Cleavage of a chiral auxiliary using RCM on an especially sterically crowded alkene: Syntheses of chiral carbo- and heterocycles

Article abstract of DOI:10.1016/j.jorganchem.2006.07.028

Chiral 1,5-, 1,6-, and 1,7-dienes generated in 3-4 steps from chiral auxiliary p-menthane-3-carboxaldehyde undergo RCM with notable discrepancies in reactivity depending on the nature and number of substituents flanking the central double bond. The chiral

Full text of DOI:10.1016/j.jorganchem.2006.07.028

Journal of Organometallic Chemistry 691 (2006) 5336–5355
www.elsevier.com/locate/jorganchem
Cleavage of a chiral auxiliary using RCM on an especially
sterically crowded alkene: Syntheses of chiral carbo- and heterocycles
*
´
Claude Spino , Luc Boisvert, Jasmin Douville, Stephanie Roy, Sophie Lauzon,
Joannie Minville, David Gagnon, Francis Beaumier, Christine Chabot
Department of Chemistry, The University of Sherbrooke, 2500 Boul. Universite´, Sherbrooke, Que., Canada J1K 2R1
Received 30 June 2006; received in revised form 24 July 2006; accepted 24 July 2006
Available online 2 August 2006
Abstract
Chiral 1,5-, 1,6-, and 1,7-dienes generated in 3–4 steps from chiral auxiliary p-menthane-3-carboxaldehyde undergo RCM with nota-
ble discrepancies in reactivity depending on the nature and number of substituents flanking the central double bond. The chiral auxiliary
is thus cleaved releasing a carbo- or heterocycle in the process. Special features concerning the RCM on these especially crowded systems
are discussed.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: p-Menthane-3-carboxaldehyde; Ring-closing metathesis; Bulky ruthenium alkylidene; Heterocycles; Carbocycles
1. Introduction
of new and more active catalysts [3]. Meanwhile, synthetic
chemists were busy making rings of all sorts and sizes with
these catalysts. Notably, heterocycles containing nitrogen
[4,5], oxygen [5], silicon [1f], and phosphorus [6] were all
found to be efficiently prepared by RCM. Sulfur-contain-
ing heterocycles remain a challenge, to this day [6].
In the last several years, we have elaborated several reac-
tion sequences, all starting from p-menthane-3-carboxalde-
hyde 1, that leads to chiral non-racemic a-substituted
carboxylic acids (4), including amino acids (4, X = NR2),
upon oxidative cleavage of the auxiliary (Scheme 1). We
realized that the sequence could lead directly to carbo- or
heterocycles (6, X = C, O, N, S) if the auxiliary in 7 could
be cleaved by RCM. The chiral auxiliary 1 would be recy-
clable via a simple ozonolysis of 5. We report herein a full
account of this work with an emphasis on the RCM cleav-
age in view of this special issue of the journal. The present
work includes the synthesis of several new carbo- and het-
erocycles [7].
From an organic synthesis standpoint, the ring-closing
alkene metathesis reaction (RCM) has undergone a formi-
dable evolution over a very short period of time: a barely
known and little-used reaction just over 15 years ago, prac-
ticing synthetic organic chemists have resurrected this
transformation in such a way that it quickly entered the
league of the most powerful synthetic tools now available
[1]. In fact, it has been a while since such excitement was
seen in the synthetic community over an organic transfor-
mation. The advent of the well-defined ruthenium-based
catalysts that are active, selective, and functional-group
tolerant is largely responsible for the current popularity
of RCM [2]. It is likely that RCM will continue to grow,
perhaps at a slower pace now, as chemists use and study
it and discover new ways to unleash its power.
Thrusted forward by the discovery of Shrock’s molybde-
num and Grubb’s ruthenium catalysts, several research
groups made important contributions to the development
2. Results and discussion
*
At the onset, the internal double bond in 7, especially in
Corresponding author. Tel.: +1 819 821 7087; fax: +1 819 821 8017.
E-mail address: Claude.Spino@USherbrooke.ca (C. Spino).
compounds bearing a quaternary allylic carbon (X, R1 and
0022-328X/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2006.07.028

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5337
R2 R1
X
O
OH R2
R2 R1
HO2C
O3
R1
X
1
4
1
2
3
O3
R2 R1
R2 R1
X
+
X
RCM
n
n
5
6
7
Scheme 1.
R2 ¼ H), did not look amenable to RCM. The double
bond substituted with the voluminous menthyl fragment
on one side and a tertiary or quaternary chiral carbon on
the other side represents a serious deterrent to trying such
a strategy.
The vast majority of RCM reported in the literature
involve two terminal double bonds and examples of
RCM involving an internal alkene substituted at both
allylic positions are rare as are examples of allylic quater-
nary carbons next to an internal or terminal alkene [1,8].
Scheme 2 provides selected examples. The center example
is perhaps closer to our own work in that it clearly shows
the detrimental effect (presumably for steric reasons) of
substituents around the diene framework on the forma-
tion of dihydropyrans 12 [9]. Thomas and co-workers
have shown that the presence of a gem-dimethyl group
at the allylic position of a terminal double bond shuts
down a metathetic macrocyclization (not shown) [10]. A
difficult RCM was successfully achieved from 13 by
microwave irradiation as well as N2 sparging to remove
ethylene (Scheme 2, bottom) [11]. Generally, the second
generation Grubbs (9) or Nolan catalysts (21, cf. Scheme
3) have contributed a great deal to widening the scope of
the RCM towards making congested double bonds
[3a,3b,12].
Exploratory experiments were conducted to replace p-
menthane-3-carboxaldehyde 1 by another, less voluminous,
aldehyde in order to increase our chances of terminating
the sequence by a RCM reaction (cf. general sequence in
Scheme 1). However, smaller auxiliaries caused problems
because the steric bulk of the menthyl nucleus actually
serves to make several transformations from 2 to 3 highly
regioselective (i.e. with transposition of the double bond),
be they displacement or rearrangement reactions [13]. So,
Mes-N
N-Mes
Cl
Ru
Ph
Cl
PCy3
9
(CH2)3OTBDPS
(CH2)3OTBDPS
NBoc
OBn
NBoc
OBn
CH2Cl2, 40˚C, 98%
8
10
R3
R1 R2 R3
yield
mol%
O
O
R1
Bn
R1
Bn
R3
R2
9
H
H
H
Me
H
H
H
5
5
5
92%
dimer
dimer
0%
DCM, reflux
Me H
R2
H
H
Me 10
O
O
11
12
Me
Et3SiO
H
HO
H
9
Me
H
H
PhMe, 300W μW, 90 min
10 mol% cat, TBAF 98%
O
O
O
O
H
H
13
14
Scheme 2.

5338
C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
Cy3P
Cl
Ru
Ph
Cl
PCy3
Me
Ph
Me
Ph
16
Ph
Ph
+
CH2Cl2, 40 °C, 85%
Me
Me
15
Me Ph
17
18
Me Me
Mes-N
Cl
N-Mes
Cl
R
Ru
Ph
PCy3
20
19a R = Me
19b R = Ph
19c R = CHMePh
21
Scheme 3.
in order to gauge the consequence of the steric volume at
the allylic positions on the diene, we effected RCM reac-
tions on a series of racemic substrates 15, 19, and 20
(Scheme 3). Cyclopentene 17 was formed in 85% yield
using Grubbs’ first generation catalyst 16, a very encourag-
ing result. Likewise, substrates 19a and 19b gave the corre-
sponding cyclohexene (>95% conversion by NMR) using
catalyst 9 or 21 in refluxing 1,2-dichloroethane under high
dilution (0.0005 M) for four days. Clearly, the presence of
the quaternary carbon next to the alkene alone is enough to
slow significantly the cyclization rate in the case of six
membered rings. Discouragingly, substrates 19c and 20
did not undergo a ring-closing metathesis using several dif-
ferent catalysts and under a wide range of reaction condi-
tions. This did not bode well as any chiral auxiliary
would have to possess at least a secondary carbon. Hope
remained, nonetheless, as the formation of the cyclopent-
enes from 15 proceeded quite well with Grubbs’ first gener-
ation catalyst 16. The difference in reactivity between 15
and 19c foretold of a trend of dramatically higher cycliza-
tion rate in the formation of five over six membered rings in
this system (vide infra).
would be otherwise undetected since it leads to the enantio-
mer of 24.
Notably, compounds 23e,g possessing a chiral quater-
nary carbon required much harsher conditions (entries 6
and 8). Increasing dilution did not give satisfactory results
in these cases. The most effective method to increase yields
was to increase catalyst loading and use normal concentra-
tion and higher temperatures [14]. Cyclohexene 24f pos-
sessing a quaternary carbon atom could not be prepared
by RCM (entry 7). We tried a large number of catalysts
and reaction conditions but it seemed that we had reached
the limit as far as the generation of these carbocycles by
RCM is concerned. The dimer of 23f was the major iso-
lated product in most cases. Microwave heating did not
improve yields. Inert gas sparging [11] would not make
any difference as ethylene or other volatile alkenes are
never produced except in unwanted metatheses. The differ-
ence in reactivity between 23e and 23f is perhaps the most
dramatic example of the kinetic preference for five-mem-
bered over six-membered ring formation in RCM [15]. This
preference has been noted in a few instances but never with
such conclusiveness [16].
Our first attempts were aimed at the generation of car-
bocycles 24 from dienes 23, themselves made from the
highly stereoselective (>99%) addition of 1-pentenyl- or
1-butenylcuprate to the diastereomerically pure pivalate
esters of 22 (Table 1) [7,13a]. We were astonished to find
that the RCM reaction on molecules like 23a–d actually
proceeded quite well to give the corresponding cycloalk-
enes 24a–d in high yield [7]. We surveyed a large number
of catalysts and reaction conditions [3]. Although, Grubbs’
first generation catalyst 16 could effect the cyclization in
one case (entry 1), the Nolan catalyst 21 (or the similar
Grubbs’ second generation catalyst 9) were consistently
giving higher yields than all of the other ones we surveyed.
We repeated each sequence of reaction shown in Table 1
with the diastereomer of 22, or independently prepared
the racemic carbocycle 24, in order to ascertain the enan-
tiomeric purity of the carbocycles 24. This is because a
Ru-catalyzed migration of the double bond around the ring
Yet, the RCM reaction was very efficient for dienes
23b,d giving cyclohexenes 24b,d having a tertiary chiral
center (entries 3 and 5). As low as 1 mol% of catalyst 21
was enough to effect the reaction. It seems that the addition
of a single alkyl group (R1, R2 ¼ H) adjacent to the alkene
is enough to drastically reduce the reaction rate or even
shut the reaction down (compare entries 2 vs. 6 and 3 vs.
7). Clearly, the initiation of the reaction at the terminal
double bond could not be the issue here, thus the added ste-
ric volume near the reacting alkene must be the culprit. It
overwhelmes any beneficial consequence of a Thorpe–
Ingold effect [17] brought about by the gem disubstitution.
Paradoxically, although the voluminous menthyl frag-
ment undoubtedly slows the rate of cyclization (kc in
Scheme 4), it may nonetheless be partly responsible for
the success of this transformation in general. The catalytic
cycle is initiated by the reaction between the active form
of the catalyst and the terminal alkene in 23 to give

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5339
Table 1
Yields of cycloalkenes 24 from the RCM of 23 using optimized conditions
OH R2
R2 R1
R2 R1
1. PivCl
R1
RCM
n
n
+
2.
CuCNMgBr
n
22
23
5
24
Entry
23
R1
R2
N
24
Cat. (mol%)
Yield 24c,d (%)
1
2
3
4
5
6
7
8
a
23a
23a
23b
23c
23d
23e
23f
23g
Bn
Bn
Bn
TBSOCH2
TBSOCH2
Bn
H
H
H
H
0
0
1
0
1
0
1
0
24a
24a
24b
24c
24d
24e
24f
24g
16 (10)a
21 (1)b
21 (1)b
21 (1)b
21 (1)b
21 (30)a
21 (30)a
21 (30)a
85
81
84
87
73
79e
0
H
Me
Me
Me
Bn
TBSO(CH2)4
70e
Conditions: ClCH2CH2Cl (0.01–0.002 M), reflux, 3 h.
CH2Cl2 (0.01–0.002 M), reflux, 3 h.
Isolated yield of 24 after flash chromatography.
ee’s >98%.
b
c
d
e
See text.
R2 R1
23
23
n
21
dimer
ki/k-i
kdi/k-di
Ru
25
5
kpr/k-pr
kc/k-c
23
24
IMes
IMes
Ru
Cl
Cl
k-de
kde
k-p
kp
Ru
inactive complexes
Cl
Cl
PCy3
26b
26a
Scheme 4.
alkylidene 25. When the latter cyclizes, it gives the desired
product 24 and a new alkylidene 26a. We believe that the
propagating alkylidene 26a, with a uniquely bulky alkylid-
ene portion, plays several important roles: (a) recombina-
tion with phosphine is slow (low kp) to give the inactive
form 26b, which must release phosphine before re-enter-
ing the catalytic cycle (Scheme 4) [18,19]; (b) 26a may
decompose more slowly (low kde) than less bulky ruthe-
nium alkylidenes to give inactive (or damaging) ruthe-
nium complexes. This allows us to carry out the
reactions for longer periods of time and at higher temper-
ature [18]; (c) the steric bulk of 26a also slows reactions
with any compound relative to 23 (kpr) (compound 24
(kꢀc) or compound 5 (k5, Scheme 5) for example, i.e. dif-
ferences in reaction rates are increased); (d) lastly, the
bulk of the menthyl fragment strongly favors the forma-
tion of productive regioisomers 27b, which contributes
to the overall efficiency of the catalytic cycle (Scheme
5). Compound 28, if produced via 27a, would probably
never re-enter the catalytic cycle because of its two highly
substituted double bonds.
Other side reactions, such as double bond migration,
were not a problem except in the worst cases (23e–g).
The increased stability of the propagating catalyst 26a
helps by slowing down the generation of metal hydrides
or other complexes that are thought to be responsible for
such side reactions [1f,20]. Note that these characteristics
are unique to our system. Using bulky ruthenium alkylid-
ene similar to 26a to initiate an RCM on a substrate having
two crowded terminal double bonds, for example, would
not help since the propagating species would be the ruthe-
nium methylidene 29.

