Reactivity of (Bicyclo[5.1.0]octadienyl)iron(1+) Cations: Application to the Synthesis of cis-2-(2′-Carboxycyclopropyl)glycines

Article abstract of DOI:10.1021/jo030259a

The addition of carbon and heteroatom nucleophiles to (bicyclo[5.1.0]octadienyl)Fe(CO)₂L⁺ cations 5 or 8 (L = CO, PPh₃) generally proceeds via attack at the dienyl terminus on the face of the ligand opposite to iron to generate 6-substituted (bicyclo[5.1.0]octa-2,4-diene)iron complexes (11 or 13). In certain cases, these products are unstable with respect to elimination of a proton and the nucleophilic substituent to afford (cyclooctatetraene)Fe(CO)₂L (4 or 7). Decomplexation of 13f, arising from addition of phthalimide to 8, gave N-(bicyclo[5.1.0]octa-3,5-dien-2-yl)phthalimide (19). Oxidative cleavage of 19 (RuCl₃/NaIO₄) followed by esterification gave the cyclopropane diester 22, which upon hydrolysis gave cis-2-(2′ -carboxycyclopropyl)glycine (CCG-III, 18) (eight steps from 4, 43% overall yield). This methodology was also utilized for preparation of stereospecifically deuterated CCG-III (d-18) and optically enriched (-)-18. Deprotonation of 22 resulted in cyclopropane ring opening to afford the benzoindolizidine (23).

Full text of DOI:10.1021/jo030259a

Rea ctivity of (Bicyclo[5.1.0]octa d ien yl)ir on (1+) Ca tion s:
Ap p lica tion to th e Syn th esis of
cis-2-(2′-Ca r boxycyclop r op yl)glycin es
Nathaniel J . Wallock and William A. Donaldson*
Department of Chemistry, Marquette University, P.O. Box 1881, Milwaukee, Wisconsin 53201-1881
william.donaldson@marquette.edu
Received August 11, 2003
The addition of carbon and heteroatom nucleophiles to (bicyclo[5.1.0]octadienyl)Fe(CO)2L+ cations
5 or 8 (L ) CO, PPh3) generally proceeds via attack at the dienyl terminus on the face of the ligand
opposite to iron to generate 6-substituted (bicyclo[5.1.0]octa-2,4-diene)iron complexes (11 or 13).
In certain cases, these products are unstable with respect to elimination of a proton and the
nucleophilic substituent to afford (cyclooctatetraene)Fe(CO)2L (4 or 7). Decomplexation of 13f, arising
from addition of phthalimide to 8, gave N-(bicyclo[5.1.0]octa-3,5-dien-2-yl)phthalimide (19). Oxidative
cleavage of 19 (RuCl3/NaIO4) followed by esterification gave the cyclopropane diester 22, which
upon hydrolysis gave cis-2-(2′-carboxycyclopropyl)glycine (CCG-III, 18) (eight steps from 4, 43%
overall yield). This methodology was also utilized for preparation of stereospecifically deuterated
CCG-III (d -18) and optically enriched (-)-18. Deprotonation of 22 resulted in cyclopropane ring
opening to afford the benzoindolizidine (23).
CHART 1
In tr od u ction
The 1,2-disubstituted cyclopropane ring appears as a
key structural feature in a number of naturally occurring
compounds [e.g., curacin A (1),1 constanolactones (2),2 and
FR-900848 (3),3 Chart 1). Of the number of routes to
access this functionality,4 the selective rearrangement of
homoallyl cations to cyclopropylcarbinyl cations5 has
become of renewed interest.6,7 This transformation is
(1) For isolation, see: (a) Gerwick, W. H.; Proteau, P. J .; Nagle, D.
G.; Hamel, E.; Blokhin, A.; Slate, D. L. J . Org. Chem. 1994, 59, 1243-
1245. For total syntheses, see: (b) Ito, H.; Imai, N.; Tanikawa, S.;
Kobayashi, S. Tetrahedron Lett. 1996, 37, 1795-1798. (c) White, J .
D.; Kim. T.-S.; Nambu, M. J . Am. Chem. Soc. 1997, 119, 103-111. (d)
Hoemann, M. Z.; Agrios, K. A.; Aube´, J . Tetrahedron 1997, 53, 11087-
11098. (e) Wipf, P.; Xu, W. J . Org. Chem. 1996, 61, 6556-6562. (f)
Lai, J .-Y.; Yu, J .; Mekonnen, B.; Falck, J . R. Tetrahedron Lett. 1996,
37, 7167-7170. (g) Muir, J . C.; Pattenden, G.; Ye, T. Tetrahedron Lett.
1998, 39, 2861-2864. (h) Onoda, T.; Shirai, R.; Koiso, Y.; Iwasaki, S.
Tetrahedron 1996, 52, 14543-14562.
(2) For isolation, see: (a) Baertschi, S. W.; Brash, A. R.; Harris, T.
M. J . Am. Chem. Soc. 1989, 111, 5003-5005. For total syntheses, see:
(b) Nagasawa, T.; Onoguchi, Y.; Matsumoto, T.; Suzuki, K. Synlett
1995, 1023-1024. Nagasawa, T.; Handa, Y.; Onoguchi, Y.; Suzuki, K.
Bull. Chem. Soc. J pn. 1995, 69, 31-39. (c) White, J . D.; J ensen, M. S.
J . Am. Chem. Soc. 1993, 115, 2970-2971.
(3) For isolation, see: (a) Yoshida, M.; Ezaki, M.; Hashimoto, M.;
Yamashita, M.; Sigematsu, N.; Okuhara, M.; Kohsaka, M.; Horikoshi,
K. J . Antibiot. 1990, 43, 748-754. For total syntheses, see: (b) Barrett,
A. G. M.; Kasdorf, K. J . Am. Chem. Soc. 1996, 118, 11030-11037. (c)
Falck, J . R.; Mekonnen, B.; Yu, J .; Lai, J .-Y. J . Am. Chem. Soc. 1996,
118, 6096-6097. (d) Verbicky, C. A.; Zercher, C. K. Tetrahedron Lett.
2000, 41, 8723-8727.
made possible by the presence of two alkyl groups (eq
1)6 or an allylsilane substituent (eq 2)7 in order to
stabilize the cyclopropylcarbinyl cation. These reactions
take place with inversion of configuration at the carbon
that undergoes ionization. The lowest energy transition
state is that in which the substituents are on opposite
sides of the forming cyclopropane ring, thus giving rise
to a trans-1,2-disubstituted cyclopropane.
(4) (a) Tsuji, T.; Nishida, S. Preparation of cyclopropyl derivatives.
In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; J ohn
Wiley and Sons: New York, 1987; pp 308-373. (b) Salaun, J . Chem.
Rev. 1989, 89, 1247-1270.
(5) Friedrich, E. C. Solvolysis of cyclopropyl-substituted derivatives.
In The Chemistry of the Cyclopropyl Group; Rappoport, Z., Ed.; J ohn
Wiley and Sons: New York, 1987; pp 633-700.
(6) Nagasawa, T.; Onoguchi, Y.; Matsumoto, T.; Suzuki, K. Synlett
1995, 1023-1024.
10.1021/jo030259a CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/25/2004
J . Org. Chem. 2004, 69, 2997-3007
2997

Wallock and Donaldson
SCHEME 1
SCHEME 2
Protonation of (cyclooctatetraene)Fe(CO)3 (4) by non-
coordinating acids is known to afford the bicyclic cation
5 possessing a cis-disubstituted cyclopropane ring (Scheme
1).8 Davison et al. originally proposed exo-protonation of
4 to give the intermediate η5-octatrienyl complex 6;
homoallyl-to-cyclopropylcarbinyl rearrangement gives the
bicyclic cation 5.8a Low-temperature NMR spectroscopic
monitoring of this reaction provided evidence for the
homoallylic cation 6.8b Notably, treatment of 5 with base
(e.g., KOH) regenerates the neutral complex 4. In com-
parison to the extensive examination of (cyclohexadienyl)-
and (cycloheptadienyl)iron(1+) cations,9,10 the reactivity
of bicyclic cation 5 with nucleophilies has been consider-
ably less studied.11 As part of our interest in the prepara-
tion of cyclopropanes by organoiron methodology,12 we
here report on the reactivity of (bicyclo[5.1.0]octadienyl)-
iron(1+) cations and application of these reactions to
organic synthesis.
ligand substitution with triphenylphosphine in the pres-
ence of trimethylamine N-oxide to give 7 in excellent yield
(Scheme 1). Like the parent complex 4,14 the phosphine-
ligated complex 7 is fluxional at 20 °C. The 1H NMR
spectrum of 7 exhibits a single peak (8H) at δ 4.95 for
the cyclooctatetraene protons due to relatively fast “ring-
whizzing” of the Fe(CO)2PPh3 moiety about the polyene
ligand.
Protonation of 7 with HBF4 gave the bicyclic cation 8
1
(Scheme 1). The H NMR spectrum of 8 in CD3OD at 30
°C exhibited only five of the six expected signals for the
bicyclo[5.1.0]octadienyl ligand (see Figure 1 in the Sup-
porting Information). The geminal protons of the cyclo-
propane ring were observed at δ 1.1-1.2 (1H) and 1.2-
1.3 (1H), as well as two broad multiplets at δ 2.3-2.5
(2H) and 5.0-5.3 (2H) and a one downfield signal (δ 7.7,
br t). Upon lowering the temperature, the two multiplets
at δ 2.3-2.5 and 5.0-5.3 (2H each) separated to give four
signals (δ 2.2-2.3, 2.3-2.5, 4.9-5.1, and 5.4-5.6; 1H
each). Additionally, two multiplets arose from the base-
line at δ 3.6-3.8 and 5.3-5.4 (1H each); these latter
signals were not observed in the 30 °C spectrum. Due to
the chemical shift difference of the latter two signals (∆δ
) ca. 1.8), coalescence of these signals at 30 °C occurs
with severe broadening such that the coalesced signal
resides in the baseline of the spectrum at ambient
temperature.
