445.
(b) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod.
2005, 68, 1556. (c) Michael, J. P. Nat. Prod. Rep. 2000, 17,
579. (d) Michael, J. P. Nat. Prod. Rep. 2002, 20, 458.
(e) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603. (f) Michael,
J. P. Nat. Prod. Rep. 2007, 24, 191. (g) Michael, J. P. Nat.
Prod. Rep. 2008, 25, 139.
(5S,6S,8aR)-6-Chloro-8a-[3-oxopropyl)-2-isopropylidene-5-(4-
methoxybenzyl)-hexahydroindolizin-7(1H)-one (36)
To a soln of oxalyl chloride (50 μL, 1.5 equiv) in CH2Cl2 (0.7 mL)
at –78 °C was added DMSO (46 μL, 1.7 equiv) dropwise. The soln
was stirred at –78 °C for 30 min followed by addition of a soln of
alcohol 35 (150 mg, 0.382 mmol) in CH2Cl2 (0.6 mL). The mixture
was stirred for 90 min followed by addition of Et3N (159 μL, 3.0
equiv). The mixture was stirred at 0 °C for 30 min and at 23 °C for
30 min. Et2O was then added and the suspension was filtered. Some
toluene was added to the filtrate and the soln was evaporated under
reduced pressure. The crude product was purified by flash column
chromatography (short column, hexane–EtOAc, 7:3) to give ketoal-
dehyde 36 (130 mg, 87%) as a yellow oil.
(2) Sakamoto, K.; Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita,
M.; Shigematsu, N.; Izumi, S.; Okuhara, M. J. Antibiot.
1996, 49, 37.
(3) For a review on the biology and the synthesis of FR901483,
see: Bonjoch, J.; Diaba, F. In Studies in Natural Products
Chemistry, Bioactive Natural Products (Part L); Vol. 32;
Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 2005, 3–60.
(4) (a) Snider, B. B.; Lin, H. J. Am. Chem. Soc. 1999, 121, 7778.
(b) Scheffer, G.; Seike, H.; Sorensen, E. J. Angew. Chem.
Int. Ed. 2000, 39, 4593. (c) Ousmer, M.; Braun, N. A.;
Ciufolini, M. A. Org. Lett. 2001, 3, 765. (d) Maeng, J.-H.;
Funk, R. L. Org. Lett. 2001, 3, 1125. (e) Kan, T.; Fujimoto,
T.; Ieda, S.; Asoh, Y.; Kitaoka, H.; Fukuyama, T. Org. Lett.
2004, 6, 2729. (f) Brummond, K. M.; Hong, S.-P. J. Org.
Chem. 2005, 70, 907. (g) Carson, C. A.; Kerr, M. A. Org.
Lett. 2009, 11, 777. (h) Ousmer, M.; Braun, N. A.; Bavoux,
C.; Perrin, M.; Ciufolini, M. A. J. Am. Chem. Soc. 2001, 123,
7534. (i) Ieda, S.; Asoh, Y.; Fujimoto, T.; Kitaoka, H.; Kan,
T.; Fukuyama, T. Heterocycles 2009, 79, 721. (j) Ieda, S.;
Kan, T.; Fukuyama, T. Tetrahedron Lett. 2010, 51, 4027.
(k) Ma, A.-J.; Tu, Y.-Q.; Peng, J.-B.; Dou, Q.-Y.; Hou, S.-
H.; Zhang, F.-M.; Wang, S.-H. Org. Lett. 2012, 14, 3604.
(l) Huo, H.-H.; Zhang, H.-K.; Xia, X.-E.; Huang, P.-Q. Org.
Lett. 2012, 14, 4834.