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C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
IMes
Ru
Ru
Cl
R
R
Ru
<<
Cl
R
23
27a
27b
26a
, k5/k-5
5
25
+ 26a
R2 R1
IMes
Cl
+
Ru CH2
Cl
Menthyl
28
29
30
Scheme 5.
Encouraged by this initial success, we looked at the pos-
sibility of preparing the more biologically relevant N-het-
erocycles by this method. Two complementary and very
useful transformations of alcohol 2 lead to the formation
of chiral allylic amines bearing a tertiary or quaternary chi-
ral carbon of high enantiomeric purity. The first uses a tan-
dem Mitsunobu/azide rearrangement sequence on alcohols
31a–d to make chiral allylic amines 34a–d and is shown in
Scheme 6 [13c]. The bulk of the menthyl fragment controls
the thermodynamic ratio of the allylic azides 32 and 33.
Only regioisomers 33a–d were observed by NMR, each
with very good diastereomeric ratio. Reduction of the azide
afforded the corresponding amines 34, which were alkyl-
ated and protected as carbamates to give 35a–d.
RCM cleavage of the auxiliary in the case of 35a–b pro-
ceeded exceedingly well using catalyst 16 (3 mol%) or 21
(1 mol%) to give dihydropyrroles 36a and 36b, respectively
(Scheme 7). Formation of tetrahydropyridines 36c–d was
nearly as efficient. As expected, protection of the amine
function as a carbamate (Boc) had been necessary because
the free secondary amines interfered with the RCM reac-
tion [21]. Reduction of the endocyclic alkene in 36d gave
(+)-N-Boc-coniine [22] while 36a was successfully trans-
formed into the a-amyloglucosidase inhibitor (+)-lentigi-
nosine in five steps [23]. Comparison of the optical
rotations with literature data confirmed the enantiomeric
purity of the products.
Primary amines 39a–b, each bearing a quaternary chiral
centers next to nitrogen, were prepared in >98% de from
alcohols 37a–b by the stereospecific rearrangement of the
corresponding cyanates to isocyanates 38a–b as shown in
Scheme 8 [24]. Amines 39a–b were then alkylated with ally-
lbromide or 1-butenylbromide to give 40 and 41, respec-
tively. Their protection proved exceedingly difficult. As it
turn out, and annoyingly, it did not matter because allyl-
or homoallylcarbamates 40, 41, 42, or 43 refused to
undergo the RCM reaction. Increasing the temperature
and catalyst loading had little effect except to spur decom-
position of the starting material. Once more, the difference
in reactivity between carbamate 35d, bearing a tertiary chi-
ral carbon, and carbamate 43, bearing a quaternary chiral
carbon, appears out of proportion. These two compounds
OH
H
N3
H
H R
N3
HN3, PPh3
DEAD
LiAlH4
R
R
80-90%
31a R = (CH2)4OTBDPS
31b R = -Bu
31c R = CH2Ph
31d R = -Pr
32a-d
33a 95:5 dr
33b 94:6 dr
33c 97:3 dr
33d 92:8 dr
t
n
Br
H R
NH2
H R
1. K2CO3
MeCN
Boc
0,1
N
2. Boc2O, DMF
60-80%
0,1
34a-d
35a R = (CH2)4OTBDPS, n = 0
35b R = -Bu, n = 0
35c R = CH2Ph, n = 1
35d R = -Pr, n = 1
t
n
Scheme 6.

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5341
16, 3 mol% (35a
21, 1 mol% (35b
)
)
H R
Boc
35a,b
35c,d
N
H
CH2Cl2, reflux
0.005M
HO
N
5 steps
36a R = (CH2)4OTBS, 99%
36b R = -Bu, 91%
t
HO
(+)-lentiginosine
H R
21, 3 mol%
Boc
N
CH2Cl2, reflux
0.005M
36c R = CH2Ph, 82%
36d R = -Pr, 96%
n
Scheme 7.
OH R2
R1 R2
1. FmOH, Ti(Ot-Bu)4
1. Cl3C(CO)NCO
MeOH, H2O, K2CO3
95%, >99%de
R1
N
C
O
2. piperidine, 98%
2. TFAA, CH2Cl2, Et3N
37a R1 = (CH2)4OBn, R2 = (CH2)3OTIPS
37b R1 = -Pr, R2 = Me
38a (undeter. dr)
38b (99:1 dr)
n
OBn
Br
(CH2)3OTIPS
R
R1 R2
NH2
n
-Pr Me
N
0,1
R
or
N
CsOH-H2O
DMF, 52-54%
41 R = H
Boc2O
Et3N
<10%
Boc2O
Et3N
36%
39a
39b
40 R = H
43 R = Boc
42 R = Boc
RCM
RCM
n
-Pr Me
(CH2)3OTIPS
BnO
R
N
R
N
44
45
Scheme 8.
only differ by a methyl group. Clearly, steric effects are
prominent in influencing the rate of cyclization, especially
for the formation of six-membered rings. What was needed
at this stage was a more reactive ruthenium alkylidene to
increase the rate of cyclization.
Enoic carbenes are thought to be much more reactive
towards metathesis than normal ruthenium alkylidenes
[25]. Nonetheless, this was an unnatural choice of function-
ality to initiate the RCM because a,b-unsaturated carbo-
nyls are said to react sluggishly or not at all with the
catalyst [26]. Grubbs and co-workers later reported that
enoic carbenes are efficiently formed by the reaction of cat-
alyst 9 with acrylates and reacted in cross metathesis with
1,1-disubstituted olefins [25b]. Interestingly, while a series
of ester carbenes were found to be very unstable, the corre-
sponding amide was indefinitely stable under the same con-
ditions [27]. When considering a system like our own, we
must assume that initiation would occur at the conjugated
alkene. Initiation at the internal double bond is certainly
not in line with the results presented above. Tellingly, a
report by Marco shows that the RCM reaction of unsatu-
rated amides 46 using catalyst 9 fails unless initiation can
take place at the non-conjugated alkene (Scheme 9, com-
pare entries 2 vs. 3) [28].
For the reasons mentioned above, we initially used the
relay metathesis concept [29] to effect the transformation
of 50a into 51, believing that the reaction would benefit
from an intramolecular relay for the formation of the
amide ruthenium carbene (Scheme 10). However, it turns
out to be unnecessary as the yield of lactam 51 was actually
better when the acrylamide 50b was used directly, though
the reaction time was somewhat longer. The enantiomeric
purity of the heterocycles were not determined and are
assumed to be equal to the diastereomeric purity of the

5342
C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
O
O
entry R1 R2
R1
R2
yield
condit.
conditions
BnN
BnN
Ph
R2
1
2
3
4
H
H
A
A
B
B
90%
92%
0%
R1
Me H
Ph
H
Me
46a R1 = R2 = H
Me Me
0%
47
46b R1 = Me, R2 = H
46a R1 = H, R2 = Me
46a R1 = Me, R2 = Me
A. 4% cat. 16, CH2Cl2, Ti(OiPr)4
B. 16% cat. , toluene, 80-110 °C
9
Scheme 9.
O
R
Y
H
OTBDPS
NH2
H
OTBDPS
NH
49a R = (CH2)3CH=CH2, Y = OH
DCC, DMAP, DCM, 90%
R
O
49b R = H, Y = Cl
DCM, Et3N 82%
48 (97:3 dr)
50a R = (CH2)3CH=CH2
50b R = H
OTBDPS
NH
H
50a, cat. 21 (5 mol%)
0.001M DCM,Δ 10 min, 85 %
,
50b, cat. 21 (5 mol%)
0.005M DCM,Δ 1h, 92 %
,
O
51
Scheme 10.
precursors. Racemization through Ru-catalyzed double
bond migration is not possible here.
remainder being methacrylamide 55a. The latter compound
is presumably formed from the intermolecular reaction of
the amide carbene intermediate with the terminal double
bond in starting amide 55b. Thus, adding a methyl group
on that terminal double bond sufficiently slowed this inter-
molecular reaction such that amide 55c supplied the desired
lactam 56 in 91% yield in only 15 min! A priori, we did not
think RCM was possible on such a sterically loaded system
and this example underscores the usefulness of RCM in
synthesis.
The difference in reactivity between carbamate 43 and
NH-amide 53b (cf. Schemes 8 and 11) is intriguing. Our
results with NH-amide 53a–b are seemingly in contradic-
tion with the failure to initiate an RCM from amide 46
reported by Marco and co-workers (cf. Scheme 9) [28]. In
their case, however, the amide nitrogen was substituted
with a benzyl group. Although the results presented herein
do not represent a systematic study, we can suggest that the
Encouraged by this result we tried the RCM cleavage of
the auxiliary on amides 53a and 53b (made by the addition
of vinylmagnesium bromide on isocyanate 38a or 38b,
respectively) to effect formation of five-membered lactams
bearing quaternary carbon centers. We were delighted to
obtain decent yields of each of lactams 52 and 54 using
10 mol% 9 (Scheme 11).
Could we perform the cleavage of the auxiliary to pre-
pare a lactam bearing a quaternary carbon center and a
trisubstituted double bond? We hoped so because our
planned stereoselective syntheses of members of the
daphniphyllane alkaloids [30] relies on the use of an inter-
mediate very much like lactam 56. Treatment of meth-
acrylamide 55a under the usual conditions gave only
starting material (Scheme 12). However amide 55b gave
an encouraging 63% yield of the desired lactam 56, the
OBn
R2 R1
NH
Me
-Pr
n
(CH2)3OTIPS
NH
9, 10 mol%
9
, 10 mol%
NH
DCE, 0.005M
PhMe, 0.005M
Δ, 2h, 66%
O
Δ, 1.5h, 60%
O
O
53a R1 = (CH2)4OBn, R2 = (CH2)3OTIPS
52
54
53b R1 = Me, R2 =
n-Pr
Scheme 11.

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5343
Chiral non-racemic S-heterocycles were also accessible
using our methodology. We prepared S-thiocarbamates
64a–b from the rearrangement of O-thiocarbamates
derived from alcohols 63a–b, as shown in Scheme 14 [35].
The cleavage of the S-thiocarbamates 64a–b and concomi-
tant alkylation of the resulting thiols was achieved with
cesium carbonate in methanol. A portion of each sulfide
65a–c was then oxidized with peracid to the corresponding
sulfone 66a–c.
OBn
(CH2)3OTIPS
OBn
(CH2)3OTIPS
21, 10 mol%
PhMe, 0.005M
Δ, 15 min. From:
NH
NH
O
55a, 0%
55b, 63%
55c, 91%
R
O
Me
Me
55a R = H
56
55b R = (CH2)3CH=CH2
55c R = (CH2)3CH=CHMe
‘Unreliable’ would be a good word to describe the
behaviour of those sulfides and sulfones in the RCM cleav-
age of the chiral auxiliary. Sulfide 65b underwent the cycli-
zation with high efficiency (85% yield) to give 67b under
mild conditions without the use of an external Lewis acid
(Scheme 14). That in itself was a surprising result because
sulfides are thought to be real poisons for ruthenium cata-
lysts and the literature abounds in problematic RCM
involving a sulfur atom [36]. A strong coordination
between the sulfur and ruthenium metal center is often
cited as the reason for this difficulty.
Scheme 12.
amide helps the RCM cleavage of the auxiliary in two
ways; firstly, the amide carbene intermediate is more reac-
tive than normal ruthenium alkylidenes while it maybe eas-
ier to form than other enoic carbenes [31,32]; secondly, the
amide alleviates the need to further substitute the amine
(with a Boc group for example) to prevent coordination
of the free amine to the ruthenium [2b,21]. Consequently,
the system is less congested and cyclizes faster.
In support of the latter argument, six-membered lac-
tams 58a,b bearing a tertiary or quaternary stereocenter
were efficiently prepared under similar conditions (Scheme
13, right). The use of a Lewis acid was necessary in this
case because without it the alkylidene ruthenium species
coordinates very efficiently to the amide carbonyl and
the reaction stops after one catalytic turnover [33]. Com-
pound 59a is an advanced intermediate towards the syn-
thesis of pumiliotoxin C 62 [34]. The formation of a
seven-membered ring from 58c was more difficult and
led only to a 30% yield of lactam 57c in which the alkene
became conjugated with the amide carbonyl (Scheme 13,
left). The remainder was a mixture of dimer and uncyc-
lized products in which the double bond has migrated.
Still, this result is better than previous ones starting from
60, for which no cyclic product 61 was isolated. Thus the
amide strategy will help in widening the scope of our
methodology and we are hopeful we can improve on the
formation of medium-size rings.
Surprisingly, the analogous homoallylic sulfide 65c
(R = t-Bu, n = 2) was inert to a huge series of experiments
involving 10 different catalysts (Grubbs second generation
type catalysts, Grela’s, Grubbs’ chlorophenylphosphines
or bromopyridines, Hoveyda’s, Blechert’s, etc.) and doz-
ens of reaction conditions! How could the sulfide in 65c
poison the catalysts when the sulfide in 65b did not? Of
course, we have seen such a drastic difference in rate of
formation between five-membered and six-membered
carbo- and N-heterocycles (vide supra) but only when
they bore a quaternary carbon center. No such difference
was seen on substrates having a tertiary center. Are the
longer bonds between carbon and sulfur adding extra
strain to the six-membered ring? It is true that very few
dihydrothiopyranes have been prepared by RCM
[36b,36f].
To add to the confusion, the n-propyl derivative 65a
would not undergo the RCM unless a Lewis acid was
added to the reaction mixture. We have found that the best
R2 R1
NH
R2 R1
NH
n
-Pr
21, 10 mol%
9
, 10 mol%
PhBCl2
PhBCl2
NH
O
DCE, 0.005M
D, 1.5h, 32%
DCE, 0.005M
Δ
O
n
O
, 2h, 79%
58a R1 = (CH2)4OTBDPS, R2 = H, n = 1
58b R1 = Me, R2 =
-Pr, n = 1
58c R1 = H, R2 =
-Pr, n = 2
57c
59a,b
n
n
H
t
-Bu
t-Bu
RCM
Boc
Boc
H
N
N
Me
NH
H
60
61
Scheme 13.
62