This fluxional behavior is characteristic of a tetragonal
pyramidal iron complex, in which the phosphine ligand
is rapidly exchanging between basal sites (8B and 8B′,
Scheme 2). At 30 °C, the “windshield-wiper” motion of
the Ph3P(CO)2Fe moiety is sufficiently fast that only time-
averaged signals appear for the pairs H1/ H1′, H2/H2′, and
H3/H3′. As the temperature is lowered, rotation about the
Fe-dienyl ligand slows, and the phosphine occupies one
of two equivalent basal sites. With the loss of symmetry,
protons H1, H2, and H3 become nonequivalent with H1′,
H2′, and H3′, respectively. No additional resonances were
observed in the 1H NMR spectrum that might correspond
to an apical isomer conformation (8A). This was further
corroborated by a variable-temperature 31P NMR study.
In this case, only a single resonance (δ 58) was observed
in the temperature range +16 to -100 °C. Exchange of
the phosphine ligand between equivalent basal sites gives
Resu lts a n d Discu ssion
P r ep a r a tion , Ch a r a cter iza tion , a n d Rea ctivity of
Bicyclic Ca tion s. Protonation of 4, according to the
literature procedure,8 gave the tricarbonyl ligated iron
cation 5 in excellent isolated yield (Scheme 1). It is well-
known that replacement of CO by a phosphine ligand can
affect the regioselectivity of nucleophilic addition to
dienyl iron complexes.13 To this end, 4 readily underwent
(7) (a) Taylor, R. E.; Engelhardt, F. C.; Schmitt, M. J . Tetrahedron
2003, 59, 5623-5634. (b) Taylor, R. F.; Engelhardt, F. C.; Schmitt, M.
J .; Yuan, H. J . Am. Chem. Soc. 2001, 123, 2964-2969.
(8) (a) Davison, A.; McFarlane, W.; Pratt, L.; Wilkinson, G. J . Chem.
Soc. 1962, 4821-4829. (b) Brookhart, M.; Davis, E. R.; Harris, D. L.
J . Am. Chem. Soc. 1972, 94, 7853-7858.
(9) (a) Pearson, A. J . In Comprehensive Organometallic Chemistry
II; Abel, E. W., Stone, F. G. A., Wilkenson, G., Eds.; Pergamon Press:
Oxford, UK, 1995; Vol. 12, pp 637-683. (b) Pearson, A. J . In Advances
in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI Press: Green-
wich, CT, 1989; Vol. 1, pp 1-49. (c) Knoelker, H.-J . Chem. Soc. Rev.
1999, 28, 151-157.
(10) (a) Pearson, A. J .; Kole, S. L.; Ray, T. J . Am. Chem. Soc. 1984,
106, 6060-6074. (b) Pearson, A. J .; Burello, M. P. Organometallics
1992, 11, 448. (c) Pearson, A. J .; Srinivasan, K. J . Org. Chem. 1992,
57, 3965. (d) Pearson, A. J .; Srinivasan, K. Synlett 1992, 983. (e)
Hirschfelder, A.; Eilbracht, P. Synthesis 1996, 488.
(11) (a) Niemer, B.; Briemair, J .; Wagner, B.; Polborn, K.; Beck, W.
Chem. Ber. 1991, 124, 2227-2236. (b) Salzer, A.; Hafner, A. Helv.
Chim. Acta 1983, 66, 1774-1785. (c) Aumann, R.; Knecht, J . Chem.
Ber. 1976, 109, 174-179. (d) Aumann, R. Angew. Chem., Int. Ed. Engl.
1973, 12, 574-575. (e) Holmes, J . D.; Pettit, R. J . Am. Chem. Soc. 1963,
85, 2531-2532.
(12) Yun, Y. K.; Godula, K.; Cao, Y.; Donaldson, W. A. J . Org. Chem.
2003, 68, 901-910.
(13) (a) Pearson, A. J .; Kole, S. L.; Ray, T. J . Am. Chem. Soc. 1984,
106, 6060-6074. (b) McDaniel, K. F.; Kracker, L. R.; Thamburaj, P.
K. Tetrahedron Lett. 1990, 31, 2373-2376. (c) Millot, N.; Guillou, C.;
Thal, C. Tetrahedron Lett. 1998, 39, 2325-2326. (d) Barmann, H.;
Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.; Donaldson, W. A.
Tetrahedron 2000, 56, 2283-2295.
(14) (a) Kreiter, C. G.; Maasbol, A.; Anet, F. A. L.; Kaesz, H. D.;
Winstein, S. J . Am. Chem. Soc. 1966, 88, 3444-3445. (b) Keller, C.
E.; Shoulders, B. A.; Pettit, R. J . Am. Chem. Soc. 1966, 88, 4760-
4761. (c) Cotton, F. A.; Davidson, A.; Faller, J . W. J . Am. Chem. Soc.
1966, 88, 4507-4509.
2998 J . Org. Chem., Vol. 69, No. 9, 2004

Reactivity of (Bicyclo[5.1.0]octadienyl)iron(1+) Cations
TABLE 1. Nu cleop h ilic Ad d ition to
(Bicyclo[5.1.0]octa d ien yl)F e(CO)2L+
SCHEME 3
cation
nucleophile
products (isolated yields, %)
5
5
5
5
5
5
8
8
8
8
8
8
NaBH4/Et2O/ice water
11a /12 (5:1), Nu ) H (90)a
MeLi/CuBr/SMe2/Et2O 11b, Nu ) Me (62)
LiCH(CO2Me)2/Et2O
EtOH/NaOAc
EtSH/NaOAc/Et2O
KNPhth/acetone
NaBH3CN/moist Et2O
LICH(CO2Me)2/Et2O
H2NCH/Me)Ph
11c, Nu ) CHE2 (62)
11d , Nu ) OEt (65)
11e, Nu ) SEt (85)
11f, Nu ) NPhth (41), 4 (12)
13a , Nu ) H (50)
13c, Nu ) CHE2 (61)
7 (80)
EtOH/MaOAc
EtSH/NaOAc/Et2O
KNPhth/ether
7 (86)
13e, Nu ) SEt (95)
13f, Nu ) NPhth (>99)
In comparison, reaction of phosphine-ligated cation 8
with ethanol or R-methylbenzylamine gave only (COT)-
Fe(CO)2PPh3 (7), while reaction with hydride, malonate
anion, thiolate anion, and phthalimide anion gave pre-
dominantly the diene complexes 13a ,c,e,f in good to
excellent yields (eq 3, Table 1). In comparison to the
tricarbonyl-ligated complexes 11, the phosphine ligated
complexes 13a ,c,e,f are isolated as air-stable solids.
Complexes 13 were assigned as bicyclo[5.1.0]octa-2,4-
diene structures on the basis of their NMR spectral data.
In particular, the 1H NMR spectra for complexes 13
exhibit four high-field resonances corresponding to the
cyclopropane hydrogens, while the 13C NMR spectra
contain three upfield signals at ca. δ 16-21, two signals
at ca. δ 60-67, and two signals at ca. δ 87-90 corre-
sponding to the cyclopropane, terminal diene, and inter-
nal diene carbons, respectively. For both cations 5 and
8, nucleophilic addition occurs in a stereoselective fash-
ion; only one diastereomer is obtained. Attack on the face
of the dienyl ligand opposite to the metal was tentatively
assigned by analogy to the direction of attack on (cyclo-
a
Reference 11c,d.
rise to a single 31P NMR resonance signal; if basal-apical
exchange of the phosphine ligand had occurred, an
additional 31P NMR resonance would be expected at low
temperature due to the apical phosphine rotomer. The
cyclopropane methine protons (H1 and H1′) coalesce at 0
q
°C, corresponding to kc ) 119 s-1 and ∆Gc ) 13.3 kcal
mol-1. This activation energy is comparable with that
found for apical-basal phosphite exchange in (hexadienyl)-
Fe(CO)2(EPTB)+ (9) and (heptadienyl)Fe(CO)2(EPTB)+
(10) (9.8 and 11.4 kcal mol-1, respectively).15
Aumann has previously reported11c,d that the reaction
of cation 5 with BH4 gave a mixture of bicyclo[5.1.0]-
-
octadiene complex 11a and the σ-alkyl-π-allyl complex
12 (eq 3, Table 1). Similarly, the reaction of 5 with a
variety of carbon and heteroatom nucleophiles gave
predominantly the corresponding 6-substituted bicyclo-
[5.1.0]octa-2,4-diene complexes 11b-f, along with vary-
ing amounts of (COT)Fe(CO)3 (4). This latter product
arises either from direct deprotonation of the cation 5 or
from nucleophilic attack followed by elimination.16 No-
tably, diene complexes 11d -f are relatively unstable in
solution and/or to exposure to typical chromatographic
adsorbents (Al2O3, SiO2) with respect to elimination.
J udicious solvent selection is critical to obtaining a good
yield of the addition product. Complexes 11b-f were
assigned as bicyclo[5.1.0]octa-2,4-diene structures by
comparison of their 1H NMR spectral data with that of
+
heptadienyl)Fe(CO)3 cations.10a This tentative assign-
ment was eventually corroborated for complex 13f (vide
infra).
In contrast, reaction of 8 with MeLi/CuBr gave an
inseparable mixture of diene complex 13b and (η4-7-
ethylcyclohepta-1,3,5-triene)Fe(CO)3 14b (2:7 ratio, Scheme
3); the latter product results from nucleophilic attack at
the cyclopropane ring. The structure of 14b was assigned
on the basis of its NMR spectral data. In particular, a
triplet in the 1H NMR spectrum at δ 0.78 (3H) was
assigned to the CH3 of the ethyl group, while signals at
δ 128.5 and 130.0 in the 13C NMR spectrum were
assigned to the uncomplexed olefinic carbons. While the
mixture of 13b and 14b was inseparable by chromatog-
raphy, a chemical separation was affected by treatment
of the mixture with a stoichiometric amount of OsO4 to
give a separable mixture of 13b and the (cyclohepta-3,5-
dienone)iron complex 15 (Scheme 3). On the basis of the
initial ratio of 13b and 14b, the recovery of 13b was ca.
the known11c compound 11a . In particular, the H NMR
1
spectra for complexes 11 exhibit four high field reso-
nances corresponding to the cyclopropane hydrogens,
while the 13C NMR spectra contain two signals at ca. δ
86-92 corresponding to the internal diene carbons.
(15) Whitesides, T. H.; Budnik, R. A. Inorg. Chem. 1975, 14, 664-
676.
(16) For an example of an addition-elimination reaction of 5, see:
Aumann, R. J . Organomet. Chem. 1974, 78, C31-C34.
