Dynamic kinetic resolution during iron carbonyl promoted [6+2] ene-type reactions

Article abstract of DOI:10.1016/j.tetlet.2005.02.166

Intramolecular coupling of cyclohexadiene-Fe(CO)₃ complexes with pendant alkenes, to form spirolactams, proceed with excellent stereocontrol, using chiral amide substrates that lead to dynamic kinetic resolution.

Full text of DOI:10.1016/j.tetlet.2005.02.166

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3123–3126
Dynamic kinetic resolution during iron carbonyl promoted
[6+2] ene-type reactions
Anthony J. Pearson* and Xiaolong Wang
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Received 7 February 2005; accepted 21 February 2005
Available online 16 March 2005
Abstract—Intramolecular coupling of cyclohexadiene–Fe(CO)3 complexes with pendant alkenes, to form spirolactams, proceed with
excellent stereocontrol, using chiral amide substrates that lead to dynamic kinetic resolution.
Ó 2005 Elsevier Ltd. All rights reserved.
Transition metal promoted cyclocoupling reactions of
alkenes have a rich history, and occupy an important
place in organic synthesis methodology.1 These pro-
cesses often complement their more traditional organic
counterparts in terms of stereochemistry and our ability
to carry out reactions that are symmetry forbidden, or
compromised by more facile competing processes. While
such transformations in the coordination sphere of a
metal are often not concerted single-step reactions, they
are nevertheless usually stereospecific, a result of conti-
nual attachment of the reacting ligand(s) as the key
bond-forming steps proceed.
case illustrated, a mixture of epimers 2a and 3a is ob-
tained. We have developed a number of approaches to
control the stereochemical outcome of this reaction,
one of which uses a methoxy substituent on the diene
(R = OMe, 1b). In this case a mixture of regioisomers
2b/3b is generated, but removal of the metal, followed
by hydrolysis of the resulting mixture of dienol ethers
affords a single enone 4.3
Another problem that arises with the unsubstituted ser-
ies (R = H) is that the same thermal rearrangement that
converts 2 to 3 also occurs with the reactant 1, in that
case leading to racemization of optically pure com-
plexes. This too has been overcome by attaching suitable
substituents to the cyclohexadienyl ring,4 but it also pro-
vides an avenue for dynamic kinetic resolution in cases
where the pendant alkene has a stereogenic centre,
which is the subject of this Letter.
We have developed a novel coupling reaction between a
diene–Fe(CO)3 complex and a pendant alkene, that is
equivalent to a [6+2] ene reaction.2 While this is a
non-concerted transformation, the key bond-forming
event is nevertheless stereospecific, as illustrated in
Scheme 1. The initial product from amide 1 is lactam
2, but this undergoes rearrangement of the diene–
Fe(CO)3 system, via a hydride shift, to afford 3 under
the reaction conditions. Thus, when R = H in the simple
Consider the reaction shown in Scheme 2. If there is a
significant difference in the rates of cyclization of the
two diastereomers 5 and 6 (5 being faster), compared
O
O
R
R
O
2b + 3b:
R
(OC)3Fe
(OC)3Fe
(OC)3Fe
CuCl2, EtOH
Bu2O, 140 ºC
1 atm. CO
Bu2O, 140 ºC
Me
Me
Me
X
X
X
X
O
1
a R = H
O
2
4
b R = OMe
3
X = CH2 or NPh
Scheme 1.
*
Corresponding author. Tel.: +1 216 368 5920; fax: +1 216 368 3006; e-mail: ajp4@po.cwru.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.166