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C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
OH
H
R H
i) NaH, THF
ii) PhN=C=S, Δ
Cs2CO3-MeOH
Sealed tube, 80˚C
R
S
iii) PPTS, THF
Δ, 1-3h
n
Br
PhHN
O
63a R =
63b R =
n
-Pr
64a R =
64b R =
n
-Pr (99:1 dr)
t
-Bu
t
-Bu (99:1 dr)
R H
R H
m-CPBA
CH2Cl2
S
SO2
n
n
77-99%
65a R =
65b R =
65c R =
n
-Pr, n = 1
-Bu, n = 1
-Bu, n = 2
66a R =
66b R =
66c R =
n
-Pr, n = 1
t
t-Bu, n = 1
t
t
-Bu, n = 2
21, 10%, 0.01M
CH2Cl2, reflux
L.A. (see text)
21, 10%, 0.01M
CH2Cl2, reflux
L.A. (see text)
R H
S
R H
S
R H
SO2
R H
SO2
67a 97%
67b 85%
67c 0%
68a 99%
68b 84%
68c 0%
Scheme 14.
additive was ((C6H6)RuCl2)2. This is, to our knowledge,
the first time that a ruthenium additive has been used to
improve a Ru-catalyzed RCM. The problem with 65a is
therefore a detrimental complexation between the sulfur
and the metathesis catalyst. Only the added steric bulk of
the t-butyl group in 65b could have alleviated the need
for a Lewis acid by hindering coordination between sulfur
and ruthenium.
Sulfones 66a and 66b underwent the RCM reaction very
efficiently and without additive in dichloromethane at
40 ꢁC (99% and 84% yield, respectively). When the reaction
was carried out in refluxing 1,2,-dichloroethane, sulfur
dioxide was extruded from the resulting sulfolenes 68a–b
and the corresponding dienes were recovered. No six-mem-
bered cyclic sulfone could be isolated when substrate 66c
was submitted to different catalysts and reaction
conditions.
In summary, we have developed very useful synthetic
sequences that terminate with a RCM cleavage of the chiral
auxiliary and directly forms enantioenriched carbo- and
heterocycles. The RCM reactions reported herein all
involve a very sterically demanding 1,2-disubstituted dou-
ble bond. One of the salient features of these RCM reac-
tions is that the propagating ruthenium alkylidene is
unusually bulky, which slows undesired reaction rates to
the advantage of productive ones. The difference in cycliza-
tion rates of some five vs. six-membered rings were some-
times stunning. Many of the chiral heterocycles formed
by RCM were or are currently being used to prepare natu-
ral products.
3. Experimental section
3.1. Syntheses of alcohols 31a, 37a–b: general procedure
The vinyl iodide (1.2 eq) was dissolved in anhydrous
diethyl ether and the solution was cooled to ꢀ78 ꢁC. A
2.5 M solution of n-BuLi in hexanes (1.2 eq) was added
at ꢀ78 ꢁC dropwise. The reaction was stirred at ꢀ78 ꢁC
during 30 min, warmed to rt and stirred for 30 min at rt.
A 2 M solution of AlMe3 in hexanes (2.5 eq) was added
at rt. After cooling to ꢀ78 ꢁC, menthyl 3-carboxaldehyde
(1 eq) was added and the reaction was stirred overnight
while allowing to slowly warm to rt. The reaction mixture
was quenched with saturated K2CO3 and then 2 N HCl
was added to dissolve carbonate salts. The phases were sep-
arated and the aqueous phase was extracted three times
with Et2O. The organic layers were combined, washed once
with brine, dried over magnesium sulfate and concentrated
under reduced pressure to give a yellow oil. Diastereomeric
excess (% de) were evaluated by GC or HPLC. The crude
product was purified by flash chromatography on a silica
gel column eluting with hexanes and ethyl acetate.
3.1.1. Alcohol 31a
Colorless oil (9.41 g, 56%, >99% de by HPLC). 1H
NMR (CDCl3, 300 MHz): d 7.66 (dd, 4H, J = 7.7 Hz,
1.7 Hz), 7.45–7.34 (m, 6H), 5.65–5.47 (m, 2H), 4.36 (d,
1H, J = 4.4 Hz), 3.66 (t, 2H, J = 6.1 Hz), 2.13 (qd, 1H,
J = 6.6 Hz, 2.2 Hz), 2.04 (q, 2H, J = 7.2 Hz), 1.72–1.46
(m, 9H), 1.44–1.24 (m, 3H), 1.04 (s, 9H), 1.05–0.79 (m,

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5345
3H), 0.93 (d, 3H, J = 7.2 Hz), 0.87 (d, 3H, J = 6.6 Hz), 0.76
(d, 3H, J = 7.2 Hz). IR (neat, cmꢀ1): 3447, 3069, 2956,
2931, 2859, 1472, 1428, 1111, 973. LRMS (m/z (relative
intensity)): 449 ((MꢀC4H9)+, 10), 293 (14), 233 (21), 199
(100), 177 (22), 137 (49), 109 (29), 95 (64), 81 (39). HRMS
calc. for C29H41O2Si: 449.2876, found 449.2870.
NMR (CDCl3, 300 MHz): d 7.66 (dd, 4H, J = 7.7 Hz,
1.7 Hz), 7.45–7.34 (m, 6H), 5.51–5.43 (m, 1H), 5.36–5.27
(m,1H), 3.76 (q, 1H, J = 6.6 Hz), 3.64 (t, 2H, J = 6.6 Hz),
1.96–1.85 (m, 2H), 1.75–1.70 (m, 1H), 1.65–1.25 (m,
10H), 1.04 (s, 9H), 1.05–0.83 (m, 3H), 0.86 (d, 3H,
J = 7.1 Hz), 0.85 (d, 3H, J = 6.6 Hz), 0.71 (d, 3H,
J = 6.6 Hz). IR (neat, cmꢀ1): 3072, 3049, 2962, 2868,
2095, 1471, 1428, 1237, 1111, 973. LRMS (m/z (relative
intensity)): 503 ((MꢀN2)+, 8), 446 (100), 308 (11), 248
(30), 199 (68), 183 (23), 135 (20), 81 (18). HRMS calc.
20
½aꢁD ¼ ꢀ7:7ꢂ (c 2.57, CHCl3).
3.1.2. Alcohol 37a
1
Colorless oil (636 mg, 97%, >99% de by GC). H NMR
(300 MHz, CDCl3) d (ppm) 7.35–7.27 (m, 5H), 5.38 (d, 1H,
8.1 Hz), 4.68 (d, 1H, J = 8.1 Hz), 4.51 (s, 2H), 3.66 (t, 2H,
J = 6.3 Hz), 3.48 (t, 2H, J = 6.3 Hz), 2.24–2.14 (m, 2H),
2.12–2.01 (m, 3H), 1.74–1.46 (m, 9H), 1.36–1.22 (m, 4H),
1.15–1.00 (m, 5H), 1.06 (d, 18H, J = 2.8 Hz), 0.96–0.63
(m, 3H), 0.93 (d, 3H, J = 6.6 Hz), 0.89 (d, 3H,
for C33H53N4OSi: 549.3988, found 549.3984 (for
20
(MNH4)+). ½aꢁ ¼ ꢀ25:1 (c3.67, CHCl3).
D
3.3. Synthesis of amine 34a
In a 100 mL rb flask was dissolved the azide 33a (1.00 g,
1.88 mmol) in THF (20 mL). This solution was cooled to
0 ꢁC and LiAlH4 (powder 95%, 107 mg, 2.82 mmol) was
added by small portions. The resulting mixture in stirred
at 0 ꢁC for 10 min and then at rt. After 18 h, the reaction
mixture was cooled to 0 ꢁC and treated with water and a
1 N aqueous solution of HCl. The suspension was then fil-
tered on a pad of celite and the filtrate was treated with a
1 N aqueous solution of NaOH. The aqueous phase was
extracted with three portions of EtOAc and the combined
organic extracts were washed once with water and once
with brine, dried over anhydrous MgSO4, filtered and con-
centrated under reduced pressure to give a colorless oil.
The crude product was purified on silica gel with 30:70/
J = 6.6 Hz), 0.77 (d, 3H, J = 7.2 Hz). IR (neat) m (cmꢀ1
)
3573–3294 (br), 3029, 2945, 2865, 1461, 1099, 876. LRMS
(m/z, relative intensity) 555 ([MꢀOH]+, 1), 529
((MꢀC3H7)+, 20), 433 (50), 259 (50), 151 (43), 91 (100),
83 (60). HRMS calc. for C27H42O2 ([MꢀC3H7]+):
20
529.4077, found: 529.4064. ½aꢁD ꢀ 18:2ꢂ (c = 1.52, CHCl3).
3.1.3. Alcohol 37b
White solid (464 mg, 77%, 99% de by GC); m.p.: 30–
31 ꢁC; 1H NMR (300 MHz, CDCl3) d 5.34 (d, 1H,
J = 8.2 Hz), 4.67 (dd, 1H, J = 8.3 Hz, 3.9 Hz), 2.19 (septd,
1H, J = 6.6 Hz, 1.7 Hz), 1.98 (t, 2H, J = 7.7 Hz), 1.73–1.65
(m, 3H), 1.63 (s, 3H), 1.44 (sext, 2H, J = 7.5 Hz), 1.38–1.28
(m, 3H), 1.12 (d, 1H, J = 4.4 Hz), 0.95–0.86 (m, 12H), 0.79
(d, 3H, J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) d 136.7
(s), 126.9 (d), 67.6 (d), 44.8 (d), 43.1 (t), 41.8 (d), 35.1 (t),
34.0 (t), 32.7 (d), 26.3 (d), 24.2 (t), 22.8 (q), 21.6 (q), 20.8
EtOAc:hexanes as eluant to afford
a colorless oil
1
(820 mg, 86%). H NMR (CDCl3, 300 MHz): d 7.66 (dd,
4H, J = 7.7, 1.7 Hz), 7.45–7.34 (m, 6H), 5.31–5.28 (m,
2H), 3.64 (t, 2H, J = 6.6 Hz), 3.24 (m, 1H), 1.85 (qi, 2H,
J = 6.6 Hz), 1.73–1.67 (m, 1H), 1.62–1.52 (m, 5H), 1.49–
1.26 (m, 5H), 1.04 (s, 9H), 1.01–0.74 (m, 3H), 0.85 (d,
3H, J = 6.6 Hz), 0.84 (d, 3H, J = 6.6 Hz), 0.69 (d, 3H,
J = 6.6 Hz). IR (neat, cmꢀ1): 3891, 3366, 3070, 2955,
2929, 2859, 1472, 1428, 1111, 971. LRMS (m/z (relative
intensity)): 506 ((MH)+, 84), 489 (49), 448 (100), 293 (30),
194 (100), 137 (13), 95 (8). HRMS calc. for C33H52NOSi:
(q), 16.4 (t), 15.5 (q), 13.7 (q). IR (CHCl3/NaCl) m (cmꢀ1
)
3349 (br), 2955, 2925, 2871, 1450. MSLR (m/z, relative
intensity) 252 (M+Å, 22), 209 ((M+ÅꢀC3H7), 10), 113
(100). MSHR calc. for C17H32O: 252.2453, found:
20
252.2448. ½aꢁD ¼ ꢀ51:1 (c = 1.15, CHCl3).
3.2. Synthesis of azide 33a
20
506.3818, found 506.3821. ½aꢁD ¼ ꢀ20:5ꢂ (c 2.34, CHCl3).
In a 50 mL rb flask, was dissolved the allylic alcohol 31a
(1.50 g, 2.96 mmol) and triphenylphosphine (1.55 g,
5.92 mmol) in benzene (30 mL) and this solution was
cooled to 0 ꢁC. A solution of hydrazoic acid (4.2 mL,
1.4 M in benzene, 5.92 mmol) and diethylazodicarboxylate
(DEAD) (1.03 g, 5.92 mmol) were added dropwise simulta-
neously at 0 ꢁC and the reaction mixture was stirred for 6 h
letting the temperature warm slowly to rt. The resulting
reaction mixture was then diluted with hexanes and filtered
over a pad of celite to remove the triphenylphosphine
oxide. The mother liquor was washed with two portions
of 70:30 MeOH/H2O, once with brine, dried over anhy-
drous MgSO4, filtered and concentrated under reduced
pressure to give a yellow oil. The crude product was puri-
fied on silica gel with 5:95/EtOAc:hexanes as eluant to
3.4. Synthesis of carbamate 35a
In a 100 mL r.b. flask was dissolved the amine 34a
(1.58 g, 3.114 mmol) in acetonitrile (31 mL). Anhydrous
K2CO3 (452 mg, 3.270 mmol) was added into the solution
and this solution was stirred 5 min at rt. Then, the allyl
bromide (414 mg, 3.425 mmol) was added very slowly
(20 lL/min) and the resulting suspension was stirred at rt
for 1.5 h and an excess of allyl bromide (0.2 eq) was added.
The resulting mixture was stirred again for a another 2 h at
rt, diluted in water and extracted with three portions of
EtOAc. The combined organic extracts were washed once
with brine, dried over anhydrous MgSO4, filtered and con-
centrated under reduced pressure to give a yellow oil. The
crude product was purified on silica gel with 1:1/Et2O:hex-
1
afford a colorless oil (1.55 g, 98%, 97% de by HPLC). H