J . Org. Chem, Vol. 69, No. 9, 2004 2999

Wallock and Donaldson
CHART 2
SCHEME 4
66%, while the yield of converted 15 was ca. 49%. The
structural assignment of 15 was based on its spectral
data. In particular, an IR absorption at 1708 cm-1 along
with a signal at δ 207.7 provided evidence for the ketone
1
functionality, while the triplet in the H NMR spectrum
at δ 0.75 (3H) was assigned to the CH3 of the ethyl group.
(Cyclohepta-3,5-dienone)iron complex 15 presumably
arises via dihydroxylation of the uncomplexed olefin of
14b on the face opposite to iron to give 16,17 followed by
a pinacol rearrangement (Scheme 3). Selective ionization
of the hydroxyl adjacent to the complexed diene of 16
occurs since the resultant carbocation 17 is stabilized by
electron donation from iron.
SCHEME 5
Syn t h esis of (()-cis-2-(2′-Ca r b oxycyclop r op yl)-
glycin e.18 L-Glutamic acid (Chart 2) is the major exci-
tatory neurotransmitter for a wide variety of receptors
in mammalian systems.19 The selective activation of
different glutamate receptors may depend on recognition
of a particular conformer of this flexible molecule. In
particular, the folded conformation, as exemplified by cis-
2-(2′-carboxycyclopropyl)glycine (CCG-III, 18) and trans-
pyrrolidine-2,4-dicarboxylate (TPDC), is believed to be a
common feature for inhibitors of glutamate transport.20
Stereoselective routes to 18 have been previously re-
ported.21
analysis, which demonstrated that the phthalimide sub-
stituent is endo with respect to the bicyclic ring system.22
Initial attempts at oxidative cleavage of the diene of 19
proved frustratingly difficult. Ozonolysis of 19 gave
uncharacterizable mixtures, regardless of the nature of
the workup (oxidative or reductive) of the intermediate
ozonide. Similarly, osmylation under Lemieux-J ohnson
conditions23 (OsO4-IO4-) also failed to give the expected
dialdehyde. Cleavage of the cycloheptadiene ring was
eventually accomplished by exhaustive hydroxylation of
19 with catalytic OsO4/NMO to give a mixture of partially
separable diastereomeric tetrols 20a and 20b (2:1 ratio
Complex rac-13f readily underwent oxidative decom-
plexation with ceric ammonium nitrate (CAN) to liberate
the ligand rac-19 (Scheme 4). The tentative structural
assignment for rac-19 was based on its NMR spectral
1
data. In particular, the H NMR spectrum of 19 contains
four upfield signals which are coupled to each other (δ
0.99, 1.28, 1.90, 2.25) which correspond to the cyclopro-
pane hydrogens, while the 13C NMR spectrum exhibits
seven downfield signals corresponding to the four olefinic
and three aryl carbons. This tentative assignment was
eventually corroborated by single-crystal X-ray diffraction
1
by H NMR integration). Glycol cleavage of the mixture
of tetrols 20a /b in aqueous THF gave a dialdehyde which
was unstable to chromatography on silica. Oxidation of
the crude dialdehyde with J ones reagent cleanly gave the
diacid 21. Since purification of 21 by column chromatog-
raphy proved difficult, direct esterification gave the
diester 22. Alternatively, Sharpless oxidation24 (RuCl3/
IO4-) of 19 gave the diacid 21, which was subsequently
protected by esterification to give 22 in excellent overall
yield. Acidic hydrolysis of 22, followed by treatment of
the hydrochloride salt with propylene oxide, gave rac-
CCG-III (rac-18, Scheme 5). The 1H and 13C NMR
spectral data of rac-18 were consistent with published
spectral data.21c In summary, rac-CCG-III was prepared
(17) For other examples of dihydroxylation of (cycloheptatriene)iron
complexes, see: Pearson, A. J .; Srinivasan, K. J . Chem. Soc., Chem.
Commun. 1991, 392-394. Pearson, A. J .; Srinivasan, K. J . Org. Chem.
1992, 57, 3965-3973.
(18) Preliminary communication: Wallock, N. J .; Donaldson, W. A.
Tetrahedron Lett. 2002, 43, 4541-4543.
(19) Conn, P. J .; Pin, J .-P. Annu. Rev. Pharmacol. Toxicol. 1997,
37, 205-237.
(20) For isolation of 18, see: (a) Fowden, L.; Smith, A.; Millington,
D. S.; Sheppard, R. C. Phytochemistry. 1969, 8, 437-443. For biological
activity of 18, see: (b) Bridges, R. J .; Stanley, M. S.; Anderson, M. W.;
Cotman, C. W.; Chamberlin, A. R. J . Med. Chem. 1991, 34, 717-725.
(c) Bridges, R. J .; Lovering, F. E.; Koch, H.; Cotman, C. W.; Chamberlin,
A. R. Neurosci. Lett. 1994, 174, 193-197. (d) O’Shea, R. D.; Fodera,
M. V.; Aprico, K.; Dehnes, Y.; Danbolt, N. C.; Crawford, D.; Beart, P.
M. Neurochem. Res. 2002, 27, 5-13.
(21) For previous syntheses of 18 see: (a) Yamanoi, K.; Ohfune, Y.
Tetrahedron Lett. 1988, 29, 1181-4. (b) Shimamoto, K.; Ohfune, Y.
Tetrahedron Lett. 1989, 30, 3803-4. (c) Pellicciari, R.; Natalini, B.;
Marinozzi, M.; Monahan, J . B.; Snyder, J . P. Tetrahedron Lett. 1990,
31, 139-142. (d) Shimamoto, K.; Ishida, M.; Sinozaki, H.; Ohfune, Y.
J . Org. Chem. 1991, 56, 4167-76. (e) Sagnard, I.; Sasaki, N. A.;
Chiaroni, A.; Riche, C.; Potier, P. Tetrahedron Lett. 1995, 36, 3149-
3152. (f) Rife´, J .; Ortun˜o, R. M.; Lajoie, G. A. J . Org. Chem. 1999, 64,
8958-8961.
-
from 4 in eight steps (via the RuCl3/IO4 route) in 43%
overall yield.
With the preparation of the rac-CCG-III completed,
it was envisioned that the trans-2-(2′-carboxycyclopropyl)-
(22) Bennett, D. W. Siddiquee, T. A.; Haworth, D. T.; Wallock, N.
J .; Donaldson, W. A. J . Chem. Cryst. 2003, 33, 209-211.
(23) Pappo, R.; Allen, D. S., J r.; Lemieux, R. U.; J ohnson, W. S. J .
Org. Chem. 1956, 21, 478-479.
(24) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
3000 J . Org. Chem., Vol. 69, No. 9, 2004

Reactivity of (Bicyclo[5.1.0]octadienyl)iron(1+) Cations
SCHEME 6
SCHEME 7
SCHEME 8
glycine (CCG-I) might be prepared by epimerization of
22, followed by hydrolysis.25 In an attempt to effect this
isomerization, the diester rac-22 was treated with
KHMDS in THF at -78 °C, followed by quench with
acetic acid. The trans-diester was not formed, but rather
benzoindolizidine rac-23 was afforded in moderate yield
(Scheme 5). The structural assignment of rac-23 was
based on its NMR spectral data. In particular, the
expected highfield cyclopropane signals were absent from
metrize cation 8 by addition of a chiral amine, R-meth-
ylbenzylamine, were nonproductive resulting in the
formation of (COT)Fe(CO)2PPh3 (see Table 1). Alterna-
tively, Howell has reported diastereoselective addition of
cyanide anion to a (cyclohexadienyl)iron(1+) cation bear-
ing a chiral phosphine ligand (ca. 2:1 dr).28 To this end,
4 readily underwent ligand substitution with (S)-neo-
menthyldiphenylphosphine [NMDPP] in the presence of
trimethylamine N-oxide [TMANO] to give phosphine-
ligated (-)-24 in high yield (Scheme 7). The structural
assignment of (-)-24 was aided by comparison of its 13C
NMR spectral data with that for the known28 (cyclo-
hexadiene)Fe(CO)2(NMDPP). In particular, the spectrum
of (-)-24 contained two M-CO resonances at δ 218.8 and
217.0, with both signals appearing as doublets due to
C-P coupling (J CP ) 15.6 and 10.9 Hz, respectively).
Additionally, eight signals were observed in the aromatic
region (δ 127-138) which were assigned to the diaste-
reotopic phenyl groups. Finally a singlet at δ 99.2 was
assigned to the octatetraene ligand (averaged due to
“ring-whizzing”).
1
the H NMR spectrum of 23, while the aromatic region
contained four distinct signals, whose splitting pattern
did not resemble the AA′BB′ multiplet typically observed
for phthalimide adducts. Additionally, a single olefinic
1
proton resonance was observed at δ 6.29 in the H NMR
spectrum, typical of the â-proton of an unsaturated
carbonyl compound, and a quarternary carbon signal was
observed at δ 84 in the 13C NMR spectrum corresponding
to the aminal carbon.26 The relative stereochemistry of
the tricyclic ring system could not be determined by
spectral analysis. Presumably, benzoindolizidine rac-23
arises from the deprotonation of 22 at the glycinyl C1-
center (Scheme 5). Subsequent ring opening of this anion
gives the ester enolate anion and intramolecular addition
to the phthalimide carbonyl gives 23 upon acidic workup.
It has been established that deuteration of 4 occurs
via direct attack on the ligand on the face opposite to
the metal, resulting in the stereospecifically exo-deuter-
ated product 5.8b,c Similarly, reaction of the phosphine-
ligated complex 7 with D2SO4, followed by anion meta-
thesis gave the deuterated cation d -8 (Scheme 6). Inte-
Protonation of (-)-24 with HPF6 gave the bicyclic
cation (+)-25 (Scheme 7). Attempts to characterize (+)-
1
25 by either H or 13C NMR spectroscopy proved fruitless,
due to the fluxional nature of the cation and signal
overlap. The room-temperature 31P NMR spectrum of (+)-
25 consisted of a broad singlet (δ 61.4) for the phosphine
ligand as well as a septet for the hexafluorophosphate
anion (δ -141.8). Upon cooling (5 °C), the singlet sepa-
rated into two signals (δ 65.3 and 57.5) of unequal
intensity, while at -65 °C the spectrum exhibited a total
of four signals (δ 67.2, 64.2, 57.5, and 53.8) of unequal
intensity. It should be noted that the basal-phosphine
conformers 25B and 25B′ (Scheme 8) are diastereomeric,
and therefore, a unique 31P NMR shift should be observed
for each rotamer. The observation of four signals at lower
temperature may be due to rotamers about the Fe-P
bond for each of the individual conformers.29 It was not
possible to assign which diastereomeric rotomer was the
major species.