3124
A. J. Pearson, X. Wang / Tetrahedron Letters 46 (2005) 3123–3126
Fe(CO)3
Fe(CO)3
(CO)3Fe
(CO)3Fe
R
R
Me
R
Me
*
*
*
NP
NP
NP
R
R
Fe(CO)
N
N
3 O
O
O
O
O
P
6
P
5
6
8
7
Scheme 2.
with their rate of interconversion (which occurs by iron-
mediated hydride transfer), then we should observe pre-
dominant formation of 7 over 8. Indeed, if the equilibra-
tion between 5 and 6 is sufficiently facile, and the
cyclization rates are greatly different, a mixture of these
two complexes might afford a single product. Note that
the diene–Fe(CO)3 unit in 6 is enantiomeric with that in
5 (see the alternate drawing of 6, which is derived by
rotation about the diene–carbonyl C–C bond). Of
course, 7 will undergo the same rearrangement as noted
for 2, but this is also a controllable event.5 Should this
process occur as proposed, then the newly generated ste-
reocentres are controlled by the stereochemistry at C*,
and the requisite amide can be prepared from a racemic
cyclohexadienoic acid complex.
duce a pair of diastereomeric amides, 14 and 15, which
were separated (Scheme 4). Complex 14 was also pre-
pared from the amine and enantiomerically pure acid
of known stereochemistry,8 which allowed unambiguous
structural assignment of 14 and 15. Cyclization of 14
gave a 1:1 mixture of epimeric spirolactams 16 in 75%
isolated yield (4 h, 100% conversion; minor by-products
appear to be from demetallation of 16). It should be
noted that, according to our earlier observations on this
reaction, 16a is the initial product and this undergoes
thermal rearrangement to give 16b. Direct cyclization
of 15 did not afford any of the products 17. Instead,
upon heating 15 rearranged to give its diastereomer
14, which then cyclized to give products 16 in 65% yield
(8 h, 60% conversion). Cyclization of a 1:1 mixture of 14
and 15 gave the same pair of epimers 16 in 63% isolated
yield. The much slower cyclization of 15 compared with
14 is consistent with the proposition that complex 15
must undergo rearrangement of the diene, to form 14
first. The mixture of epimeric lactams 16 was demetal-
lated (Me3NO), followed by hydrogenation to give a
single product 18, thus confirming that efficient dynamic
kinetic resolution indeed occurs.
The amide derivatives (X = NR) are chosen for illustr-
ation here because the requisite amines can be prepared
from the corresponding readily available amino acids.
We also chose to use a trisubstituted pendant alkene
unit, for reasons that will become apparent later in the
discussion. For this purpose, we required amine deriva-
tive 11, which was prepared from phenylalanine as out-
lined in Scheme 3. Thus, the protected amino aldehyde 9
was prepared using a literature procedure,6 and sub-
jected to Horner–Wadsworth–Emmons reaction under
two sets of reaction conditions. The phosphonyl enolate
derived by treatment of the precursor phosphonoester
with n-BuLi afforded a mixture of E and Z alkenoic
esters 10 favouring the E isomer, but in only a 4:1 ratio,
though these can be separated chromatographically.
Use of DBU/LiCl7 produced essentially single E isomer
in good yield. N-Deprotection of (E)-10 afforded 11. It
should be noted that the minor (Z) isomer from the
BuLi-promoted reaction underwent spontaneous form-
ation of lactam 12 on deprotection, as expected, so
our study of the [6+2] ene cyclization reaction was con-
fined to the E isomer at this time.
The difference in reactivity between 14 and 15 can be
rationalized by considering the strain energies of puta-
tive intermediates, which can be calculated by molecular
mechanics using PC Spartan. According to the mecha-
nism, 14 and 15 have to be converted to the intermedi-
ates 18 and 19, respectively. Intermediate 18 is lower
in energy than 19 by 1.8 kcal/mol. Formation of 19 from
15 is therefore likely to be slow compared with isomeri-
zation of 15 to 14, which prevents formation of 17a. At
the same time, conversion of 14 to 18 occurs more easily
and 18 then cyclizes to form 16a.
As mentioned earlier, we considered that a trisubstituted
alkene residue would be needed for efficient dynamic
kinetic resolution. This supposition was based on the
fact that intermediate 19 has a destabilizing non-bonded
interaction between the methyl and benzyl groups, as
The chiral trisubstituted amino ester 11 was coupled
with the racemic acid 13, via its acyl mesylate, to pro-
1) 4-MeOC6H4COCl
Bn
Bn
Bn
CO2Et
Bn
(>95%)
EtO2C(Me)CHPO(OEt)2
+
O
BocN
PMB
BocN
PMB
BocN
-Cl +H3N
CO2Et
10 (E)
CO2Me
2) LiAlH4 (98%)
Conditions:
10 (Z)
3) Boc2O, dioxane (98%)
4) Swern (70%)
(a) n-BuLi, THF, -78 ºC, 3h (74%)
(b) DBU, CH3CN, 0 ºC, 2h (76%)
Conditions: (a) 4:1 E/Z; (b) >100:1 E/Z
OMe
9
Bn
TFA, CH2Cl2
TFA, CH2Cl2
10 (E)
10 (Z)
HN
PMB
O
0 ºC, 10 min.
>95%
CO2Et
0 ºC, 10 min.
>95%
Bn
N
PMB
12
11
Scheme 3.