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1
anes as eluant to afford a colorless oil (986 mg, 59%). H
NMR (300 MHz, CDCl3): d 7.65 (dd, 4H, J = 7.7,
1.7 Hz), 7.44–7.34 (m, 6H), 5.91 (ddt, 1H, J = 17.0, 16.5,
6.1 Hz), 5.27 (dd, 1H, J = 15.4, 8.8 Hz), 5.17–5.07 (m,
3H), 3.63 (t, 2H, J = 6.6 Hz) 3.28 (dd, 1H, J = 13.8,
5.5 Hz), 3.10 (dd, 1H, J = 13.8, 6.6 Hz), 3.02–2.90 (m,
1H), 1.98–1.83 (m, 2H), 1.74–1.67 (m, 1H), 1.59–1.24 (m,
10H), 1.04 (s, 9H), 1.02–0.64 (m, 3H), 0.87 (d, 6H,
J = 6.6 Hz), 0.83 (d, 3H, J = 6.6 Hz), 0.70 (d, 3H,
J = 6.6 Hz). IR (film) m (cmꢀ1): 3071, 2945, 2930, 2859,
1471, 1455, 1427, 1111, 909. LRMS (m/z, relative inten-
sity): 545 ((M+Å), 2), 504 ((MꢀC3H5)+, 23), 488
((MꢀC4H9)+, 31), 234 (100), 199 (18), 183 (10), 96 (43).
HRMS calc. for C36H55NOSi: 545.4053, found 545.4038.
(58), 288 (49), 83 (100). HRMS calc. for C29H42NO3Si
20
(MH)+: 480.2934, found: 480.2942. ½aꢁD ¼ þ3:5 (c = 1.25,
CHCl3).
3.6. Syntheses of isocyanates 38a–b: general procedure
Trichloroacetylisocyanate (1.5 eq) was added dropwise
to a solution of the alcohol (1 eq) in CH2Cl2 at 0 ꢁC. The
solution was stirred for 1 h at 0 ꢁC. The solvent was then
evaporated under reduced pressure and the resulting pre-
cipitate was dissolved in a 2:1 mixture of methanol and
water. This solution was cooled to 0 ꢁC and potassium car-
bonate (3 eq) was slowly added. The mixture was allowed
to warm slowly to room temperature while stirring over-
night. Methanol was then evaporated under reduced pres-
sure and the aqueous layer was extracted with 3 · 15 mL of
dichloromethane. The organic layers were combined,
washed with brine, dried with MgSO4, filtered and evapo-
rated. The crude compound can be used directly in the next
step or it can be purified by flash chromatography eluting
with EtOAc/hexanes.
Triethylamine (3 eq) and TFAA (0.95 eq) were both
added dropwise to a solution of the allylcarbamate (1 eq)
in CH2Cl2 at 0 ꢁC. The solution was stirred for 15 min at
0 ꢁC before quenching with saturated aqueous NH4Cl
(15 ml). The layers were separated and the aqueous layer
was extracted with 3 · 15 mL of dichloromethane. The
organic layers were combined, washed with brine, dried
with MgSO4, filtered and evaporated. The crude compound
was purified by flash chromatography eluting with Et2O/
hexanes (5:95).
20
½aꢁD ¼ ꢀ21:7 (c = 1.09, CHCl3).
In a 100 mL rb flask was dissolved the alkylated amine
(1.31 g, 2.400 mmol) in DMF (20 mL) and this solution
was stirred at rt for 5 min. Then, triethylamine (368 mg,
3.600 mmol) was added and this solution was stirred for
an another 5 min at rt and the di-tert-butyldicarbonate
(786 mg, 3.600 mmol) was added and this resulting mixture
was stirred at rt during 23 h. The mixture was then treated
with a saturated solution of NH4Cl and the aqueous phase
was extracted with three portions of EtOAc and the com-
bined organic extracts were washed once with water and
once with brine, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure to give a yellow
oil. The crude product was purified on silica gel with
3:97/AcOEt:hexanes as eluant to afford a colorless oil
1
(1.26 g, 82%). H NMR (CDCl3, 300 MHz): d 7.65 (dd,
4H, J = 7.7, 1.7 Hz), 7.44–7.34 (m, 6H), 5.82–5.70 (m,
1H), 5.40–5.23 (m, 2H), 5.10 (d, 1H, J = 17.2 Hz), 5.02
(d, 1H, J = 7.9 Hz), 3.63 (t, 2H, J = 6.6 Hz), 1.90–1.51
(m, 9H), 1.44 (s, 9H), 1.35–1.25 (m, 6H), 1.04 (s, 9H),
0.97–0.79 (m, 10 H), 0.67 (d, 3H, J = 6.6 Hz). LRMS
(m/z (relative intensity)): 589 ((MꢀC4H9)+, 1), 532 (44),
455 (61), 282 (51), 278 (100), 235 (70), 199 (41), 140 (49).
HRMS calc. for C37H55NO3Si: 589.3951, found 589.3942.
3.6.1. Isocyanate 38a
Colorless oil (1.07 g, 99%). 1H NMR (300 MHz, CDCl3)
d 7.38–7.25 (m, 5H), 5.42 (dd, 1H, J = 15.3, 9.6 Hz), 5.17
(d, 1H, J = 15.3 Hz), 4.50 (s, 2H), 3.73–3.63 (m, 2H),
3.46 (t, 2H, J = 6.3 Hz), 1.96–1.17 (m, 15H), 1.16–0.99
(m, 23H), 0.95–0.82 (m, 3H), 0.86 (d, 6H, J = 6.6 Hz),
0.68 (d, 3H, J = 7.1 Hz). IR (neat) m (cmꢀ1) 3044, 2946,
2866, 2263, 1457, 1105. LRMS (m/z, relative intensity)
554 ([MꢀC3H7]+, 22), 421 (12), 91 (100). HRMS calc. for
C34H56NO3Si ([MꢀC3H7]): 554.4029, found: 554.4041.
3.5. Synthesis of dihydropyrrole 36a
In a 500 mL rb flask was dissolved the carbamate 35a
(1.00 g, 1.548 mmol) in dry CH2Cl2 (310 mL, 0.005 M)
and the reaction was refluxed for 10 min. The reflux was
stopped and catalyst 16 (63.7 mg, 0.0774 mmol) was added
in small portions and the reaction mixture was refluxed for
18 h. The resulting solution was concentrated under
reduced pressure and the crude product was purified on sil-
ica gel with 1:20/EtOAc:hexanes as eluant to afford a col-
20
½aꢁD ꢀ 31:6 (c = 1.29, CHCl3).
3.6.2. Isocyanate 38b
1
Colorless oil (43 mg, 95%, >99% de by GC). H NMR
(300 MHz, CDCl3)
d
5.42 (dd, 1H, J1 = 15.4 Hz,
J2 = 8.8 Hz), 5.31 (d, 1H, J = 15.4 Hz), 1.93–1.70 (m,
3H), 1.64–1.52 (m, 4H) 1.49–1.26 (m, 4H), 1.36 (s, 3H),
1.02–0.81 (m, 6H), 0.92 (d, 3H, J = 7.2 Hz), 0.87 (d, 3H,
J = 6.6 Hz), 0.69 (d, 3H, J = 6.6 Hz). 13C NMR
(75.5 MHz, CDCl3) d 133.6 (d), 133.1 (d), 110.0 (s), 61.6
(s), 47.1 (d), 45.7 (t), 44.2 (d), 43.2 (t), 35.1 (t), 32.4 (d),
29.4 (q), 28.1 (d), 24.1 (t), 22.5 (q), 21.3 (q), 17.6 (t), 15.3
(q), 14.1 (q). IR (neat/NaCl) m (cmꢀ1) 2957, 2929, 2873,
2260, 1455, 972. MSLR (m/z, relative intensity) 277 (M+Å,
5), 234 (M+ÅꢀHNCO, 58), 191 (38), 96 (100). MSHR calc.
1
orless oil (743 mg, 100%). H NMR (300 MHz, CDCl3):
d 7.65 (dd, 4H, J = 7.7, 2.2 Hz), 7.44–7.33 (m, 6H), 5.75–
5.68 (br d, 2H, J = 6.6 Hz), 4.50 (m, 1H), 4.17 (br d, 1H,
J = 13.2 Hz), 3.98 (dd, 1H, J = 9.9, 5.5 Hz), 3.63 (t, 2H,
J = 6.6 Hz), 1.69–1.51 (m, 4H), 1.46 (s, 9H), 1.35–1.24
(m, 2H), 1.04 (s, 9H). IR (neat) m (cmꢀ1): 3071, 2924,
2861, 1704, 1697, 1427, 1392, 1174, 1111, 910. LRMS
(m/z, relative intensity): 480 ((MH)+, 39), 380 (62), 366

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5347
20
for C18H31NO: 277.2405, found: 277.2399. ½aꢁD ¼ ꢀ73:4
bromide (30 ll, 0.35 mmol). The resulting suspension was
stirred at room temperature for 48 h before quenching with
saturated aqueous NaHCO3 (10 ml). The layers were sepa-
rated and the aqueous layer was extracted with 3 · 10 mL
of Et2O. The organic layers were combined, washed with
brine, dried with MgSO4, filtered and evaporated. The
crude compound was purified by flash chromatography
eluting with Et2O/hexanes (20:80) to yield 93 mg (54%) of
the desired compound as a colorless oil. 1H NMR
(300 MHz, CDCl3) d (ppm) 7.37–7.25 (m, 5H), 5.92 (ddt,
1H, J = 16.8, 10.8, 5.8 Hz), 5.26–5.15 (m, 2H), 5.14 (dd,
1H, J = 16.8, 1.1 Hz), 5.03 (d, 1H, J = 10.8 Hz), 4.49 (s,
2H), 3.67–3.64 (m, 2H), 3.45 (t, 2H, J = 6.8 Hz), 3.03 (d,
2H, J = 5.8 Hz), 1.95–1.15 (m, 18H), 1.14–0.91 (m, 22H),
0.90–0.79 (m, 2H), 0.85 (d, 6H, J = 7.2 Hz), 0.67 (d, 3H,
J = 6.6 Hz). IR (neat) m (cmꢀ1) 3065, 3032, 2943, 2865,
1464, 1103. LRMS (m/z, relative intensity) 611 (M+Å, 2),
448 (100), 396 (97). HRMS calc. for C39H69NO2Si:
(c = 1.23, CHCl3).
3.7. Syntheses of amines 39a–b: general procedure
Ti(Ot-Bu)4 (0.1 or 0.2 eq) was added to a solution of the
isocyanate (1 eq) and 9-fluorenemethanol (1.5 eq) in ben-
zene (10 ml) at 0 ꢁC. The solution was refluxed for 3 h
before quenching with saturated aqueous NH4Cl (20 ml).
The layers were separated and the aqueous layer was
extracted with 3 · 20 mL of Et2O. The organic layers were
combined, washed with brine, dried with MgSO4, filtered
and evaporated.
Piperidine (3 eq) was added to a solution of the Fmoc-
protected amine (1 eq) in a 2:1 mixture of DMF and
CH2Cl2. The solution was stirred at rt overnight before
quenching with saturated aqueous NaHCO3. The layers
were separated and the aqueous layer was extracted with
3 · 20 mL of Et2O. The organic layers were combined,
washed with brine, dried with MgSO4, filtered and evapo-
rated. The crude compound was purified by flash chroma-
tography eluting with EtOAc/hexanes/Et3N (25:74:1).
20
611.5097, found: 611.5078. ½aꢁD ꢀ 27:2 (c = 0.37, CHCl3).
3.8.1. Amine 41
1
Same procedure as per amine 40. H NMR (300 MHz,
CDCl3) d (ppm) 5.75 (ddt, 1H, J = 17.0, 9.9, 7.2 Hz),
5.23 (d, 1H, J = 16.0 Hz), 5.17–5.00 (m, 4H), 2.51 (t, 2H,
J = 7.2 Hz), 2.20 (q, 2H, J = 7.2 Hz), 1.93–1.78 (m, 2H),
1.74–1.70 (m, 1H), 1.63–1.53 (m, 2H), 1.46–1.29 (m, 3H),
1.28–1.16 (m, 2H), 1.08 (s, 3H), 1.02–0.79 (m, 7H), 0.90
(d, 3H, J = 7.7 Hz), 0.86 (d, 3H, J = 6.6 Hz), 0.69 (d, 3H,
J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) d (ppm) 136.8
(d), 136.1 (d), 133.8 (d), 116.1 (t), 56.2 (s), 47.2 (d), 45.0
(d), 43.7 (t), 43.6 (t), 41.3 (t), 35.2 (t), 34.9 (t), 32.5 (d),
28.1 (d), 24.0 (t), 23.6 (q), 22.6 (q), 21.4 (q), 17.1 (t), 15.1
(q), 14.7 (q). IR (neat, cmꢀ1) 3077, 2956, 2928, 2871,
2843, 1695, 1641, 1455, 1370, 978, 912. LRMS (m/z, rela-
tive intensity) 304 ((MꢀH)+, 1), 290 ((MꢀCH3)+, 7), 262
((MꢀC3H7)+, 100), 84 (50). HRMS calc. for C21H38N
3.7.1. Amine 39a
Colorless oil (506 mg, 98%). 1H NMR (300 MHz,
CDCl3) d (ppm) 7.39–7.25 (m, 5H), 5.36–5.18 (m, 2H),
4.49 (s, 2H), 3.65 (t, 2H, J = 5.5 Hz), 3.48–3.42 (m, 2H),
1.97–1.21 (m, 18H), 1.11–0.94 (m, 23H), 0.91–0.78 (m,
2H), 0.85 (d, 3H, J = 6.6 Hz), 0.84 (d, 3H, J = 7.2 Hz),
0.68 (d, 3H, J = 7.1 Hz). IR (neat) m (cmꢀ1) 3032, 2944,
2865, 1457, 1104. LRMS (m/z, relative intensity) 571
(M+Å, 2), 528 ([MꢀC3H7]+, 10), 409 (100), 356 (65), 91
(68). HRMS calc. for C36H65NO2Si: 571.4784, found:
20
571.4773. ½aꢁD ꢀ 22:4 (c = 1.21, CHCl3).
3.7.2. Amine 39b
20
Colorless oil (308 mg, 92%). 1H NMR (300 MHz,
CDCl3) d (ppm) 5.42 (d, 1H, J = 16.0 Hz), 5.21 (dd, 1H,
J = 16.0, 9.1 Hz), 1.91–1.84 (m, 2H), 1.82–1.69 (m, 1H),
1.63–1.54 (m, 2H), 1.40–1.19 (m, 6H), 1.13 (s, 3H), 1.02-
0.78 (m, 6H), 0.91 (d, 3H, J = 7.2 Hz), 0.86 (d, 3H,
J = 6.6 Hz), 0.69 (d, 3H, J = 6.6 Hz). 13C NMR
(75.5 MHz, CDCl3) d (ppm) 138.2 (d), 131.2 (d), 52.7 (s),
47.2 (d), 46.3 (t), 44.5 (d), 43.5 (t), 35.1 (t), 32.4 (d), 28.8
(q), 27.9 (d), 24.0 (t), 22.5 (q), 21.3 (q), 17.4 (t), 15.1 (q),
14.6 (q). IR (neat, cmꢀ1) 2955, 2928, 2916, 2871, 1455,
975. LRMS (m/z, relative intensity) 250 ((MꢀH)+, 1),
236 ((MꢀCH3)+, 16), 234 ((MꢀNH3)+, 3), 208
((MꢀC3H7)+, 100). HRMS calc. for C17H32N (MꢀH):
(MꢀH)+: 304.3004, found: 304.3009. ½aꢁD ¼ ꢀ67:0
(c = 1.00, CHCl3).
3.9. Synthesis of carbamate 43
The amine 41 (126 mg, 0.41 mmol) and triethylamine
(86 lL, 0.62 mmol) were dissolved in dimethylformamide
(4 mL). Then, (Boc)2O (135 mg, 0.62 mmol) was added to
the reaction mixture. The reaction was stirred at rt for a
week. A saturated solution of NaHCO3 was poured in
the reaction mixture and the product was extracted with
3 · 10 mL of diethyl ether. Organic layers were combined,
washed with brine, dried over MgSO4, filtered and concen-
trated under reduced pressure. The resulting light yellow oil
was purified by flash chromatography (from 100% hexanes
to 70% diethyl ether in hexanes) to yield pure (R)-protected
amine (60 mg, 36%) as a colorless oil and 40 mg of starting
20
250.2535, found: 250.2540. ½aꢁD ¼ ꢀ65:3 (c = 1.03,
CHCl3).
3.8. Synthesis of amine 40
1
material (32%). H NMR (300 MHz, CDCl3) d 5.71 (ddt,
A mixture of the amine 39a (161 mg, 0.28 mmol), CsO-
H Æ H2O (45 mg, 0.27 mmol), and 4 A MS (75 mg) were
stirred in DMF (0.5 ml) for 30 min before adding allyl
1H, J = 17.0, 9.9, 6.6 Hz), 5.62 (d, 1H, J = 15.9 Hz), 5.25
(dd, 1H, J = 15.9, 9.4 Hz), 5.02 (dd, 1H, J = 17.0,
1.7 Hz), 4.99 (dd, 1H, J = 9.9, 1.7 Hz), 3.22 (t, 2H,
˚