1
gration of the H NMR spectrum of d -8 prepared in this
fashion indicated >80% D incorporation at the 8-exo
position. Beginning with d -8, the deuterated CCG-III
1
(d -18) was prepared in 31% yield. The H NMR spectra
of the deuterated intermediates d -19 and d -22 were
similar to those of the nondeuterated intermediates, with
the exception of simplification of the cyclopropyl reso-
nances. The percentage deuteration remained ca. 80%
throughout the synthesis within limits of error of 1H
NMR and MS spectral analysis.
Syn t h esis of Op t ica lly E n r ich ed cis-2-(2′-Ca r -
boxycyclop r op yl)glycin e. Because cation 8 possesses
a plane of symmetry, the above syntheses necessarily
produce rac-18. Pearson et al. have reported the diaste-
reoselective addition of chiral enolate nucleophiles to
(cycloheptadienyl)- and (cyclohexadienyl)Fe(CO)2L+ cat-
ions (20-50% de).27 Unfortunately, attempts to desym-
(27) (a) Pearson, A. J .; Blystone, S. L.; Nar, H.; Pinkerton, A. A.;
Roden, B. A.; Yoon, J . J . Am. Chem. Soc. 1989, 111, 134-144. (b)
Pearson, A. J .; Khetani, V. D.; Roden, B. J . Org. Chem. 1989, 54, 5141-
5147.
(25) For epimerization of methyl cyclopropanecarboxylates see:
Shimamoto, K.; Ohfune, Y. Synlett 1993, 919-920.
(26) For comparison, see: Yoon, U. C.; Oh, S. W.; Lee, S. M.; Cho,
S. J .; Gamlin, J .; Mariano, P. S. J . Org. Chem. 1999, 64, 4411-4418.
(28) Howell, J . A. S.; Thomas, M. J . J . Chem. Soc. 1983, 1401-1409.
(29) Howell, J . A. S.; Palin, M. G.; Tirvengadum, M.-C.; Cunning-
ham, D.; McArdle, P.; Goldschmidt, Z.; Gottlieb, H. E. J . Organomet.
Chem. 1991, 413, 269-286.
J . Org. Chem, Vol. 69, No. 9, 2004 3001

Wallock and Donaldson
SCHEME 9
face opposite to the iron to give 6-substituted (bicyclo-
[5.1.0]octa-1,4-diene)iron complexes 11 or 13. In certain
cases, the products 11/13 were unstable with respect to
elimination of a proton and the nucleophile to afford a
(cyclooctatetraene)iron product. This methodology was
applied to the synthesis of racemic cis-2-(2′-carboxycy-
clopropyl)glycine 18. Nucleophilic addition of phthalimide
to a chiral phosphine-ligated (bicyclo[5.1.0]octadienyl)-
iron cation proceeded with modest diastereoselectivity;
the product was utilized in the preparation of optically
enriched (-)-18. Our planned studies on the reactivity
of bicyclo[5.1.0]octadienes produced from cation 5, par-
ticularly with respect to [4 + 2] cycloaddition and
intramolecular olefin metathesis, will be reported in due
course.
Exp er im en ta l Section 30
Dica r bon yl(cycloocta tetr a en e)(tr ip h en ylp h osp h in e)-
ir on (7). To a solution of tricarbonyl(cyclooctatetraene)iron
(2.50 g, 10.0 mmol) and triphenylphosphine (4.00 g, 15.1 mmol)
in acetone (90 mL) was added anhydrous trimethylamine
N-oxide (1.34 g, 17.5 mmol) in one portion. Effervescence was
observed upon the addition. The reaction was stirred at rt
under a blanket of N2 and was monitored by TLC. After 60
min, additional triphenylphosphine (1.00 g, 3.77 mmol) and
TMANO (0.36 g, 4.7 mmol) were added. After another 30 min,
a final portion of TMANO (0.36 g, 4.7 mmol) was added. After
being stirred for a total of 2.25 h, the reaction mixture was
passed through a short bed of silica and the filter bed was
washed with reagent acetone until the washings were color-
less. The filtrates were concentrated, and the resulting red
solid was adsorbed to silica using acetone. The material was
purified by column chromatography (SiO2, hexanes-ethyl
acetate ) 20:1 f 10:1 f 4:1 gradient) to give 7 as a red solid
(4.46 g, 93%): mp 169-171 °C; IR (KBr) 3053, 1969, 1913,
The reaction of (+)-25 with potassium phthalimide at
0 °C gave a mixture of diastereomeric phthalimide
adducts 26 and 27 (ca. 3:1 ratio), along with the depro-
tonation product (-)-24 (Scheme 9). Unfortunately, at-
tempted separation of the diastereomers 26 and 27 was
complicated by partial decomplexation. Therefore, the
mixture of diastereomers 26/27 was decomplexed to give
optically enriched (-)-19. The absolute configurations of
diastereomers 26 and 27 were ultimately assigned by
preparation of optically enriched target CCG-III. This
level of diastereoselectivity is comparable with that
observed by Pearson for the addition of chiral enolate
nucleophiles to (cycloheptadienyl)- and (cyclohexadienyl)-
Fe(CO)2L+ cations (20-50% de, L ) CO, PPh3)27 and to
the diastereoselectivity observed by Howell for nucleo-
philic addition to (cyclohexadienyl)Fe(CO)2(NMDPP)+
cation.28 Finally, and perhaps most interestingly, there
exists an unusual temperature dependence on the prod-
uct ratio of 26/27. Performing the reaction (in Et2O)
either at ambient temperature or at 0 °C gave similar
diastereomeric ratios (ca. 3:1). When the nucleophilic
addition was carried out at -60 °C, a reversal in the
asymmetric induction was observed favoring the other
diastereomer (i.e., 26/27 ca. 1:2). No change in the ratio
of 26/27 was observed upon allowing this mixture to
stand in ether in the presence of potassium phthalimide
at 23 °C for 15 h. Thus, in this case nucleophilic addition
does not appear to be reversible. This unusual temper-
ature-dependent diastereoselectivity suggests a complex
mechanism for which a rationale is not apparent at this
time. In the absence of this rationale, we deferred an
exploration of other chiral phosphine ligands.
1481, 1433 cm-1 1H NMR (CDCl3) δ 4.95 (d, J HP ) 1.5 Hz,
;
8H), 7.37-7.43 (m, 9H), 7.47-7.57 (m, 6H); 13C NMR (CDCl3)
δ 99.4, 128.4 (d, J CP ) 9.5 Hz), 130.0 (d, J CP ) 1.7 Hz), 133.3
(d, J CP ) 10.4 Hz), 135.9 (d, J CP ) 39.2 Hz), 217.6 (d, J CP
)
14.1 Hz). Anal. Calcd for C28H23FeO2P: C, 70.31; H, 4.85.
Found: C, 70.30; H, 4.99.
Dica r b on yl(b icyclo[5.1.0]oct a d ien yl)(t r ip h en ylp h os-
p h in e)ir on (1+) Tetr a flu or obor a te (8). To an ice-cold solu-
tion of iron complex 7 (4.00 g, 8.36 mmol) in Ac2O (37 mL)
was carefully added a cold solution of aqueous tetrafluoroboric
acid (60 wt %, 7.8 mL) in Ac2O (19 mL). After several minutes
of stirring, the orange solution was added dropwise to a large
excess of ether (1300 mL). The resulting precipitate was
collected by vacuum filtration, washed with ether, and dried
in vacuo to give 8 as an orange powder (4.34 g, 92%): mp >133
°C dec; IR (KBr) 3075, 2025, 1984, 1481, 1437 cm-1; 1H NMR
(CD3OD, -20 °C) δ 1.09-1.19 (m, 1H), 1.24-1.34 (m, 1H),
2.20-2.34 (br m, 1H), 2.34-2.48 (br m, 1H), 3.63-3.79 (br m,
1H), 4.91-5.06 (br m, 1H), 5.30-5.43 (br m, 1H), 5.43-5.55
(br m, 1H), 7.45-7.68 (m, 15H), 7.71 (br t, J ≈ 5.9 Hz, 1H);
31P NMR (121 MHz, CD3OD, 16 °C) δ 58.1. Anal. Calcd for
Oxidative cleavage of (-)-19 by RuCl3/NaIO4 followed
by esterification of the intermediate diacid gave (+)-22
1
(Scheme 9). Examination of rac-22 by H NMR spectros-
C
28H24O2BF4FeP: C, 59.41; H, 4.27. Found: C, 58.99; H, 4.18.
copy in the presence of Eu(hfc)3 (CDCl3) indicated sepa-
ration of one of the methoxycarbonyl signals. By this
method, (+)-22 was determined to be 41% ee. Hydrolysis
of (+)-22, followed by treatment of the hydrochloride salt
with propylene oxide, afforded the optically enriched
Dicar bon yl(bicyclo[5.1.0]octa-2,4-dien e)(tr iph en ylph os-
p h in e)ir on (13a ). To a stirring suspension of cation 8 (0.1332
g, 0.2353 mmol) in water-saturated ether (5 mL) under
nitrogen was added NaBH3CN (0.062 g, 0.9373 mmol) in
portions over a period of 20 min. One hour after the first
addition, the mixture was diluted with ether, washed with
water followed by brine, dried, and concentrated. The residue
was purified by rapid column chromatography (SiO2, hexanes-
ethyl acetate) 30:1) to give 13a as an unstable yellow solid
(0.0560 g, 50%): mp 126-130 °C; IR (KBr) 3061, 1960, 1900,
target (-)-18. Comparison of the optical rotation ([R]20
D
) -7.9) for this product with literature values indicated
that the product was ca. 38% ee, in favor of the non-
natural configuration.
In summary, nucleophilic attack on (bicyclo[5.1.0]-
octadienyl)iron(1+) cations 4 or 7 generally occurs on the
(30) For general experimental data, see the Supporting Information.