A. J. Pearson, X. Wang / Tetrahedron Letters 46 (2005) 3123–3126
3125
CO2Et
Fe(CO)3
Bn
CO2Et
100% conversion
N
75% yield
4 hours
Bn
Fe(CO)3
Fe(CO)3
H
H
PMB
1) 13, MsCl, Et3N,
H
H
O
4Å MS,CH2Cl2, 0 oC, 1h
EtO2C
Bn
EtO2C
Bn
14
NH
2) 11/Et3N, CH2Cl2, rt, 16h
PMB
n-Bu2O, CO
142 oC
11
N
N
O
83%
O
PMB
8 hours
PMB
(OC)3Fe
HO
CO2Et
65% yield
16a
16b
60% conversion
Bn
N
O
PMB
1) Me3NO, PhH, 50 oC, 4h
2) H2/Pd-C, MeOH, rt, 16h
Fe(CO)3
Racemic
O
15
52% (two steps)
13
X
H
EtO2C
H
H
H
CO2Et
N
H
H
CO2Et
N
Fe(CO)3
Bn
Fe(CO)3
N
O
Bn
Bn
18
PMB
O
O
PMB
PMB
17a
17b
Scheme 4.
E
steric = 149.1 Kcal/mol
Esteric = 147.3 Kcal/mol
Fe(CO)3
O
O
H
H CO2Et
H
O
O
EtO2C11
C C
10
5
EtO2C
Me
C
C
CO2Et
Me
Fe(CO)3
H
4
Bn
Bn
Fe
Fe
6
3
N
N2
O
1
O
H
N
PMB
H
H
N
PMB
Bn
H
PMB
16a
Bn
17a
O
O
PMB
18
19
15
14
Scheme 5.
indicated on the structure. This interaction is absent in
intermediate 18 (note that steric interaction with the
ester residue is not possible because of the double bond
stereochemistry). In fact, we have observed that similar
complexes lacking the methyl substituent give much
poorer selectivity (ca. 2.5:1), but these results are not
included here because mixtures of four diastereomers
were generally obtained (analogous to diastereomers
16a/b and 17a/b in Scheme 5), and the products were
not fully characterized.
moted [6+2] ene-type reaction in a single direction by
dynamic kinetic resolution. Multiple stereogenic centres
can be produced in a single enantiomeric form. This
chemistry is interesting because of the similarity between
the spirolactam structure 18 and cytochalasin structures
such as the HIV protease inhibitor 18-deoxycytochalasin
H,9 though the stereochemistry of this molecule would
require us to use the amide derived from the Z isomer
of 11. Future work will examine methods to prepare this
system and its cyclization, as well as tandem reactions
that are analogous to those described earlier,5 that will
afford multicyclic structures derived only from 16a,
which avoids the problem of 16a/16b mixture formation.
OH
O
OAc
H
Bn
N
H
Acknowledgements
18-deoxycytochalasin H
In summary, it is possible to use a chiral amide substitu-
ent to drive the stereochemical outcome of the iron pro-
We are grateful to the National Science Foundation for
financial support of this research.

3126
A. J. Pearson, X. Wang / Tetrahedron Letters 46 (2005) 3123–3126
2. Pearson, A. J.; Zettler, M.; Pinkerton, A. A. J. Chem. Soc.,
Supplementary data
Chem. Commun. 1987, 264–266; Pearson, A. J.; Zettler, M.
W. J. Am. Chem. Soc. 1989, 111, 3908–3918.
3. Pearson, A. J.; Bennouna-Dorange, I. J. Org. Chem. 2001,
66, 3140–3145.
4. Pearson, A. J.; Zettler, M. W. J. Chem. Soc., Chem.
Commun. 1987, 1243–1245.
Spectroscopic data for all new compounds reported.
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.
2005.02.166.
5. Pearson, A. J.; Wang, X. J. Am. Chem. Soc. 2003, 125, 638–
639.
References and notes
6. Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem. 1995,
60, 8074–8080.
7. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183–2186.
8. Birch, A. J.; Bandara, B. M. R. Tetrahedron Lett. 1980, 21,
2981–2982.
9. Kim, B. M.; Guare, J. P. Heterocycles 1995, 41, 403–408,
and references cited therein; For a recent example of
cytochalasin synthesis, see: Vedejs, E.; Duncan, S. M.
J. Org. Chem. 2000, 65, 6073–6081.
1. Reviews: Lautens, M.; Klute, W.; Tam, W. Chem. Rev.
1996, 96, 49–92; Ojima, I.; Tzamariiudaki, M.; Li, Z.;
Donovan, R. J. Chem. Rev. 1996, 96, 635–662; Fruhauf,
¨
H.-W. Chem. Rev. 1997, 97, 523–596; Hegedus, L. S. Coord.
Chem. Rev. 1997, 161, 129–255; Hartley, R. C.; Caldwell, S.
T. Novel J. Chem. Soc., Perkin Trans. 1 2000, 477–501;
Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.;
Hubbard, R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.;
Zhang, L. Pure Appl. Chem. 2002, 74, 25–31; Rigby, J. H.
Tetrahedron 1999, 55, 4521–4538.