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C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
J = 8.0 Hz), 2.22 (sept, 1H, J = 7.4 Hz), 1.92–1.70 (m, 6H),
1.66–1.54 (m, 2H), 1.45 (s, 9H), 1.40 (s, 3H), 1.22 (sext.,
2H, J = 7.7 Hz), 1.03–0.78 (m, 8H), 0.87 (d, 3H,
J = 7.2 Hz), 0.86 (d, 3H, J = 6.6 Hz), 0.70 (d, 3H,
J = 6.6 Hz). 13C NMR (75.5 MHz, CDCl3) d 155.4 (s),
135.8 (d), 134.6 (d), 132.8 (d), 115.8 (t), 78.9 (s), 61.4 (s),
47.3 (d), 45.7 (t), 44.9 (d), 43.2 (t), 42.3 (t), 35.3 (t), 35.1
(t), 32.4 (d), 28.5 (q), 28.2 (d), 24.4 (q), 24.1 (t), 22.5 (q),
21.4 (q), 17.6 (t), 15.3 (q), 14.5 (q). IR (CHCl3/NaCl) m
(cmꢀ1) 3077, 2956, 2929, 2871, 1699, 1455, 1385, 1365,
1173, 1134. LRMS (m/z, relative intensity) 405 (M+Å, 1),
349 ((MꢀC4H8)+, 88), 306 (100), 262 (47), 235 (61), 168
(50), 97 (77). HRMS calc. for C26H47NO2: 405.3607,
3.11. Synthesis of amine 50b
Amine 48 (823 mg, 1.79 mmol) was dissolved in CH2Cl2
(30 mL). Acryloyl chloride (52 lL, 0.518 mmol) and Et3N
(37 lL, 0.518 mmol) were added and the mixture was stirred
15 min at rt. The reaction mixture was quenched with a sat-
urated solution of ammonium chloride. The two phases
were separated and the aqueous phase was extracted twice
with DCM. The organic phases were combined, washed
once with brine, dried with anhydrous magnesium sulfate
and concentrated under reduced pressure. Flash chroma-
tography on silica gel, eluting with hexanes and ethyl acetate
(4:1) furnished a clear oil (182 mg, 82%). 1H NMR (CDCl3,
300 MHz) d 7.66–7.59 (m, 4H), 7.47–7.32 (m, 6H), 6.25 (dd,
1H, J = 17.0, 1.6 Hz), 6.05 (dd, 1H, J = 17.0, 10.4 Hz), 5.80
(d, 1H, J = 8.8 Hz), 5.64 (dd, 1H, J = 10.4, 1.6 Hz), 5.50
(dd, 1H, J = 15.4, 5.0 Hz), 5.42 (dd, 1H, J = 15.4, 7.7 Hz),
4.68–4.59 (m, 1H), 3.74 (d, 2H, J = 3.9 Hz), 1.98–1.77 (m,
2H), 1.76–1.65 (m, 1H), 1.64–1.53 (m, 1H), 1.44–1.17 (m,
1H), 1.25 (s, 1H), 1.06 (s, 9H), 0.96 (d, 2H, J = 10.4 Hz),
0.93–0.75 (m, 2H), 0.86 (d, 3H, J = 7.1 Hz), 0.84 (d, 3H,
J = 7.7 Hz), 0.69 (d, 3H, J = 6.6 Hz). IR (neat, cmꢀ1):
3345–3185 (br), 2952, 2924, 2860, 1657, 1543, 1111, 703.
LRMS (m/z (relative intensity)): 517 (M+Å, 5), 460
(M+ÅꢀC4H9, 100), 252 (65). HRMS calc. for C33H47NO2Si:
20
found: 405.3604. ½aꢁD ¼ ꢀ37:8 (c = 1.02, CHCl3).
3.9.1. Amine 48
Same procedure as per amine 34a. Colorless oil (34 mg,
73%). 1H NMR (CDCl3, 300 MHz) d 7.66 (d, 4H,
J = 7.7 Hz), 7.46–7.34 (m, 6H), 5.45–5.40 (m, 2H), 3.73–
3.61 (m, 1H), 3.60–3.50 (m, 2H), 2.45–1.82 (m, 2H),
1.81–1.64 (m, 2H), 1.63–1.56 (m, 2H), 1.38–1.21 (m, 1H),
1.25 (s, 2H), 1.06 (s, 9H), 0.97–0.75 (m, 3H), 0.84 (d, 3H,
J = 6.1 Hz), 0.81 (d, 3H, J = 7.1 Hz), 0.64 (d, 3H,
J = 6.6 Hz). IR (neat, cmꢀ1): 2953, 2927, 2862, 1111, 703.
LRMS (m/z (relative intensity)): 406 (M+ÅꢀC4H9, 30),
194 (100). HRMS calc. for C26H36NOSi (M+Å+C4H9):
20
517.3376, found: 517.3393. ½aꢁD ¼ ꢀ42:4 (c = 6.70, CHCl3).
20
406.2566, found: 406.2570. ½aꢁD ¼ ꢀ27:7 (c = 1.06,
CHCl3).
3.12. Synthesis of lactam 51
3.10. Synthesis of amide 50a
Amide 50a (34 mg, 0.058 mmol) or 50b (30 mg,
0.058 mmol) was dissolved in DCM (12 mL, concentration:
0.005 M). Argon was bubbled through the mixture for
15 min and then the solution was heated to reflux. The
reflux was stopped and then the second generation Grubbs
catalyst (2.5 mg, 0.0029 mmol, 5 mol%) was added to the
reaction mixture. The reaction was stirred at reflux of
DCM for 1 h (50b) or 10 min (50a). The solvent was evap-
orated and the crude product was purified by flash chroma-
tography on a silica gel column eluting with hexanes and
ethyl acetate (1:1) to give lactam 51 as a colorless oil
Amine 48 (823 mg, 1.79 mmol) was dissolved in CH2Cl2
(30 mL) and cooled to 0 ꢁC. DCC (736 mg, 3.57 mmol)
and DMAP (43.7 mg, 0.358 mmol) were added and the
mixture was stirred 1 h at 0 ꢁC. The reaction mixture was
quenched with a saturated solution of ammonium chlo-
ride. Phases were separated and the aqueous phase was
extracted twice with pentane. Organic phases were com-
bined, washed once with brine, dried with anhydrous mag-
nesium sulfate and concentrated under reduced pressure.
Flash chromatography on silica gel, eluting with hexanes
and ethyl acetate (9:1) furnished a clear oil (940 mg,
90%). 1H NMR (CDCl3, 300 MHz) d 7.63 (d, 4H,
J = 7.7 Hz), 7.43–7.34 (m, 6H), 6.79 (dt, 1H, J = 14.8,
7.2 Hz), 5.80 (ddt, 1H, J = 17.0, 10.4, 6.8 Hz), 5.73–5.62
(m, 2H), 5.49 (dd, 1H, J = 15.4, 4.4 Hz), 5.41 (dd, 1H,
J = 15.4, 7.1 Hz), 5.05–4.96 (m, 2H), 4.68–4.56 (m, 1H),
3.74 (d, 2H, J = 3.8 Hz), 2.19 (q, 2H, J = 7.2 Hz), 2.09
(q, 2H, J = 6.8 Hz), 1.96–1.73 (m, 2H), 1.72–1.47 (m,
4H), 1.42–1.15 (m, 2H), 1.06 (s, 9H), 0.96 (d, 2H,
J = 9.9 Hz), 0.90–0.73 (m, 2H), 0.86 (d, 3H, J = 6.6 Hz),
0.84 (d, 3H, J = 7.7 Hz), 0.68 (d, 3H, J = 7.1 Hz). IR
(neat, cmꢀ1): 3400–3150 (br), 3064, 2951, 2931, 2863,
1629, 1543, 1111, 703. LRMS (m/z (relative intensity)):
585 (M+Å, 10), 528 (M+ÅꢀC4H9, 100). HRMS calc. for
1
(17 mg, 85% from 50a, 19 mg, 92% from 50b). H NMR
(CDCl3, 300 MHz): 7.67–7.60 (m, 4H), 7.51–7.35 (m,
6H), 7.02 (d, 1H, J = 5.0 Hz), 6.41 (br s, 1H), 6.13 (d,
1H, J = 5.5 Hz), 4.34 (t, 1H, J = 6.5 Hz), 3.77 (dd, 1H,
J = 9.9, 5.0 Hz), 3.57 (dd, 1H, J = 9.9, 8.2 Hz) 1.06 (s,
9H). 13C NMR (CDCl3, 75 MHz): 173.8 (s), 146.7 (d),
135.5 (d), 132.7 (s), 130.0 (d), 128.6 (d) 127.8 (d), 65.1 (t),
61.7 (d), 26.7 (q), 19.2 (s). IR (neat, cmꢀ1): 3639–3040
(br), 2936, 2860, 1696, 1111, 704. LRMS (m/z (relative
intensity)): 351 (M+Å, 20), 294 (40), 199 (100), 84 (95).
HRMS calc. for C21H25NO2Si: 351.1654, found:
20
351.1658. ½aꢁD ¼ þ10:6 (c = 1.10, CHCl3).
3.13. Synthesis of amide 53a
20
C38H55NO2Si: 585.4002, found: 585.4006. ½aꢁD ¼ ꢀ39:3
Vinylmagnesium bromide (1.0 M in THF, 0.42 ml,
0.42 mmol) was added dropwise to a solution of the isocy-
(c = 2.76, CHCl3).

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5349
anate (207 mg, 0.34 mmol) in THF (2.3 ml) at 0 ꢁC. The
solution was stirred at 0 ꢁC for 2 h before quenching with
saturated aqueous NH4Cl (15 ml). The layers were sepa-
rated and the aqueous layer was extracted with 3 · 15 mL
of Et2O. The organic layers were combined, washed with
brine, dried with MgSO4, filtered and evaporated. The
crude compound was purified by flash chromatography
eluting with Et2O/hexanes (15:85) to yield 140 mg (65%)
of the desired compound as a colorless oil. 1H NMR
(300 MHz, CDCl3) d 7.33–7.24 (m, 5H), 6.21 (dd, 1H,
J = 16.8, 1.7 Hz), 6.06 (dd, 1H, J = 16.8, 9.9 Hz), 5.57
(dd, 1H, J = 9.9, 1.7 Hz), 5.36 (d, 1H, J = 15.9 Hz), 5.38
(s, 1H), 5.17 (dd, 1H, J = 15.9, 8.8 Hz), 4.48 (s, 2H),
3.70–3.57 (m, 2H), 3.44 (t, 2H, J = 6.9 Hz), 2.27–2.05 (m,
2H), 1.98–1.17 (m, 16H), 1.13–0.95 (m, 21H), 0.92–0.80
(m, 2H), 0.86 (d, 6H, J = 6.6 Hz), 0.69 (d, 3H,
J = 7.1 Hz). IR (neat) m (cmꢀ1) 3379-3211 (br), 3022,
2946, 2865, 1660, 1549, 1457, 1103. LRMS (m/z, relative
intensity) 625 (M+Å, 5), 582 ([MꢀC3H7], 57), 91 (100).
HRMS calc. for C39H67NO3Si: 625.4890, found:
heated to reflux. The reflux was stopped and catalyst 9
(9.7 mg, 10 mol%) was added to the solution. The reaction
mixture was heat to reflux for 1.5 h. Dichloroethane was
then evaporated under reduced pressure. The resulting
dark brown oil was purified by flash chromatography
(80% ethyl acetate in hexanes) to yield pure dihydropyrro-
1
lone 52 (9.5 mg, 60%). H NMR (300 MHz, CDCl3) 6.93
(dd, 1H, J = 5.5 Hz, 1.7 Hz), 6.80 (br s, 1H), 5.96 (dd,
1H, J = 5.5 Hz, 1.1 Hz), 1.70-1.52 (m, 2H), 1.40–1.12 (m,
2H), 1.34 (s, 3H), 0.89 (t, 3H, J = 7.2 Hz). 13C NMR
(75.5 MHz, CDCl3) d 173.1 (s), 155.6 (d), 125.2 (d), 64.3
(s), 40.9 (t), 24.2 (q), 17.6 (t), 14.2 (q). IR (neat, cmꢀ1
)
3214, 2960, 2932, 2873, 1685, 817. LRMS (m/z, relative
intensity) 139 (M+Å, 1), 124 ((MꢀCH3)+, 3), 96
((MꢀC3H7)+, 100). HRMS calc. for C8H13NO: 139.0997,
20
found: 139.0992. ½aꢁD ¼ ꢀ51:2 (c = 0.87, CHCl3).
3.16. Synthesis of lactam 54
The acrylamide 53a (40.0 mg, 0.064 mmol) was dis-
solved in toluene (13 ml, 0.005 M) and argon was bubbled
through this solution for 15 min. The solution was then
brought to reflux and cooled down to room temperature.
Grubbs second generation catalyst 9 (5.5 mg, 10 mol%)
was then added to the solution. The resulting mixture
was refluxed for 2 h. The solvent was then evaporated
under vacuum and the crude product was purified by flash
chromatography eluting with EtOAc/hexane (7:3) to yield
19.5 mg (66%) of the desired compound. 1H NMR
(300 MHz, CDCl3) d 7.34–7.28 (m, 5H), 6.88 (d, 1H,
6.1 Hz), 6.01 (d, 1H, J = 6.1 Hz), 5.86 (br, 1H), 4.48 (s,
2H), 3.66 (t, 2H, J = 6.1 Hz), 3.43 (t, 2H, J = 6.3 Hz),
1.76–1.06 (m, 13H), 1.06 (d, 18H, J = 3.9 Hz). 13C NMR
(75.5 MHz, CDCl3) d (ppm), 173.1 (s), 154.6 (d), 138.4
(s), 128.3 (d), 128.3 (d), 127.7 (d), 127.6 (d), 126.3 (d),
73.0 (t), 68.8 (t), 67.2 (s), 63.0 (t), 37.0 (t), 33.7 (t), 29.9
20
625.4878. ½aꢁD ꢀ 26:8 (c = 1.14, CHCl3).
3.14. Synthesis of amide 53b
To a solution of isocyanate 38b (44 mg, 0.16 mmol) in
THF (1.1 mL, 0.15 M) at 0 ꢁC was added vinyl magnesium
bromide (0.85 M in THF, 0.2 mL, 0.17 mmol). The solu-
tion was stirred at 0 ꢁC for 2 h. The reaction mixture was
then poured over a saturated aqueous solution of ammo-
nium chloride. The solution was extracted three times with
diethyl ether (5 mL). Organic layers were combined,
washed with brine, dried with MgSO4, filtered and concen-
trated under reduced pressure. The resulting oil was puri-
fied by flash chromatography (30% of diethyl ether in
hexanes) to yield pure acrylamide 53b (46 mg, 96%, color-
less oil). 1H NMR (300 MHz, CDCl3) 6.22 (dd, 1H,
J = 17.1 Hz, 1.7 Hz), 6.04 (dd, 1H, J = 17.1 Hz, 9.9 Hz),
5.59 (d, 1H, J = 15.9 Hz), 5.56 (dd, 1H, J = 9.9 Hz,
1.7 Hz), 5.37 (s, 1H), 5.25 (dd, 1H, J = 16.0 Hz, 9.4 Hz),
1.95–1.65 (m, 5H), 1.62–1.56 (m, 2H), 1.44 (s, 3H), 1.42–
1.16 (m, 3H), 1.06–0.75 (m, 7H), 0.86 (d, 3H,
J = 7.2 Hz), 0.85 (d, 3H, J = 6.6 Hz), 0.69 (d, 3H,
J = 7.1 Hz). 13C NMR (75.5 MHz, CDCl3) d 164.4 (s),
134.1 (d), 133.4 (d), 132.1 (d), 125.5 (t), 57.0 (s), 47.2 (d),
44.7 (d), 43.2 (t), 42.0 (t), 35.1 (t), 32.4 (d), 28.1 (d), 24.6
(q), 24.0 (t), 22.5 (q), 21.4 (q), 17.3 (t), 15.2 (q), 14.4 (q).
IR (neat, cmꢀ1) 3287, 3063, 2956, 2928, 2871, 2844, 1659,
1625, 1549. LRMS (m/z, relative intensity) 305 (M+Å, 9),
262 ((MꢀC3H7)+, 42), 124 (100). HRMS calc. for
(t), 27.2 (d), 20.7 (t), 18.0 (q), 11.9 (d). IR (neat) m (cmꢀ1
)
3375–3141 (br), 3062, 3035, 2941, 2865, 1694, 1461, 1099.
LRMS (m/z, relative intensity) 416 ((MꢀC3H7)+, 100), 91
(40). HRMS calc. for C24H38O3Si (MꢀC3H7): 416.2621,
20
found: 416.2607. ½aꢁD ꢀ 6:9ꢂ (c = 0.57, CHCl3).
3.17. Synthesis of amide 55a
Isopropenylmagnesium bromide (0.5 M in THF,
1.40 mL, 0.70 mmol) was added dropwise to a solution of
the isocyanate 38a (348 mg, 0.58 mmol) in THF (5 mL)
at 0 ꢁC. The solution was stirred at 0 ꢁC for 2 h before
quenching with saturated aqueous NH4Cl (20 mL). The
layers were separated and the aqueous layer was extracted
with 3 · 20 mL of Et2O. The organic layers were combined,
washed with brine, dried with MgSO4, filtered and evapo-
rated. The crude compound was purified by flash chroma-
tography eluting with Et2O/hexanes (15:85) to yield 351 mg
(94%) of the desired compound as a colorless oil. 1H NMR
(300 MHz, CDCl3) d 7.36–7.24 (m, 5H), 5.62 (s, 1H), 5.58
(s, 1H), 5.35 (d, 1H, J = 15.9 Hz), 5.26 (s, 1H), 5.17 (dd,
20
C20H35NO: 305.2718, found: 305.2712. ½aꢁD ¼ ꢀ77:7
(c = 0.91, CHCl3).
3.15. Synthesis of lactam 52
Acrylamide 53b (34.8 mg, 0.114 mmol) was dissolved in
dichloroethane (23 mL, 0.005 M) and argon was bubbled
through this solution for 15 min. The mixture was then