3002 J . Org. Chem., Vol. 69, No. 9, 2004

Reactivity of (Bicyclo[5.1.0]octadienyl)iron(1+) Cations
1479, 1434, 1090, 696 cm-1; 1H NMR (CDCl3) δ -0.42 to -0.50
(m, 1H), 0.49-0.60 (m, 1H), 0.77-0.93 (m, 1H), 1.19-1.34 (m,
1H), 2.03-2.17 (m, 1H), 2.23-2.39 (m, 1H), 2.50-2.69 (m, 1H),
2.88-3.02 (m, 1H), 4.27-4.37 (m, 1H), 4.50-4.60 (m, 1H),
7.31-7.41 (m, 9H), 7.41-7.51 (m, 6H); 13C NMR (CDCl3) δ
14.9, 15.6, 17.5, 25.0, 60.0, 61.5, 85.7, 88.0, 127.9 (d, J CP ) 9.2
Hz), 129.2 (d, J CP ) 1.7 Hz), 132.8 (d, J CP ) 10.4 Hz), 135.6
(d, J CP ) 36.9 Hz). A satisfactory elemental analysis was not
obtained for this compound.
1H), 4.27-4.37 (m, 1H), 4.51-4.61 (m, 1H), 7.29-7.41 (m, 9H),
7.41-7.53 (6H).
15: mp >122 °C dec; IR (KBr) 3062, 2950, 2923, 1967, 1916,
1
1708, 1480, 1434, 1091 cm-1; H NMR (CDCl3) δ 0.75 (t, J )
7.5 Hz, 3H), 1.17-1.32 (m, 1H), 1.49-1.64 (m, 1H), 2.21-2.31
(m, 1H), 2.31-2.42 (m, 1H), 2.61 (ddd, J ) 1.9, 5.4, 15.7 Hz,
1H), 2.79-2.88 (m, 1H), 2.86-2.96 (m, 1H), 4.67-4.78 (m, 1H),
4.78-4.88 (m, 1H), 7.37-7.50 (m, 15H); 13C NMR (CDCl3) δ
12.0, 27.1, 45.0, 50.6, 55.32, 55.33, 58.0, 89.3, 89.8, 128.5 (d,
J CP ) 9.2 Hz), 130.0 (d, J CP ) 1.7 Hz), 133.2 (d, J CP ) 10.4
Hz), 134.9 (d, J CP ) 38.6 Hz), 207.7. Anal. Calcd for C29H27O3-
PFe: C, 68.25; H, 5.33. Found: C, 68.45; H, 5.39.
Tr ica r b on yl(6-m e t h ylb icyclo[5.1.0]oct a -2,4-d ie n e )-
ir on (11b). To a stirring mixture of CuBr-SMe2 (0.3331 g,
1.604 mmol) in freshly distilled THF (20 mL) at -65 °C was
added a solution of methyllithium (2.0 mL, 1.6 M in ether, 3.2
mmol). The solution was stirred for 1 h, and then solid cation
5 (0.1779 g, 0.5361 mmol) was added in a single portion. The
mixture was stirred for 2 h, after which time it was allowed
to warm to rt for 30 min. The cold mixture was poured onto
saturated aqueous NH4Cl and extracted with Et2O. The
combined extracts were washed with brine, dried, and filtered
through a short column of alumina. The filtrate was concen-
trated to give 11b as a low-melting, volatile yellow solid
(0.1085 g, 78%): mp < 35 °C; IR (neat) 2962, 2041, 1971, 1452
Tr ica r bon yl[d im eth yl 2-(Bicyclo[5.1.0]octa -3′,5′-d ien -
2′-yl)p r op a n ed ioa te]ir on (11c). To a cold stirring solution
of dimethyl malonate (0.160 mL, 1.36 mmol) in dry ether (4.5
mL) was added a solution of n-BuLi (0.54 mL, 2.5 M in
hexanes, 1.4 mmol). The mixture was stirred for 10 min at rt,
at which time cation 5 (0.400 g, 1.21 mmol) was added in one
portion. After 2 h, the orange reaction mixture was quenched
with water and the biphasic solution was extracted with ether
until the extractions were colorless. The combined organic
layers were dried and concentrated. Purification of the residue
by column chromatography (Al2O3, hexanes-ethyl acetate )
10:1) gave 11c as a yellow crystalline solid (0.283 g, 62%): mp
95-96 °C; IR (KBr) 3005, 2044, 1986, 1952, 1754, 1727, 613
1
cm-1; H NMR (CDCl3) δ -0.38 (dddd, J ) 0.6, 4.1, 4.7, 6.9
Hz, 1H), 0.55 (ddd, J ) 3.8, 8.2, 9.4 Hz, 1H), 0.77-0.90 (m,
1H), 1.13 (d, J ) 6.7 Hz, 3H), 1.31-1.42 (m, 1H), 2.43-2.56
(m, 1H), 2.97 (tdd, J ) 1.1, 4.1, 8.2 Hz, 1H), 3.66 (ddd, J )
1.5, 7.0, 8.3 Hz, 1H), 4.97 (dddd, J ) 0.6, 1.2, 4.7, 7.9 Hz, 1H),
5.10 (ddd, J ) 1.6, 4.9, 8.2 Hz, 1H); 13C NMR (CDCl3) δ 15.58,
15.62, 21.2, 26.7, 28.7, 64.2, 69.1, 86.1, 87.5, 211.6. Anal. Calcd
for C12H12O3Fe: C, 55.42; H, 4.65. Found: C, 55.62; H, 4.69.
1
cm-1; H NMR (CDCl3) δ -0.26 to -0.35 (m, 1H), 0.60-0.70
(m, 1H), 0.90-1.04 (m, 1H), 1.41-1.53 (m, 1H), 2.83-2.90 (m,
1H), 3.20-3.26 (m, 2H), 3.66 (br t, J ≈ 7.6 Hz, 1H), 3.72 (s,
3H), 3.79 (s, 3H), 4.94-5.02 (m, 1H), 5.14-5.21 (m, 1H); 13C
NMR (CDCl3) δ 16.6, 17.0, 18.1, 34.9, 52.9, 53.0, 61.0, 61.8,
63.7, 87.3, 87.7, 167.4, 168.2, 209.6. A satisfactory elemental
analysis was not obtained for this compound.
Dica r bon yl(η4-7-eth ylcycloh ep ta -1,3,5-tr ien e)(tr ip h e-
n ylph osph in e)ir on (13b) an d Dicar bon yl(6-m eth ylbicyclo-
[5.1.0]octa -2,4-d ien e)(tr ip h en ylp h osp h in e)ir on (14b). The
reaction of 8 (0.315 g, 0.556 mmol) with CH3Li/CuBr was
carried out in the same fashion as for the reaction of 5 with
CH3Li/CuBr. Purification of the residue by column chroma-
tography (Al2O3, hexanes-ethyl acetate ) 20:1) gave an
inseparable mixture of triene 14b and diene 13b (0.209 g, 76%)
in a ratio of ∼7:2 as determined by integration of the 1H NMR
spectrum. Data for 14b as a mixture with 13b: 1H NMR
(CDCl3) δ 0.78 (t, J ) 7.5 Hz, 3H), 1.26-1.42 (m, 2H), 2.32-
2.49 (m, 3H), 4.71-4.84 (m, 2H), 5.01-5.09 (m, 1H), 5.73-
5.83 (m, 1H), 7.34-7.41 (m, 9H), 7.42-7.51 (m, 6H); 13C NMR
(CDCl3) δ 11.8, 31.8, 44.0, 53.5, 64.2, 88.2, 94.7, 128.3 (d, J CP
) 9.2 Hz), 128.5, 129.7 (d, J CP ) 2.3 Hz), 130.0, 133.2 (d, J CP
) 11.0 Hz), 135.7 (d, J CP ) 38.0 Hz), 217.9 (d, J CP ) 15.0 Hz),
218.3 (d, J CP ) 12.7 Hz). This mixture was used in the next
reaction without further characterization.
Dica r bon yl[d im eth yl 2-(bicyclo[5.1.0]octa -3′,5′-d ien -2′-
yl)p r op a n ed ioa te](tr ip h en ylp h osp h in e)ir on (13c): The
reaction of 8 (0.302 g, 0.533 mmol) with lithium dimethyl
malonate was carried out in a fashion similar to the reaction
of 5 with lithium dimethyl malonate. Purification of the
residue by column chromatography (Al2O3, hexanes-ethyl
acetate ) 8:1 f 4:1 gradient) gave 13c as a yellow foam (0.200
g, 61%): mp >49 °C dec; IR (KBr) 2951, 1971, 1913, 1735,
1434, 697 cm-1 1H NMR (CDCl3) δ -0.38 to -0.49 (m, 1H),
;
0.46-0.57 (m, 1H), 0.88-1.07 (m, 1H), 1.37-1.51 (m, 1H),
2.23-2.38 (m, 1H), 2.94-3.06 (m, 1H), 3.09 (br d, J ) 10.0
Hz, 1H), 3.22-3.33 (m, 1H), 3.58 (s, 3H), 3.68 (s, 3H), 4.36-
4.56 (m, 2H), 7.32-7.46 (m, 15H); 13C NMR (CDCl3) δ 15.9,
17.2, 18.6, 35.5, 52.67, 52.73, 59.1, 60.6, 62.4, 87.3, 87.7, 128.0
(d, J CP ) 9.2 Hz), 129.4 (d, J CP ) 1.7 Hz), 132.8 (d, J CP ) 10.4
Hz), 135.1 (d, J CP ) 37.4 Hz), 167.7, 168.3. Anal. Calcd for
C
33H31O6PFe: C, 64.93; H, 5.12. Found: C, 65.40; H, 5.21.
Ch em ica l Der iva tiza tion /Sep a r a tion of 13b a n d 14b.
To a stirring mixture of 13b and 14b (0.209 g, 0.423 mmol,
7:2, respectively) in pyridine (1.5 mL) and THF (2.8 mL) was
added a solution of OsO4 in toluene (3.2 mL, 0.20 M, 0.64
mmol). After 24 h, saturated sodium bisulfite was added, and
the black mixture was stirred for an additional 16 h and then
filtered through a bed of filter-aid. The filter bed was washed
with ethyl acetate, the filtrate and washings were combined,
and the biphasic solution was transferred to a separatory
funnel. The aqueous layer was removed, and the organic phase
was washed with water followed by brine and concentrated.
The residue was purified by column chromatography (SiO2,
hexanes-ethyl acetate ) 20:1 f 8:1 f 1:1 gradient) to give
the unreacted diene 13b (Rf ) 0.42, hexanes-ethyl acetate )
8:1) as a viscous yellow oil (0.0303 g, ∼66% recovery based
upon theoretical quantity) followed by dienone 15 (Rf ) 0.20,
hexanes-ethyl acetate ) 8:1) as a light yellow foam (0.0829
g, 49% based upon theoretical quantity). Complex 15 was
recrystallized from pentane-ethyl acetate.