1H NMR (300 MHz, CDCl3): δ = 9.48 (s, 1 H), 7.09 (d, J = 8.6 Hz,
2 H), 6.77 (d, J = 8.6 Hz, 2 H), 4.47 (d, J = 10.6 Hz, 1 H), 3.76 (d,
J = 13.3 Hz, 1 H), 3.72 (s, 3 H), 3.56 (d, J = 13.3 Hz, 1 H), 3.37 (dd,
J = 14.5, 2.8 Hz, 1 H), 3.16 (dt, J = 10.9, 3.1 Hz, 1 H), 2.66 (dd, J =
14.5, 10.9 Hz, 1 H), 2.53 (d, J = 13.3 Hz, 1 H), 2.35 (d, J = 13.3 Hz,
1 H), 2.22–2.10 (m, 2 H), 2.07–1.94 (m, 2 H), 1.66–1.57 (m, 2 H),
1.59 (s, 3 H), 1.54 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 201.2, 199.7, 158.2, 130.6, 129.5,
126.2, 125.3, 113.7, 98.4, 66.5, 63.6, 63.5, 55.2, 48.6, 48.4, 40.3,
37.6, 35.8, 25.4, 20.81, 20.80.
(1R,6S,7S,8R)-7-Chloro-8-hydroxy-3-isopropylidene-6-(4-
methoxybenzyl)-5-azatricyclo[6.3.1.01,5]dodecan-9-one (37);
Tricyclic Core of FR90483
In a flame-dried round bottom flask under an argon atmosphere
containing the triazolium salt 39 (39 mg, 0.5 equiv) was added tol-
uene (1.0 mL). A soln of KHMDS (18 mg, 0.45 equiv) in toluene
(1.0 mL) was added. The mixture was stirred at 23 °C for 20 min
and the volatiles were then removed under high vacuum. Toluene
(1.0 mL) was added and the mixture was heated to 70 °C. A soln of
ketoaldehyde 36 (80 mg, 0.205 mmol) in toluene (2.0 mL) was add-
ed and argon was bubbled for 5 min. The mixture was stirred at 70
°C for 6 h and concentrated under reduced pressure. The crude
product was purified by flash column chromatography (hexane–
(5) For synthetic approaches leading to the tricyclic framework
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W. Org. Lett. 2001, 3, 2353. (c) Suzuki, H.; Yamazaki, N.;
Kibayashi, C. Tetrahedron Lett. 2001, 42, 3013.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 719–728

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S. Perreault, T. Rovis
FEATURE ARTICLE
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and TAN-1251 Compounds, In Biomimetic Organic
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in press. DOI: 10.1039/C3SC50271F.
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(a) Theobald, A. E.; Lingard, R. G. Spectrochim. Acta, Part
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(17) This kind of strained aziridinium intermediate has been
previously invoked: (a) ref. 5h. (b) For a review on
aziridinium ring opening, see: Metro, T. X.; Duthion, B.;
Pardo, D. G.; Cossy, J. Chem. Soc. Rev. 2010, 39, 89.
(18) (a) Enders, D.; Niemeier, O.; Henseler, A. Chem. Rev. 2007,
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(19) (a) Breslow, R. Chem. Ind. (London) 1957, 893.
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(22) A screen of pre-catalysts (thiazolium and triazolium salts)
did not improve the yield of this cyclization.
(23) At lower concentration (0.01 M instead of 0.05 M) only the
starting material was observed. Increasing the temperature
or the catalyst loading did not affect the yield, while
lowering the temperature or the catalyst loading led to no
ring-formed product.
(8) (a) Friedman, R. K.; Rovis, T. J. Am. Chem. Soc. 2009, 131,
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2009, 38, 3149. (b) Keller-Friedman, R.; Oberg, K. M.;
Dalton, D. M.; Rovis, T. Pure Appl. Chem. 2010, 82, 1353.
(10) 4-Methoxybenzylacetylene (7) was made according to a
two-step procedure from 4-methoxybenzyl chloride: 1. 2
mol% Co(acac)3, BrMgC≡CTMS, THF, 23 °C followed by
purification by distillation (bp 90 °C/4 Torr) to give the
TMS-protected alkyne (83% yield): Kuni, A.; Saino, N.;
Kamachi, T.; Okamoto, S. Tetrahedron Lett. 2006, 47, 2591;
2. KF·2H2O, DMF, 23 °C followed by purification by
distillation (bp 52 °C/5.3 mbar) to give 7 (85% yield).
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(12) Queignec, R.; Kirschleger, B.; Lambert, F.; Aboutaj, M.
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(14) For selected examples of [3,3]-sigmatropic rearrangements
of cyanates into isocyanates, see: (a) Ichikawa, Y. Synlett
Synthesis 2013, 45, 719–728
© Georg Thieme Verlag Stuttgart · New York