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C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
1H, J = 15.9, 8.8 Hz), 4.48 (s, 2H), 3.70–3.57 (m, 2H), 3.44
(t, 2H, J = 6.6 Hz), 2.20–2.06 (m, 2H), 1.98–1.55 (m, 9H),
1.93 (s, 3H), 1.51–1.20 (m, 5H), 1.13–0.96 (m, 23H),
0.97–0.80 (m, 2H), 0.86 (d, 6H, J = 6.6 Hz), 0.69 (d, 3H,
J = 6.6 Hz). IR (neat) m (cmꢀ1) 3474–3266 (br), 3027,
2944, 2865, 1677, 1629, 1497, 1454, 1103. LRMS (m/z, rel-
ative intensity) 639 (M+Å, 13), 596 ([MꢀC3H7], 100), 476
(36). HRMS calc. for C40H69NO3Si: 639.5046, found:
J = 15.9, 8.8 Hz), 4.47 (s, 2H), 3.70–3.56 (m, 2H), 3.43 (t,
2H, J = 6.6 Hz), 2.20–2.00 (m, 6H), 1.99–1.22 (m, 20H),
1.81 (s, 3H), 1.12–0.96 (m, 22H), 0.92–0.79 (m, 2H), 0.86
(d, 6H, J = 7.2 Hz), 0.70 (d, 3H, J = 7.2 Hz). IR (neat) m
(cmꢀ1) 3458–3261 (br), 3017, 2943, 2865, 1672, 1638,
1496, 1455, 1103. LRMS (m/z, relative intensity) 721
(M+Å, 10), 678 ([MꢀC3H7]+, 100), 558 (48), 91 (78). HRMS
calc. for C46H79NO3Si: 721.5829, found: 721.5834.
20
20
639.5058. ½aꢁD ꢀ 20:6 (c = 0.81, CHCl3).
½aꢁD ꢀ 23:9 (c = 1.12, CHCl3).
3.18. Synthesis of amide 55b
3.20. Synthesis of lactam 56
A solution of amine 39a (95 mg, 0.17 mmol) in CH2Cl2
(1 mL) was added dropwise to a 0 ꢁC suspension of 2-meth-
ylocta-2,7-dienoic acid (39 mg, 0.25 mmol), DCC (53 mg,
0.26 mmol) and DMAP (5.0 mg, 0.041 mmol) in CH2Cl2
(2 mL). The resulting white suspension was allowed to
slowly warm up to room temperature while stirring for
48 h before quenching with saturated aqueous NH4Cl
(10 mL). The layers were separated and the aqueous layer
was extracted with 3 · 15 mL of Et2O. The organic layers
were combined, washed with brine, dried with MgSO4, fil-
tered and evaporated. The crude compound was purified
by flash chromatography eluting with Et2O/hexanes
(20:80) to yield 60 mg (51%) of the desired compound as a
A toluene (12.8 mL) solution of methylacrylamide 55c
(22.9 mg, 0.032 mmol), in which argon had been bubbled
for 15 min, was slowly added over a period of 30 min to
a refluxing toluene (6.4 mL) solution of catalyst 9
(2.7 mg, 10 mol%). The resulting mixture was further
refluxed for 30 min while continuously bubbling argon
through the reaction. The solvent was then evaporated
under vacuum and the crude product was purified by flash
chromatography eluting with EtOAc/hexane (4:6) to yield
13.6 mg (91%) of the desired compound. 1H NMR
(300 MHz, CDCl3) d 7.37–7.25 (m, 5H), 6.49 (s, 1H),
5.80 (s, 1H), 4.48 (s, 2H), 3.63 (t, 2H, J = 6.0 Hz), 3.42
(t, 2H, J = 6.3 Hz), 1.86 (s, 3H), 1.70–1.18 (m, 11H),
1.10–0.99 (m, 20H). 13C NMR (75.5 MHz, CDCl3) d
173.7 (s), 147.0 (d), 138.4 (s), 133.8 (s), 128.4 (d), 127.7
(d), 127.5 (d), 72.9 (t), 69.9 (t), 64.1 (s), 63.2 (t), 37.4 (t),
33.9 (t), 29.9 (t), 27.4 (t), 20.7 (q), 18.0 (q), 11.9 (d), 10.7
(q). IR (neat) m (cmꢀ1) 3375–3132 (br), 3061, 3032, 2942,
2865, 1694, 1103. LRMS (m/z, relative intensity) 473
(M+Å, 1), 430 ((MꢀC3H7)+, 100), 91 (17). HRMS calc.
1
colorless oil. H NMR (300 MHz, CDCl3) d 7.36–7.24 (m,
5H), 6.24 (t, 1H J = 7.2 Hz), 5.80 (ddt, 1H, J = 17.1, 10.5,
6.6 Hz), 5.52 (s, 1H), 5.36 (d, 1H, J = 15.9 Hz), 5.17 (dd,
1H, J = 15.9, 9.8 Hz), 5.02 (dd, 1H, J = 17.1, 1.7 Hz), 4.98
(dd, 1H, J = 10.5, 1.7 Hz), 4.48 (s, 2H), 3.70–3.56 (m, 2H),
3.43 (t, 2H, J = 6.6 Hz), 2.21–2.04 (m, 6H), 1.99–1.15 (m,
16H), 1.81 (s, 3H), 1.13–0.95 (m, 22H), 0.92–0.79 (m, 3H),
0.86 (d, 6H, J = 7.2 Hz), 0.70 (d, 3H, J = 6.6 Hz). IR (neat)
m (cmꢀ1) 3477–3265 (br), 3074, 3032, 2943, 2865, 1672, 1638,
1497, 1463, 1103. LRMS (m/z, relative intensity) 707 (M+Å,
12), 664 ([MꢀC3H7]+, 100), 544 (48), 492 (42), 91 (66).
HRMS calc. for C45H77NO3Si: 707.5672, found: 707.5681.
20
for C28H47O3Si: 473.3325, found: 473.3317. ½aꢁD ꢀ 7:1ꢂ
(c = 1.34, CHCl3).
3.21. Synthesis of amide 58a
20
½aꢁD ꢀ 28:5 (c = 0.66, CHCl3).
Prepared as per amide 50a. Colorless oil (300 mg, 87%).
1H NMR (300 MHz, CDCl3) d 7.70–7.68 (m, 4H), 7.42–
7.35 (m, 6H), 5.98–5.91 (m, 1H), 5.89–5.79 (m, 1H),
5.44–5.17 (m, 3H), 4.45–4.38 (m, 1H), 3.68 (t, 3H,
J = 6.0 Hz), 2.99 (d, 2H, J = 7.2 Hz), 1.87–1.3 (m, 10H),
1.08 (s, 9H), 1.04–0.84 (m, 12H), 0.71 (d, 3H,
J = 7.2 Hz). 13C NMR (75.5 MHz, CDCl3) d 169.5 (s)
136.6 (d), 135.6 (d), 134.0 (s), 131.7 (d), 129.5 (d), 127.6
(d), 119.2 (t), 63.7 (t), 50.9 (d), 47.2 (d), 44.5 (d), 43.0 (t),
41.8 (t), 35.1 (t), 35.0 (t), 32.6 (t), 28.0 (d), 26.9 (q), 24.1
(t), 22.7 (q), 22.2 (t), 21.4 (t), 19.2 (s), 15.4 (q). IR (neat,
NaCl): cmꢀ1 3276; 3069; 2957; 2927; 2863; 1647; 1115.
LRMS (m/z relative intensity): 573 (M+Å, 8), 516 (100),
266 (40), 199 (30). HRMS calc. for: C37H55NO2Si:
573.4002; found: 573.4016.
3.19. Synthesis of amide 55c
A solution of amine 39a (70 mg, 0.12 mmol) in CH2Cl2
(1 mL) was added dropwise to a 0 ꢁC suspension of 2-meth-
ylnona-2,7-dienoic acid (31 mg, 0.18 mmol), DCC (37 mg,
0.18 mmol) and DMAP (4.0 mg, 0.033 mmol) in CH2Cl2
(2 mL). The resulting white suspension was allowed to
slowly warm up to room temperature while stirring for
six days before quenching with saturated aqueous NH4Cl
(10 mL). The layers were separated and the aqueous layer
was extracted with 3 · 15 mL of Et2O. The organic layers
were combined, washed with brine, dried with MgSO4, fil-
tered and evaporated. The crude compound was purified
by flash chromatography eluting with Et2O/hexanes
(10:90) to yield 31 mg (36%) of the desired compound as
3.22. Synthesis of amide 58b
1
a colorless oil. H NMR (300 MHz, CDCl3) d 7.33–7.24
(m, 5H), 6.23 (t, 1H J = 7.4 Hz), 5.52 (s, 1H), 5.46–5.41
(m, 2H), 5.35 (d, 1H, J = 15.9 Hz), 5.16 (dd, 1H,
Prepared as per amide 53b. Colorless oil (125 mg, 99%).
1H NMR (300 MHz, CDCl3) d 5.92 (ddt, 1H, J = 17.1, 9.9,