Rea ction of 8 w ith (S)-R-Meth ylben zyla m in e. To a
stirring mixture of 8 (0.567 g, 1.00 mmol) in dry Et2O (10 mL)
under N2 was added (S)-R-methylbenzylamine (0.19 g, 0.16
mmol). After 45 min, additional (S)-R-methylbenzylamine (0.19
g, 0.16 mmol) was added to the reaction mixture. After being
stirred for an additional 30 min, the red mixture was trans-
ferred to a separatory funnel and washed with water. The
organic phase was dried and filtered through a short bed of
silica gel using Et2O to wash the pad. The filtrate and
washings were combined and concentrated. Purification of the
residue by column chromatography (SiO2, hexanes-ethyl
acetate ) 10:1) gave 7 as a red solid (0.381 g, 80%).
Tr ica r b on yl(6-e t h oxyb icyclo[5.1.0]oct a -2,4-d ie n e )-
ir on (11d ). A solution of cation 5 (0.402 g, 1.21 mmol) and
powdered anhydrous sodium acetate (0.41 g, 4.9 mmol) in
absolute ethanol (10 mL) was stirred for 45 min, during which
time the reaction mixture became orange. The mixture was
filtered, and the filtrate was concentrated. Purification of the
residue by column chromatography (Al2O3, hexanes-ethyl
acetate ) 40:1) gave 11d (0.228 g, 65%) as an unstable orange
13b: IR (neat): 3058, 3001, 2955, 2919, 2866, 1965, 1907,
1480, 1434, 1091 cm-1; 1H NMR (CDCl3) δ -0.45 to -0.57 (m,
1H), 0.34-0.46 (m, 1H), 0.75-0.92 (m, 1H), 1.03 (d, J ) 6.5
Hz, 3H), 1.23-1.37 (m, 1H), 2.40-2.60 (m, 2H), 2.85-2.97 (m,
oil: IR (Neat) 2977, 2866, 2043, 1964, 1381, 1071 cm-1 1H
;
NMR (CDCl3) δ 0.03-0.12 (m, 1H), 0.76 (ddd, J ) 4.1, 8.5, 9.1
Hz, 1H), 1.00-1.12 (m, 1H), 1.22 (t, J ) 7.0 Hz, 3H), 1.52-
J . Org. Chem, Vol. 69, No. 9, 2004 3003

Wallock and Donaldson
1.64 (m, 1H), 3.02 (dd, J ) 4.5, 8.1 Hz, 1H), 3.44-3.72 (m,
3H), 4.31 (dd, J ) 4.5, 7.5 Hz, 1H), 5.09 (ddd, J ) 0.8, 5.0, 7.9
Hz, 1H), 5.36 (ddd, J ) 1.5, 5.0, 7.9 Hz, 1H); 13C NMR (CDCl3)
δ 16.6, 18.5, 18.6, 19.9, 61.4, 63.6, 63.8, 75.8, 87.5, 89.3, 209.7.
A satisfactory elemental analysis was not obtained for this
compound.
stirring suspension of cation 8 (4.33 g, 7.65 mmol) in dry ether
(175 mL) under N2 was added potassium phthalimide (10.11
g, 53.49 mmol) in portions over a 24 h period. Periodically
during this time, the orange ethereal mother liquors were
decanted from any solid and the reaction flask was charged
with additional ether (150 mL). This was repeated until the
mother liquors were colorless. The resulting ethereal layers
were combined and concentrated to give rac-13f as an orange
solid (4.81 g, >99%), which was used in the next reaction
without further purification. An analytically pure sample could
be prepared by chromatography (SiO2, hexanes-ethyl acetate
) 4:1) to give rac-13f as a yellow foam, at the expense of
reduced yields due to elimination of potassium phthalimide.
The reaction time could be dramatically reduced from ca. 24-
36 h to ca. 1.5 h by using water-saturated ether, with no
change in the yield of 13f: mp >82 °C dec; IR (KBr) 3055,
Rea ction of 8 w ith Eth a n ol. Reaction of 8 (0.401 g, 0.708
mmol) with ethanol and powdered anhydrous sodium acetate
was carried out in a fashion similar to the reaction of 5. During
the 90 min of reaction time, the mixture became red in color.
The reaction mixture was concentrated, and the residue was
purified by column chromatography (SiO2, hexanes-ethyl
acetate ) 4:1) to give 7 as a red solid (0.29 g, 86%), as indicated
1
by H NMR spectral analysis.
Tr ica r bon yl(6-eth a n esu lfa n ylbicyclo[5.1.0]octa -2,4-d i-
en e)ir on (11e). To a mixture of 5 (0.3334 g, 1.005 mmol) and
anhydrous sodium acetate (0.3321 g, 4.008 mmol) in ether (10
mL) was added ethanethiol (1.2 mL, 16 mmol). After 90 min,
the mixture was filtered through a short bed of Al2O3, and the
filter pad was washed with ether. The filtrate and washings
were combined and concentrated to give 11e as an unstable
red-brown oil (0.2602 g, 85%): IR (neat) 2972, 2042, 1966, 1455
1
2954, 1972, 1914, 1764, 1708 cm-1; H NMR (CDCl3) δ 0.52-
0.61 (m, 2H), 1.00-1.13 (m, 1H), 1.45-1.56 (m, 1H), 2.27-
2.37 (m, 1H), 2.83-2.96 (m, 1H), 4.53-4.64 (m, 1H), 4.83-
4.96 (m, 1H), 5.44 (ddd, J ) 0.9, 3.8, 7.6 Hz, 1H), 7.34-7.40
(m, 9H), 7.41-7.50 m, 6H), 7.63-7.70 (AA′BB′, 2H), 7.74-7.81
(AA′BB′, 2H); 13C NMR (C6D6) δ 18.10, 18.12, 19.1, 51.4, 57.0,
1
cm-1; H NMR (CDCl3) δ -0.05-0.04 (m, 1H), 0.75-0.85 (m,
60.2, 87.0, 92.2, 122.7, 128.5 (d, J CP ) 9.2 Hz), 129.8 (d, J CP
2.0 Hz), 132.8, 133.1, 133.4 (d, J CP ) 10.4 Hz), 136.0 (d, J CP
)
)
1H), 1.05-1.19 (m, 1H), 1.29 (t, J ) 7.5 Hz, 3H), 1.51-1.63
(m, 1H), 2.63-2.79 (m, 2H), 3.22-3.31 (m, 1H), 3.65-3.76 (m,
2H), 4.99-5.08 (m, 1H), 5.17-5.27 (m, 1H); 13C NMR (CDCl3)
δ 15.7, 18.6, 18.9, 20.6, 26.4, 43.5, 63.5, 63.8, 87.1, 87.3, 209.8.
Anal. Calcd for C13H14FeO3S: C, 51.00; H, 4.61. Found: C,
51.25; H, 4.60.
38.0 Hz), 168.1. Anal. Calcd for C36H28FeNO4P: C, 69.13; H,
4.51; N, 2.24. Found: C, 69.28; H, 4.38; N, 2.16.
N-(Bicyclo[5.1.0]octa -3,5-d ien -2-yl)p h th a lim id e (r a c-
19). To a stirring solution of the unpurified complex rac-13f
(6.35 g, 9.96 mmol) in acetonitrile (230 mL) was added, in one
portion, ammonium cerium nitrate [CAN] (5.93 g, 10.7 mmol).
After 1 h, TLC monitoring indicated the presence of unreacted
complex rac-13f. Additional CAN (2.82 g, 5.07 mmol) was
added and the mixture was stirred for another 1 h. The
reaction mixture was filtered through a small bed of silica gel
and the filter bed washed with reagent acetone. The filtrates
were concentrated, and the resultant orange solid was taken
up in CH2Cl2 and washed with water. The organic phase was
separated, and the aqueous phase was back-extracted with
additional CH2Cl2. The organic solutions were combined and
concentrated, and the resulting solid was purified by column
chromatography (SiO2, hexanes-ethyl acetate ) 10:1 f 4:1
gradient) to give rac-19 as a colorless solid (1.87 g, 75%): mp
Dica r bon yl(6-eth a n esu lfa n ylbicyclo[5.1.0]octa -2,4-d i-
en e)(tr ip h en ylp h osp h in e)ir on (13e). The reaction of 8
(0.4247 g, 0.7502 mmol) with ethanethiol and NaOAc was
carried out in a fashion similar to the reaction of 5. After being
stirred for 4.5 h, the green solution was concentrated using a
stream of N2. The viscous material was dissolved in fresh ether
and washed with water followed by brine. The organic solution
was dried, filtered through a short bed of alumina, and
concentrated to give 13e as a yellow foam (0.3855 g, 95%),
which was unstable toward extended exposure to common
chromatographic adsorbents: mp >34 °C dec; IR (KBr) 3057,
2969, 1968, 1909, 1480, 1434, 1090, 696 cm-1; 1H NMR (C6D6)
δ 0.12-0.20 (m, 1H), 0.59-0.69 (m, 1H), 1.10-1.23 (m, 1H),
1.14 (t, J ) 7.3 Hz, 3H), 1.43-1.55 (m, 1H), 2.39 (q, J ) 7.3
Hz, 2H), 2.91-3.01 (m, 1H), 3.13-3.23 (m, 1H), 4.01 (dd, J )
4.6, 7.5 Hz, 1H), 4.34-4.43 (m, 1H), 4.51-4.60 (m, 1H), 6.93-
7.04 (m, 9H), 7.47-7.56 (m, 6H); 13C NMR (C6D6) δ 16.8, 18.7,
20.4, 22.3, 26.8, 45.2, 61.9, 64.1, 87.7, 88.2, 128.9 (d, J CP ) 9.2
Hz), 130.2 (d, J CP ) 2.3 Hz), 133.7 (d, J CP ) 10.4 Hz), 136.4
(d, J CP ) 36.9 Hz). Anal. Calcd for C30H29FeO2PS: C, 66.67;
H, 5.41. Found: C, 66.33; H, 5.49.