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5351
1.7 Hz), 5.52 (d, 2H, J = 15.4 Hz), 5.40 (bs, 1H), 5.20 (dd,
1H, J = 15.4, 9.4 Hz), 5.23–5.17 (m, 2H), 2.93 (d, 2H,
J = 7.2 Hz), 1.93–1.55 (m, 7H), 1.39 (s, 3H), 1.43–1.26
(m, 1H), 1.24–1.13 (m, 2H), 1.06–0.77 (m, 9H), 0.86 (d,
3H, J = 7.2 Hz), 0.69 (d, 3H, J = 6.6 Hz). 13C NMR
(75.5 MHz, CDCl3) d 169.3 (s), 134.6 (d), 133.2 (d), 132.1
(d), 119.3 (t), 56.8 (s), 47.2 (d), 44.7 (d), 43.2 (t), 42.8 (t),
41.9 (t), 35.1 (t), 32.4 (d), 28.1 (d), 24.7 (q), 24.1 (t), 22.5
(q), 21.4 (q), 17.3 (t), 15.2 (q), 14.3 (q). IR (neat/NaCl) m
(cmꢀ1) 3297, 3077, 2955, 2928, 2871, 1650, 1546. LRMS
(m/z, relative intensity) 320 (MH+, 86), 319 (M+Å, 74),
276 (M+ÅꢀC3H7, 97), 191 (62), 154 (61), 138 (100), 86
(99). HRMS calc. for C21H37NO: 319.2875, found:
1674; 1659; 1109. LRMS (m/z relative intensity): 350
((MꢀC4H9)+, 80), 272 (100), 199 (45), 96 (550). HRMS
calc. for C25H33NO2Si: 350.1576; found: 350.1578.
3.25. Synthesis of lactam 59b
The amide 58b (22 mg, 0.068 mmol) was dissolved in
dichloroethane (13 mL, 0.005 M), heat to reflux, and
argon was bubbled through this solution for 15 min.
The reflux was stopped and dichlorophenylborane (8 lL,
0.068 mmol) and catalyst 9 (5.0 mg, 10 mol%) was added
to the solution. The reaction mixture was heat to reflux
for 2 h. Dichloroethane was then evaporated under
reduced pressure. The resulting dark brown oil was puri-
fied by flash chromatography (80% ethyl acetate in hex-
anes) to yield pure dihydropyridinone 59b (8.4 mg,
79%); m.p.: 86–87 ꢁC; 1H NMR (300 MHz, CDCl3) d
(ppm) 6.19 (s(br), 1H), 5.70 (dt, 1H, J = 10.5, 3.3 Hz),
5.52 (dq, 1H, J = 10.5, 2.2 Hz), 2.87 (dd, 2H, J = 3.3,
2.2 Hz), 1.56–1.40 (m, 2H), 1.38–1.18 (m, 2H), 1.29 (s,
3H), 0.88 (t, 3H, J = 7.4 Hz). 13C NMR (75.5 MHz,
CDCl3) d (ppm) 169.7 (s), 130.3 (d), 120.3 (d), 57.9 (s),
45.4 (t), 30.8 (t), 29.9 (q), 17.2 (t), 14.0 (q). IR (CHCl3/
NaCl) m (cmꢀ1) 3201, 3154, 3033, 2959, 2933, 2910,
2873, 1678, 1661, 1446, 1400, 1153. LRMS (m/z, relative
intensity) 153 (M+Å, 1), 138 ((MꢀCH3)+, 27), 110
((MꢀC3H7)+, 100). HRMS calc. for C9H15NO:
20
319.2868. ½aꢁD ¼ ꢀ68:9 (c = 0.93, CHCl3).
3.23. Synthesis of amide 58c
Prepared as per amide 53b. White solid (124 mg, 85%);
m.p.: 41–42 ꢁC; 1H NMR (300 MHz, CDCl3) d (ppm)
5.83 (ddt, 1H, J = 17.0, 10.5, 6.6 Hz), 5.39–5.24 (m, 3H),
5.07 (dd, 1H, J = 17.0, 1.7 Hz), 5.01 (d, 1H, J = 10.5 Hz),
4.47–4.38 (m, 1H), 2.40 (dt, 2H, J = 6.6, 7.1 Hz), 2.28–
2.24 (m, 2H) 1.91–1.68 (m, 3H), 1.63–1.49 (m, 2H), 1.47–
1.42 (m, 2H), 1.39–1.25 (m, 2H), 1.01–0.77 (m, 5H), 0.91
(t, 3H, J = 7.7 Hz), 0.86 (d, 6H, J = 6.6 Hz), 0.68 (d, 3H,
J = 7.1 Hz). 13C NMR (75.5 MHz, CDCl3) d (ppm) 171.1
(s), 137.1 (d), 136.4 (d), 129.2 (d), 115.4 (t), 50.5 (d), 47.0
(d), 44.5 (d), 43.2 (t), 37.7 (t), 36.0 (t), 35.1 (t), 32.4 (d),
29.7 (t), 28.0 (d), 24.0 (t), 22.5 (q), 21.4 (q), 19.0 (t), 15.2
(q), 13.9 (q). IR (neat, cmꢀ1) 3277 (br), 3077, 2955, 2918,
2870, 2849, 1640, 1547. LRMS (m/z, relative intensity)
319 (M+Å, 34), 276 ((MꢀC3H7)+, 55), 180 (68), 138 (74),
98 (100). HRMS calc. for C21H37NO: 319.2875, found:
20
153.1154, found: 153.1156. ½aꢁD ¼ ꢀ59:1 (c = 1.52,
CHCl3).
3.26. Synthesis of lactam 57c
Prepared as per lactam 59b. Colorless oil (2.9 mg, 30%).
1H NMR (300 MHz, CDCl3) d 6.60 (ddd, 1H, J = 9.9, 5.5,
3.3 Hz), 5.91 (d, 1H, J = 9.9 Hz), 5.42 (s(br), 1H), 3.60
(sext., 1H, J = 6.0 Hz), 2.38 (dt, 2H, J = 17.6, 5.5 Hz),
2.14 (ddt, 1H, J = 17.6, 11.0, 3.3 Hz), 1.60–1.45 (m, 3H),
1.42–1.21 (m, 2H), 0.95 (t, 3H, J = 7.2 Hz). 13C NMR
(75.5 MHz, CDCl3) d 169.2 (s), 140.7 (d), 124.4 (d), 50.8
(d), 46.3 (t), 37.5 (t), 30.0 (t), 18.5 (t), 13.8 (q). IR
(CHCl3/NaCl) m (cmꢀ1) 3223, 2959, 2929, 2874, 1678,
1612. LRMS (m/z, relative intensity) 153 (M+Å, 3), 138
((MꢀCH3)+, 3), 110 ((MꢀC3H7)+, 20), 96 (100). HRMS
calc. for C9H15NO: 153.1154, found: 153.1150.
20
319.2870. ½aꢁD ¼ ꢀ16:6 (c = 1.04, CHCl3).
3.24. Synthesis of lactam 59a
In a 25 mL round-bottomed flask was added amide 58a
(200 mg, 0.35 mmol) and dichloromethane (70 mL). The
solution was heated to reflux and then it was degassed by
bubbling argon for 15 min. Then the heating was briefly
stopped and dichlorophenylborane (35 lL, 0.35 mmol)
was added followed by catalyst 9 (29 mg, 0.034 mmol)
was added to the warm solution. The solution was heated
to reflux for 3 h. The solvent was evaporated under reduced
pressure and the crude product was purified by flash chro-
matography on silica gel (60% EtOAc/dichloromethane) to
20
½aꢁD ¼ ꢀ89:2 (c = 0.10, CHCl3).
3.27. Synthesis of carbamate 60
1
afford 110 mg of pyridone 59a (77%) as a colorless oil. H
NMR (300 MHz, CDCl3)
d
(ppm) 7.66 (dd, 4H,
Prepared by the same procedure as per carbamate 35b,
J = 7.7 Hz, 1.9 Hz), 7.56–7.26 (m, 6H), 6.60 (br s, 1H),
5.75 (d, 1H, J = 10.4 Hz), 5.65 (d, 1H, J = 10.6 Hz),
4.10–3.98 (m, 1H), 3.66 (t, 2H, J = 6.3 Hz), 2.93–2.85 (m,
2H), 1.62–1.50 (m, 4H), 1.46–1.37 (m, 2H), 1.05 (s, 9H).
13C NMR (75.5 MHz, CDCl3) d (ppm) 169.7 (s), 135.6
(d), 133.9 (s), 129.5 (d), 127.6 (d), 125.3 (d), 121.7 (d),
63.5 (t), 53.8 (d), 36.8 (t), 32.2 (t), 26.9 (q), 20.8 (t), 19.1
(s). IR (neat, NaCl): cmꢀ1: 3201; 3071; 3039; 2931; 2853;
except in this case, the reaction was stopped after 30 h. Col-
orless oil (969 mg, 83%). H NMR (CDCl3, 300 MHz) d
1
5.84–5.70 (m, 1H), 5.60–5.25 (m, 2H), 4.99 (d, 1H,
J = 17.0 Hz), 4.95 (d, 1H, J = 9.3 Hz), 4.45–4.18 (m, 1H),
3.30–3.15 (m, 1H), 3.00–2.80 (m, 1H), 2.00–1.27 (m,
12H), 1.45 (s, 9H), 1.10–0.76 (m, 9H), 0.88 (s, 9H), 0.69
(d, 3H, J = 6.6 Hz). IR (neat, cmꢀ1): 3082, 2920, 1696,
1453, 1174. LRMS (m/z (relative intensity)): 362

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C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
(M+ÅꢀC4H9, 15), 306 (100), 262 (30). HRMS calc. for
3.29. Synthesis of sulfides 65a–c: general procedure
20
C23H40NO2: 362.3059, found: 362.3064. ½aꢁD ¼ ꢀ28:2
(c = 1.60, CHCl3).
The thiocarbamate (1 eq) and the alkyl bromide (5 eq)
were solubilized in of methanol and cesium carbonate
(5 eq) was added. The mixture was stirred and heated at
80 ꢁC in a sealed tube for 4 h. A 1:1 mixture of water
and diethyl ether were added to the reaction mixture. The
two layers were separated and the aqueous layer was
extracted three times with diethyl ether. The combined
organic layers were washed with brine, dried over anhy-
drous MgSO4, filtered and evaporated in vacuo. The crude
product was purified by flash chromatography on silica gel
using hexanes/ethyl acetate.
3.28. Syntheses of S-thiocarbamate 64a–b. General
procedure
To a solution of the allylic alcohol 63a or b (1 eq) in
THF at 0 ꢁC was added NaH 60% w/w in oil (1.9 eq)
and the mixture was stirred for 1 h at this temperature
before the addition of phenylisothiocyanate (2 eq). The
reaction was heated to reflux and stirred for 3 h. It was
then cooled down to rt before the addition of pyridinium
p-toluenesulfonate (2.5 eq) in THF. The reaction was then
heated to reflux and monitored by TLC. When the reaction
was complete, it was stopped by the addition of a 1:1 mix-
ture of water and Et2O. The two phases were separated and
the aqueous layer was extracted with Et2O (3 · 10 mL).
The combined organic layers were washed with brine, dried
with anhydrous MgSO4 and concentrated in vacuo. The
crude product was purified by flash chromatography on sil-
ica gel eluting with hexanes/ethyl acetate.
3.29.1. Sulfide 65a
Colorless oil (69% yield). 1H NMR: (300 MHz, CDCl3):
d 5.79 (dddd, 1H, J = 10.2, 8.5, 8.5, 6.3 Hz), 5.16–5.05 (m,
4H), 3.17–3.00 (m, 3H), 2.04–1.80 (m, 2H), 1.79–1.29 (m,
11H), 1.02–0.67 (m, 4H), 0.87 (d, 6H, J = 6.6 Hz), 0.70
(d, 3H, J= 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 137.5
(d), 135.1 (d), 130.1 (d), 116.5 (t), 47.1 (d), 46.3 (d), 44.8
(d), 43.9 (t), 36.6 (t), 35.1 (t), 33.2 (t), 32.5 (d), 28.2 (d),
23.9 (t), 22.6 (q), 21.4 (q), 20.6 (t), 15.1 (q), 13.7 (q); IR
(neat, cmꢀ1): 3075, 2951, 2869, 1635, 1458, 1369; LRMS
(m/z (relative intensity)): 294 (M+Å, 3), 220 (80), 137
(100); Exact Mass calc. for C19H34S: 294.2381, found:
3.28.1. S-Thiocarbamate 64a
1
White solid (97%, 97% de by GC); m.p. 72–74 ꢁC; H
NMR: (300 MHz, CDCl3): d 7.44 (t, 2H, J = 8.3 Hz),
7.28 (t, 2H, J = 7.7 Hz), 7.10–1.05 (m, 1H), 5.50 (dd,
1H, J = 15.4, 8.8 Hz), 5.39 (dd, 1H, J = 15.4, 8.3 Hz),
4.13–4.05 (m, 1H), 1.93–1.56 (m, 7H), 1.47–1.33 (m,
4H), 1.02–0.76 (m, 6H), 0.92 (d, 3H, J = 7.2 Hz), 0.88
(d, 3H, J = 7.2 Hz), 0.71 (d, 3H, J = 6.6 Hz); 13C NMR
(75 MHz, CDCl3): d 165.4 (s), 137.9 (s), 137.8 (d), 129.0
(d), 128.6 (d), 124.2 (d), 119.8 (d), 47.6 (d), 47.0 (d),
44.6 (d), 42.9 (t), 37.5 (t), 35.1 (t), 32.4 (d), 28.2 (d),
24.1 (t), 22.5 (q), 21.4 (q), 20.5 (t), 15.3 (q), 13.7 (q); IR
(neat, cmꢀ1): 3297, 2956, 2927, 2871, 1656, 1600, 1440,
1309, 750; LRMS (m/z (relative intensity)): 373 (M+Å, 8),
270 (10), 221 (65), 83 (100); Exact Mass calc. for
20
294.2376; ½aꢁD ¼ ꢀ5:7 (c 1.18, CHCl3).
3.29.2. Sulfide 65b
Colorless oil (79% yield). 1H NMR: (300 MHz, CDCl3):
d 5.76 (dddd, 1H, J = 16.5, 10.7, 8.4, 5.9 Hz), 5.31 (dd, 1H,
J = 14.8, 10.4 Hz), 5.12–5.04 (m, 3H), 3.07 (dd, 1H,
J = 13.8, 5.5 Hz), 2.99 (dd, 1H, J = 14.0, 8.5 Hz), 2.83 (d,
1H, J = 9.9 Hz), 2.03–1.56 (m, 4H), 1.43–1.32 (m, 1H),
1.25–0.67 (m, 11H), 0.97 (s, 9H), 0.71 (d, 3H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 137.6 (d),
135.2 (d), 127.5 (d), 116.5 (t), 58.8 (d), 47.2 (d), 45.2 (d),
44.2 (t), 35.1 (t), 33.8 (t), 33.2 (s), 32.6 (d), 28.2 (q), 28.1
(d), 23.8 (t), 22.6 (q), 21.4 (q), 15.0 (q); IR (neat, cmꢀ1):
2955, 2920, 2871, 1458, 1366, 971, 912; LRMS (m/z (rela-
tive intensity)): 308 (M+Å, 6), 267 ((MꢀC3H5)+, 24), 257
((MꢀC4H9)+, 100), 177 (78), 97 (88); Exact Mass calc.
20
C23H35ONS: 373.2439, found: 373.2448; ½aꢁD ¼ þ42:5 (c
1.02, CHCl3).
3.28.2. S-Thiocarbamate 64b
20
White solid (96%, 98.5% de by GC); m.p. 102–103 ꢁC;
1H NMR: (300 MHz, CDCl3): d 7.41 (d, 2H, J = 8.3 Hz),
7.30 (t, 2H, J = 8.0 Hz), 7.11–7.07 (m, 2H), 5.50–5.47 (m,
2H), 3.97–3.94 (m, 1H), 1.91–1.78 (m, 2H), 1.70 (d, 1H,
J = 12.1 Hz), 1.62–1.53 (m, 2H), 1.36–1.21 (m, 1H), 1.01
(s, 9H), 0.98–0.78 (m, 4H), 0.85 (d, 3H, J = 7.2 Hz), 0.82
(d, 3H, J = 6.6 Hz), 0.70 (d, 3H, J = 7.2 Hz); 13C NMR
(75 MHz, CDCl3): d 165.1 (s), 138.1 (d), 137.9 (s), 129.0
(d), 127.0 (d), 124.1 (d), 119.5 (d), 59.9 (d), 47.0 (s), 44.9
(d), 42.9 (t), 35.1 (t), 34.4 (d), 32.5 (d), 28.2 (d), 27.9 (q),
23.9 (t), 22.5 (q), 21.4 (q), 15.1 (q); IR (neat, cmꢀ1):
3298, 2958, 2922, 2869, 1659, 1440, 1143, 750; LRMS (m/
z (relative intensity)): 387 (M+Å, 5), 330 (3), 177 (64), 97
(100); Exact Mass calc. for C24H37ONS: 387.2596; Found:
for C20H36S: 308.2538, found: 308.2543; ½aꢁD ¼ þ9:6 (c
1.31, CHCl3).
3.29.3. Sulfide 65c
Colorless oil (75% yield). 1H NMR: (300 MHz, CDCl3):
d 5.82 (ddt, 1H, J = 16.8, 10.3, 6.6 Hz), 5.31 (dd, 1H,
J = 15.1, 10.2 Hz), 5.15–5.07 (m, 2H), 5.02–4.99 (m, 1H),
2.88 (d, 1H, J = 10.4 Hz), 2.48–2.38 (m, 2H), 2.36–2.21
(m, 2H), 1.98–1.80 (m, 2H), 1.74–1.70 (m, 1H), 1.65–1.56
(m, 3H), 1.40–1.25 (m, 1H), 0.98–0.77 (m, 3H), 0.97 (s,
9H), 0.87 (d, 3H, J = 7.2 Hz), 0.86 (d, 3H, J = 6.6 Hz),
0.71 (d, 3H, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3): d
137.3 (d), 137.1 (d), 127.6 (d), 115.5 (t), 60.1 (d), 47.2 (d),
45.0 (d), 44.0 (s), 35.1 (t), 34.0 (t), 33.8 (q), 32.5 (d), 29.8
(t), 28.2 (d), 28.0 (q), 23.9 (t), 22.5 (q), 21.4 (t), 15.0 (q);
20
387.2591; ½aꢁD ¼ ꢀ118:7 (c 1.31, CHCl3).

C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
5353
IR (neat, cmꢀ1): 2955, 2917, 2870, 1517, 1457; LRMS (m/z
(relative intensity)): 322 (M+Å, 28), 265 (98), 205 (69), 177
(72), 127 (100); Exact Mass calc. for C21H38S: 322.2694,
found: 322.2705; ½aꢁD ¼ ꢀ12:3 (c 0.86, CHCl3).
(ddd, 1H, J = 13.8, 10.5, 5.5 Hz), 2.61–2.46 (m, 2H),
2.11–2.01 (m, 1H), 1.77–1.73 (m, 2H), 1.65–1.55 (m, 2H),
1.42–1.25 (m, 1H), 1.18 (s, 9H), 1.08–0.78 (m, 4H), 0.89
(d, 3H, J = 7.2 Hz), 0.87 (d, 3H, J = 6.1 Hz), 0.72 (d, 3H,
J = 6.6 Hz); IR (neat, cmꢀ1): 2947, 2917, 2855, 1305,
1126; LRMS (m/z (relative intensity)): 372 (MNHþ4 , 100),
235 (65); Exact Mass calc. for C21H42NO2S ðMNHþ4 Þ:
20
3.30. Synthesis of sulfones 66a–c: general procedure
20
The allylic sulfide (1 eq) was solubilized in dry dichloro-
methane and m-chloroperbenzoic acid (60%) (2 eq) was
added to the solution. The mixture was stirred for
10 min. at rt and was then cooled to 0 ꢁC before the addi-
tion of a 1:2:2 mixture of water, saturated aqueous solution
of NaHCO3, and dichloromethane. The two layers were
separated. The aqueous layer was extracted with dichloro-
methane. The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered and evapo-
rated in vacuo. The crude product was purified by flash
chromatography on silica gel eluting with a mixture of hex-
anes and ethyl acetate.
372.2936, found: 372.2942; ½aꢁD ¼ ꢀ81:1 (c 0.36, CHCl3).
3.31. Synthesis of tetrahydrothiophene 67a
Prepared as per tetrahydrothiophene 67b. Analysis of
the crude reaction mixture clearly show 97% conversion
of 65a to 67b as well as auxiliary by-product 5. However,
any attempt to purify 67a resulted in complete loss of this
highly volatile material.
3.32. Synthesis of tetrahydrothiophene 67b
A solution of sulfide 65b (92 mg, 0.298 mmol) in dry
dichloromethane (30 mL, 0.01 M), was heated to reflux
and then degassed by passing a stream of argon for
15 min. while refluxing. Catalyst 21 (25 mg, 0.030 mmol)
was quickly added while the solution was still under reflux.
The resulting pale pink solution was refluxed for 18 h. It
was cooled to rt and volatiles were removed under vacuum
without heating. Analysis of the crude reaction mixture
showed complete conversion to 67b and auxiliary by-prod-
uct 5. The crude product was purified by flash chromatog-
raphy on silica gel (100% pentane) to afford the desired
product67b (36 mg, 85%) as a colorless oil. 1H NMR:
(300 MHz, CDCl3): d 5.86 (tdd, 1H, J = 4.4, 2.2, 2.2 Hz),
5.77 (tdd, 1H, J = 4.4, 2.2, 2.2 Hz), 4.12 (br s, 1H), 3.64
(br s, 2H), 0.94 (s, 9H); 13C NMR (75 MHz, CDCl3): d
130.9 (d), 128.9 (d), 68.0 (d), 38.4 (t), 35.5 (s), 27.1 (q);
IR (neat, cmꢀ1): 2956, 2868, 1712, 1691, 1463; LRMS
(m/z (relative intensity)): 142 (M+Å, 20), 85 (100), 77 (10);
Exact Mass calc. for C8H14S: 142.0816, found: 142.0814;
3.30.1. Sulfone 66a
Colorless oil (71% yield). 1H NMR: (300 MHz, CDCl3):
d 5.90 (dddd, 1H, J = 10.2, 8.5, 8.5, 6.4 Hz), 5.58–5.30 (m,
4H), 3.83 (dd, 1H, J = 14.4, 8.5 Hz), 3.59 (dd, 1H,
J = 14.4, 6.4 Hz), 3.52 (td, 1H, J = 10.5, 3.3 Hz), 2.10–
1.95 (m, 2H), 1.77–1.61 (m, 6H), 1.50–1.32 (m, 2H),
1.30–1.18 (m, 1H), 1.03–0.82 (m, 6H), 0.93 (d, 3H,
J = 7.7 Hz), 0.88 (d, 3H, J = 6.6 Hz), 0.71 (d, 3H,
J = 7.2 Hz); 13C NMR (75 MHz, CDCl3): d 144.9 (d),
125.1 (d), 124.2 (t), 122.0 (d), 64.4 (d), 54.5 (t), 46.8 (d),
45.1 (d), 42.5 (t), 34.9 (t), 32.2 (d), 28.4 (d), 27.1 (t), 23.7
(t), 22.4 (q), 21.2 (q), 19.5 (t), 15.0 (q), 13.4 (q); IR (neat,
cmꢀ1): 2957, 2927, 2872, 1312, 1290, 1132; LRMS (m/z
(relative intensity)): 344 (MNHþ4 , 42), 221 (100), 123 (20);
Exact Mass calc. for C19H38NO2S ðMNHþ4 Þ: 344.2623,
20
found: 344.2630; ½aꢁD ¼ ꢀ48:7 (c 0.86, CHCl3).
3.30.2. Sulfone 66b
20
White solid (77% yield); m.p. 108–109 ꢁC. 1H NMR:
(300 MHz, CDCl3): d 5.88 (dddd, 1H, J = 16.0, 10.5, 9.0,
6.1 Hz), 5.60 (dd, 1H, J = 15.1, 10.2 Hz), 5.49–5.31 (m,
3H), 3.85 (dd, 1H, J = 13.8, 9.0 Hz), 3.41 (dd, 1H,
J = 13.8, 6.1 Hz), 3.32 (d, 1H, J = 10.5 Hz), 2.11–2.00
(m, 1H), 1.76–1.59 (m, 4H), 1.43–1.17 (m, 1H), 1.14 (s,
9H), 1.05–0.78 (m, 4H), 0.86 (d, 3H, J = 6.1 Hz), 0.85 (d,
3H, J = 7.7 Hz), 0.69 (d, 3H, J = 6.6 Hz); IR (CHCl3,
cmꢀ1): 3028, 2957, 1310, 1126; LRMS (m/z (relative inten-
sity)): 358 (MNHþ4 , 30), 235 (100), 97 (70); Exact Mass calc.
for C20H40NO2S ðMNHþ4 Þ: 358.2780, found: 358.2784;
½aꢁD ¼ ꢀ43:1 (c 1.23, CHCl3).
3.33. Synthesis of sulfolene 68a
A solution of sulfone 66a (54 mg, 0.166 mmol) in dry
dichloromethane (165 mL, 0.001 M), was heated to reflux
and then degassed by passing a stream of argon for
15 min. while refluxing. Catalyst 21 (10 mg, 0.012 mmol)
was quickly added while the solution was still under reflux.
The resulting pale pink solution was refluxed for 18 h. It
was cooled to rt and volatiles were removed under vacuum
without heating. The crude product was purified by flash
chromatography on silica gel (100% hexanes/40% EtOAc/
hexanes) to afford the desired product 68a (27 mg, >99%)
20
½aꢁD ¼ ꢀ73:5 (c 0.73, CHCl3).
3.30.3. Sulfone 66c
1
Colorless solid (99% yield); m.p. 102–103 ꢁC. 1H NMR:
(300 MHz, CDCl3): d 5.78 (dddd, 1H, J = 17.1, 10.5, 6.6,
6.6 Hz), 5.62 (dd, 1H, J = 15.4, 10.4 Hz), 5.48 (dd, 1H,
J = 15.4, 9.4 Hz), 5.13–5.07 (m, 2H), 3.35 (d, 1H,
J = 10.5 Hz), 3.06 (ddd, 1H, J = 13.8, 10.5, 6.0 Hz), 2.93
as a colorless oil. H NMR: (300 MHz, CDCl3): d 6.02
(s, 2H), 3.79–3.64 (m, 3H), 2.04–1.86 (m, 1H), 1.68–1.45
(m, 3H), 0.99 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz,
CDCl3): d 130.4 (d), 122.9 (d), 64.2 (d), 55.5 (t), 30.6 (t),
20.3 (t), 13.8 (q); IR (neat, cmꢀ1): 3069, 2975, 2869, 1464,

5354
C. Spino et al. / Journal of Organometallic Chemistry 691 (2006) 5336–5355
1310, 1121; LRMS (m/z (relative intensity)): 178 (MNHþ4 ,
[8] (a) M. Lee, T. Lee, E.–Y. Kim, H. Ko, D. Kim, S. Kim, Org. Lett. 8
(2006) 745–748;
81), 161 (MH+, 20), 96 (100); Exact Mass calc. for
(b) L.F. Basil, H. Nakano, R. Frutos, M. Kopach, A.I. Meyers,
Synthesis (2002) 2064–2074;
(c) V. Rodeschini, P. Van de Weghe, C. Tarnus, J. Eustache,
Tetrahedron Lett. 46 (2005) 6691–6695;
20
C7H13SO2 (MH+): 161.0636, found: 161.0641; ½aꢁD
¼
ꢀ21:7 (c 2.38, CHCl3).
(d) S. Kim, H. Ko, T. Lee, D. Kim, J. Org. Chem. 70 (2005) 5756–
5759.
3.34. Synthesis of sulfolene 68b
[9] S. Gowrisankar, Y.K. Lee, J.N. Kim, Tetrahedron 62 (2006) 4052–
4058.
[10] M. Ball, B.J. Bradshaw, R. Dumeunier, T.J. Gregson, S. MacCor-
mick, H. Omori, E.J. Thomas, Tetrahedron Lett. 47 (2006) 2223–
2227.
[11] B. Nosse, A. Schall, W.B. Jeong, O. Reiser, Adv. Synth. Catal. 347
(2005) 1869–1874.
[12] A. Furstner, O.R. Thiel, L. Ackermann, H.-J. Schanz, S.P. Nolan, J.
¨
Prepared as per sulfolene 68a (21 mg, 84%) and the
dimer of 66b (7 mg), both as colorless oils. 1H NMR:
(300 MHz, CDCl3): d 6.17–6.06 (m, 2H), 3.74–3.56 (m,
2H), 3.55–3.53 (m, 1H), 1.18 (s, 9H); 13C NMR
(75 MHz, CDCl3): d 129.1 (d), 124.0 (d), 74.4 (d), 56.4
(t), 34.5 (s), 2.71 (q); IR (neat, cmꢀ1): 2963, 2868, 1298,
1245, 1109; LRMS (m/z (relative intensity)): 192 (MNHþ4 ,
Org. Chem. 65 (2000) 2204–2207.
40), 175 (MH+, 5), 110 (100); Exact Mass calc. for
[13] (a) C. Spino, C. Godbout, C. Beaulieu, M. Harter, T.M. Mwene-
Mbeja, L. Boisvert, J. Am. Chem. Soc. 126 (2004) 13312–13319;
(b) C. Spino, C. Beaulieu, Angew. Chem. Int. Ed. 39 (2000) 1930–
1932;
20
C8H15SO2 (MH)+: 175.0793, found: 175.0790; ½aꢁD
¼
ꢀ15:2 (c 1.96, CHCl3).
(c) D. Gagnon, S. Lauzon, C. Godbout, C. Spino, Org. Lett. 7 (2005)
4769–4771.
Acknowledgements
[14] A similar effect was reported in T.F. Briggs, G.B. Dudley, Tetrahe-
dron Lett. 46 (2005) 7793–7796.
[15] Even if the formation of 24e is under thermodynamic control (which
we don’t believe it is), the fact that 24f does not form is still best
explained by the difference in reaction kinetics.
[16] (a) T.A. Kirkland, R.H. Grubbs, J. Org. Chem. 62 (1997) 7310–7318;
(b) K.J. Quinn, A.K. Isaacs, R.A. Arvarry, Org. Lett. 6 (2004) 4143–
4145;
(c) S. Michaelis, S. Bletchert, Org. Lett. 7 (2005) 5513–5516.
[17] For a recent review of the Thorpe–Ingold effect see M.E. Jung, G.
Piizzi, Chem. Rev. 105 (2005) 1735–1766.
We thank the Natural Sciences and Engineering Re-
search Council (NSERC) of Canada, AstraZeneca Mon-
treal R&D, Bristol-Myers-Squibb (Canada) Ltd., and the
´
Universite de Sherbrooke for financial support. L.B.,
J.D., S.R., J.M., D.G., F.B., and C.C. are grateful to
NSERC for graduate scholarships.
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