1
162-163 °C; IR (KBr) 3023, 1765, 1711, 1607, 1381 cm-1; H
NMR (CDCl3) δ 0.99 (dddd, J ) 0.9, 4.7, 8.5, 8.8 Hz, 1H), 1.22-
1.34 (m, 1H), 1.85-1.95 (m, 1H), 2.25 (ddd, J ) 5.6, 5.6, 5.6
Hz, 1H), 5.43-5.62 (m, 3H), 5.83 (ddd, J ) 2.8, 6.0, 11.5 Hz,
1H), 6.23 (dd, J ) 7.5, 11.5 Hz, 1H), 7.69-7.76 (AA′BB′, 2H),
7.82-7.89 (AA′BB′, 2H); 13C NMR (CDCl3) δ 9.0, 15.2, 43.8,
49.8, 122.6, 123.4, 126.2, 126.9, 132.1, 134.1, 135.2, 167.9; GC/
MS m/z 251. Anal. Calcd for C16H13NO2: C, 76.48; H, 5.21; N,
5.57. Found: C, 76.20; H, 5.28; N, 5.48.
Tr icar bon yl[N-(bicyclo[5.1.0]octa-3′,5′-dien -2′-yl)ph th al-
im id e]ir on (11f). A solution of cation 5 (0.509 g, 1.53 mmol)
and potassium phthalimide (0.58 g, 3.1 mmol) in reagent
acetone (35 mL) was stirred for 1 h, during which time the
reaction mixture turned brown. The mixture was filtered
though filter-aid, and the filtrate was concentrated to give a
red residue. The residue was purified by column chromatog-
raphy (Al2O3, hexanes-ethyl acetate ) 100% hexanes f 40:1
f 20:1 f 10:1 gradient) to give 4 (0.044 g, 12%) identified by
1H NMR spectroscopy, followed by 11f (0.245 g, 41%) as a
sticky yellow foam: IR (KBr) 3007, 2044, 1964, 1767, 1708
D i c a r b o n y l(7-d e u t e r i o b i c y c lo [5.1.0]o c t a d i e n y l)-
(tr ip h en ylp h osp h in e)ir on (1+) Tetr a flu or obor a te (d -8).
To an ice-cold stirring solution of 7 (1.2814 g, 2.6790 mmol)
in dry ether (13.5 mL) was added a solution of D2SO4 in D2O
(3.3 g, 98 wt %, 33 mmol of D2SO4) over a period of 5 min. The
mixture was stirred for 20 min during which time the starting
material dissolved and a yellow precipitate formed. A solution
of NH4BF4 (0.595 g, 5.68 mmol) in water (15.4 mL) was then
added and the mixture stirred for an additional 30 min. The
solid was collected by filtration, washed with water followed
by ether, and dried in vacuo for an extended period of time to
give d -8 as a yellow-orange powder (1.4516 g, 96%): mp >136
°C dec; IR (KBr) 3076, 2025, 1984, 1481, 1436 cm-1; 1H NMR
(CD3OD, 17 °C) δ 1.10-1.18 (m, 1H), 2.34 (br s, 2H), 5.14 (br
s, 2H), 7.45-7.68 (m, 15H), 7.71 (br t, J ≈ 6.4 Hz, 1H). A
residual multiplet was also present at 1.26-1.33 due to
incomplete deuteration (>80% by 1H NMR) of the exo position.
At ambient temperature, 2 H’s have coalesced into the base-
line. Anal. Calcd for C28H23DBF4FeO2P‚0.1H2O: C, 59.11; H,
4.46. Found: C, 58.80; H, 4.76.
1
cm-1; H NMR (C6D6) δ 0.38 (ddd, J ) 3.8, 8.5, 8.8 Hz, 1H),
0.66-0.74 (m, 1H), 0.78-0.92 (m, 1H), 1.03-1.16 (m, 1H), 2.33
(dd, J ) 3.8, 7.6 Hz, 1H), 3.19 (t, J ) 7.3 Hz, 1H), 4.45-4.55
(m, 1H), 4.98-5.08 (m, 1H), 5.38 (dd, J ) 3.8, 7.6 Hz, 1H),
6.87-6.96 (AA′BB′, 2H), 7.42-7.52 (AA′BB′, 2H); 13C NMR
(C6D6) δ 18.7, 19.9, 20.0, 50.9, 58.8, 64.1, 87.2, 92.3, 123.3,
132.9, 133.9, 167.9, 210.7. Anal. Calcd for C19H13FeNO5‚0.1
H2O: C, 58.07; H, 3.39; N, 3.56. Found: C, 57.74; H, 3.73; N,
3.48.
Dicar bon yl[N-(bicyclo[5.1.0]octa-3′,5′-dien -2′-yl)ph th al-
im id e](tr ip h en ylp h osp h in e)ir on (r a c-13f). To a rapidly
3004 J . Org. Chem., Vol. 69, No. 9, 2004

Reactivity of (Bicyclo[5.1.0]octadienyl)iron(1+) Cations
N-(7-Deu t er iob icyclo[5.1.0]oct a -3,5-d ien -2-yl)p h t h a l-
im id e (d -19). The reaction of cation d -8 (1.2960 g, 2.2852
mmol) with potassium phthalimide in water-saturated ether
was carried out in a fashion similar to the reaction of 8 with
potassium phthalimide. The crude d -13f was dissolved in
acetonitrile and treated with CAN in a fashion similar to the
decomplexation of 13f. After workup, the residue was purified
by column chromatography (SiO2, hexanes-ethyl acetate )
10:1 f 4:1 gradient) to give d -19 as a colorless solid (0.4248
g, 74%): mp 163-164 °C; IR (KBr) 3024, 1765, 1712, 1606,
1382 cm-1; 1H NMR (CDCl3) δ 0.98 (ddd, J ) 0.9, 8.2, 9.1 Hz,
1H), 1.22-1.34 (m, 1H), 1.85-1.95 (m, 1H), 5.43-5.62 (m, 3H),
5.84 (ddd, J ) 2.6, 5.9, 11.5 Hz, 1H), 6.23 (dd, J ) 7.5, 11.5
filtered, and ether was used to wash the residual solid until
the washings were colorless. The organic filtrates were com-
bined and concentrated to give a red foam (∼1.57 g). The 1H
NMR spectrum revealed this to be a mixture of two diaster-
eomeric iron complexes 26 and 27 (26/27 ) 3:1) along with
(-)-24 produced by via elimination of phthalimide. Decom-
plexation of the mixture of 26 and 27 (1.57 g) with CAN was
carried out in a fashion similar to the decomplexation of 13f.
The reaction mixture was concentrated to ∼1/2 volume, poured
onto water, and extracted with ether followed by ethyl acetate.
The extractions were combined, dried and concentrated to give
a solid. Purification of the solid by column chromatography
(SiO2, hexanes-ethyl acetate ) 10:1 f 4:1 gradient) gave diene
1
Hz, 1H), 7.69-7.76 (AA′BB′, 2H), 7.82-7.90 (AA′BB′, 2H); 13
C
(-)-19 as a white solid (0.1682 g, 31%). The H NMR spectral
data for (-)-19 was identical with that obtained for rac-19:
NMR (CDCl3) δ 9.3 (t, J CD ) 24.7 Hz), 15.5, 44.0, 50.0, 122.2,
123.0, 125.8, 126.6, 131.7, 133.7, 134.8, 167.3; GC/MS m/z 252.
Compound d -19 was found to have 80% d-incorporation by 1H
NMR spectral analysis and 79% d-incorporation by GC/MS
analysis (M+). Anal. Calcd for C16H12DNO2: C, 76.17; H, 5.59;
N; 5.55. Found: C, 76.26; H, 5.37; N, 5.64.
mp 152-156 °C; [R]20 ) -62.4 (c 0.314, CHCl3).
D
N-(3,4,5,6-Tet r a h yd r oxyb icyclo[5.1.0]oct -2-yl)p h t h a l-
im id e (r a c-20a /b). To a stirring solution of the diene rac-19
(1.05 g, 4.18 mmol) in acetone (8.40 mL) was added a solution
of N-methylmorpholine N-oxide (1.54 g, 12.8 mmol) in water
(1.00 g) followed by a solution of OsO4 in toluene (0.20 M, 3.00
mL, 0.60 mmol, 14 mol %). After being stirred at rt for 24 h,
the reaction was quenched by the addition of Na2S2O5 (1.10
g). The black mixture was stirred for an additional 45 min,
concentrated, and adsorbed to silica using methanol. Purifica-
tion by column chromatography (SiO2, CH2Cl2-methanol )
10:1) gave partially separated diastereomers rac-20a and rac-
20b (a /b ≈ 2:1 by 1H NMR spectral integration) contaminated
with N-methylmorpholine. The impurity could be removed by
washing with ether followed by CH2Cl2 to give the products
as whites solids (total 20a + 20b: 0.99 g, 74%).
r a c-20a : mp 229-230 °C; IR (KBr) 3404, 3011, 2916, 1759,
1702, 1387 cm-1; 1H NMR (CD3OD) δ 0.74-0.89 (m, 2H), 1.19
(dddd, J ) 2.6, 6.6, 9.2, 9.2 Hz, 1H), 1.39 (dddd, J ) 4.8, 7.0,
9.2, 9.2 Hz, 1H), 3.54 (dd, J ) 2.2, 2.2 Hz, 1H), 4.10-4.14 (m,
1H), 4.27 (dd, J ) 1.8, 11.0 Hz, 1H), 4.44-4.50 (m, 1H), 5.16
(dd, J ) 2.6, 10.6 Hz, 1H), 7.76-7.89 (m, 4H); 13C NMR (CD3-
OD, “doublets” due to slowed rotation of the phthalimide
substituent shown in parentheses) δ 6.7, 18.6, 20.7, 50.7, 68.7,
69.6, 76.0, 80.9, 123.7 (124.1), 133.2 (133.6), 135.1 (135.2),
169.8 (170.2). Anal. Calcd for C16H17NO6‚0.2H2O: C, 59.51; H,
5.43; N, 4.34. Found: C, 59.56; H, 5.49; N, 4.35.
Dica r bon yl(cycloocta tetr a en e)((S)-n eom en th yld ip h e-
n ylp h osp h in e)ir on ((-)-24). The ligand substitution of tri-
carbonyl(cyclooctatetraene)iron (0.8899 g, 3.647 mmol) with
(S)-neomenthyldiphenylphosphine (1.0019 g, 3.0899 mmol)
was carried out in a fashion similar to the preparation of 7.
The reaction mixture was filtered through a small bed of
alumina using ether to wash the filter pad until the filtrates
were colorless. The combined organic material was concen-
trated and purified by column chromatography (Al2O3, basic-
Brockmann I, hexanes-ether ) 100% f 60:1 f 40:1 gradient
followed by hexanes-ethyl acetate ) 20:1) to yield (-)-24 as
a rust-colored foam (1.5209 g, 91%): mp >59 °C dec; IR (KBr)
2955, 1974, 1912, 1432, 1090, 695 cm-1; [R]20D ) -1.1 × 103 (c
1
0.0588, CHCl3); H NMR (CDCl3) δ 0.18 (d, J ) 7.0 Hz, 3H),
0.88 (d, J ) 6.8 Hz, 3H), 1.10 (d, J ) 7.0 Hz, 3H), 1.21-1.33
(m, 1H), 1.60-1.82 (m, 4H), 1.86-2.11 (m, 3H), 2.36-2.45 (m,
1H), 2.94-3.07 (m, 1H), 4.80 (d, J HP ) 1.2 Hz, 8H), 7.27-7.35
(m, 5H), 7.42-7.51 (m, 3H), 7.88-7.97 (m, 2H); 13C NMR
(DEPT, CDCl3) δ 18.4 (s, CH3), 20.7 (s, CH3), 21.6 (d, J CP
)
12.1 Hz, CH2), 24.5 (s, CH3), 28.6 (d, J CP ) 6.3 Hz, CH), 29.3
(s, CH2), 31.1 (d, J CP ) 4.0 Hz, CH), 31.5 (d, J CP ) 5.8 Hz,
CH2), 38.4 (d, J CP ) 21.9 Hz, CH), 40.2 (s, CH), 99.2 (s, CH),
127.4 (d, J CP ) 9.2 Hz, CH), 128.0 (d, J CP ) 8.1 Hz, CH), 128.3
(s, CH), 129.3 (d, J CP ) 7.5 Hz, CH), 130.1 (s, CH), 131.3 (d,
r a c-20b: mp 241-244 °C; IR (KBr) 3494, 3460, 3347, 3277,
1
3008, 2942, 1755, 1697, 1381 cm-1; H NMR (CD3OD) δ 0.63
J CP ) 29.4 Hz, C), 136.2 (d, J CP ) 9.8 Hz, CH), 137.5 (d, J CP
)
(ddd, J ) 5.3, 9.0, 9.0 Hz, 1H), 1.02-1.23 (m, 2H), 1.53-1.63
(m, 1H), 4.00 (s, 2H), 4.34 (d, J ) 3.5 Hz, 1H), 4.59 (d, J )
10.6 Hz, 1H), 5.05 (dd, J ) 2.9, 11.2 Hz, 1H), 7.75-7.87 (m,
4H); 13C NMR (CD3OD) δ 7.2, 18.0, 19.7, 51.6, 66.2, 68.6, 75.8,
76.3, 123.9 (br), 133.2 (br), 135.1 (br), 170.1 (br).
33.4 Hz, C), 217.0 (d, J CP ) 10.9 Hz, C), 218.8 (d, J CP ) 15.6
Hz, C). The product was contaminated with traces of NMDPP,
and thus a satisfactory combustion analysis was not obtained.
This product was used in the next reaction without further
purification.
1,3-Dih yd r o-R-[2-(ca r boxy)cyclop r op yl]-1,3-d ioxo-2H-
isoin d ole-2-a cetic Acid (r a c-21). To a stirring solution of
tetrols rac-20a /b (0.55 g, 1.7 mmol) in THF (7.3 mL) was added
water (7.3 mL) followed by sodium periodate (1.14 g, 5.22
mmol). After 10 min of stirring at rt, the mixture had
thickened due to the formation of sodium iodate, and ad-
ditional 50% aqueous THF (6 mL) was added. After 3 h, ethyl
acetate and water were added to the reaction mixture. The
biphasic solution was transferred to a separatory funnel, the
organic layer removed, and the aqueous layer was extracted
with ethyl acetate. The combined organic layers were dried
and concentrated to give a light yellow tacky foam (0.43 g,
Dica r bon yl(bicyclo[5.1.0]octa d ien yl)((S)-n eom en th yl-
d ip h en ylp h osp h in e)ir on (1+) Hexa flu or op h osp h a te ((+)-
25). To an ice-cold stirring mixture of chiral complex (-)-24
(1.1086 g, 2.0512 mmol) in Ac2O (7.6 mL) was added an ice-
cold solution of aqueous HPF6 (60 wt %, 4.0 mL, 27 mmol) in
Ac2O (4.0 mL). The solution was allowed to warm to rt and
stir for 10 min, at which time it was added dropwise to a
beaker containing distilled water (100 mL). The resulting
precipitate was harvested by vacuum filtration on a sintered
glass funnel. The solid was washed with distilled water
followed by pentane. The damp material was dried in vacuo
for several days to afford (+)-25 as a light yellow amorphous
solid (1.2243 g, 87%): mp >100 °C dec; IR (KBr) 2957, 2036,
1
97%): IR (KBr) 3108, 2855, 2743, 1774, 1718, 1378 cm-1; H
NMR (CDCl3) δ 1.59-1.74 (m, 2H), 2.15 (dddd, J ) 3.5, 5.3,
7.9, 8.4 Hz, 1H), 2.52 (dddd, J ) 7.0, 8.4, 8.4, 11.0 Hz, 1H),
4.74 (d, J ) 11.0 Hz, 1H), 7.72-7.79 (AA′BB′, 2H), 7.83-7.90
(AA′BB′, 2H), 9.64 (d, J ) 3.5 Hz, 1H), 9.76 (s, 1H); 13C NMR
(CDCl3) δ 14.7, 22.1, 25.0, 57.7, 123.9, 131.7, 134.6, 167.4,
194.7, 199.6. This compound was unstable to column chroma-
tography on silica gel and was used in the next step without
further purification or characterization. To a vigorously stir-
ring ice-cold solution of the above crude dialdehyde (0.53 g,
2.1 mmol) in acetone (5.2 mL) was added dropwise J ones
1993, 1436, 1092, 699 cm-1; [R]20 ) +91 (c 0.0672, CH3CN).
D
Anal. Calcd for C32H38F6FeO2P2: C, 55.99; H, 5.58. Found: C,
56.26; H, 5.38. This compound was used in the subsequent
reaction without further characterization.
Op tica lly En r ich ed N-(Bicyclo[5.1.0]octa -3,5-d ien -2-
yl)p h th a lim id e ((-)-19). To a cold (1-3 °C) rapidly stirring
suspension of cation (+)-25 (1.5040 g, 2.1910 mmol) in ether
(100 mL) was added excess potassium phthalimide (2.50 g, 13.2
mmol) in one portion. After 30 h, the red-orange mixture was
J . Org. Chem, Vol. 69, No. 9, 2004 3005

Wallock and Donaldson
reagent (2.8 mL). After the addition, the reaction mixture was
warmed to rt and stirred for 75 min. The reaction was
quenched with methanol (0.80 mL) and stirred for an ad-
ditional 15 min, at which time it was partitioned between brine
and CH2Cl2. Additional water was added to dissolve the
remaining blue precipitate. The organic layer was removed,
and the aqueous layer extracted with CH2Cl2 followed by ethyl
acetate. The combined organic layers were dried and concen-
trated to give rac-21 as a white solid (0.54 g, 91%). An
analytically pure sample was prepared by recrystallization
from water: mp 224-227 °C; IR (KBr) 3107, 2933, 1770, 1701,
1394 cm-1; 1H NMR (CD3OD) δ 1.36-1.46 (m, 2H), 1.78 (ddd,
J ) 5.7, 7.5, 8.8 Hz, 1H), 2.50 (dddd, J ) 7.0, 8.8, 8.8, 10.6
Hz, 1H), 4.87 (d, J ) 11.0 Hz, 1H), 7.80-7.89 (m, 4H); 13C
NMR (CD3OD) δ 15.5, 18.4, 22.1, 53.4, 124.2, 132.9, 135.5,
168.7, 172.1, 175.2. Anal. Calcd for C14H11NO6: C, 58.13; H,
3.83; N, 4.84. Found: C, 57.90; H, 3.91; N, 4.77.
d-incorporation by 1H NMR spectral analysis and 77% d-
incorporation by GC/MS analysis (M+). Anal. Calcd for C16H14
-
DNO6: C, 60.38; H, 5.06; N, 4.40. Found: C, 60.15; H, 4.75;
N, 4.30.
Op tica lly En r ich ed d iester (+)-22. The Sharpless oxida-
tion/esterification of diene (-)-19 (0.168 g, 0.669 mmol) was
carried out in a fashion similar to that described above.
Purification of the residue by column chromatography (SiO2,
hexanes-ethyl acetate ) 4:1 f 2:1 gradient) gave (+)-22 as a
light yellow gel (0.1359 g, 64%): [R]20D ) +4.0 (c 0.366, CHCl3).
1
The H NMR spectrum of the diester obtained in this fashion
1
was identical to that of rac-22. Analysis by H NMR spectros-
copy in the presence of a chiral shift reagent (Eu(hfc)3, CDCl3)
indicated that the product was 41% ee.
r a c-2-(2′-Ca r b oxycyclop r op yl)glycin e [r a c-CCG-III]
(r a c-18). A mixture of rac-22 (0.1506 g, 0.4746 mmol) in 6 N
HCl (30 mL) containing PTFE boiling chips was heated at
reflux for 90 min, during which time the solid dissolved. The
reaction mixture was cooled, concentrated to ∼1/2 volume, and
washed repeatedly with ether to remove phthalic acid. The
aqueous solution was concentrated, and the resulting solid was
dried in vacuo. The solid was then dissolved in absolute
ethanol (3.5 mL) to give a tan solution. Propylene oxide (1.00
mL, 14.1 mmol) was added and the mixture swirled for 45 min,
during which time the free base precipitated as a white
powder. The mixture was cooled to 0 °C and the solid collected
by vacuum filtration. The solid was washed with cold ethanol
and was combined with several aqueous washings obtained
from rinsing the funnel and reaction vessel. Water was
removed from the product using a gentle stream of N2 gas.
The resulting damp solid was dried in vacuo to afford rac-18
as a colorless powder (0.0675 g, 82% based upon 0.8 waters of
hydration), which could be further purified by recrystallization
from water. The 1H NMR and 13C NMR spectra obtained for
rac-CCG-III were consistent with literature21c spectral data:
mp 178-179 °C (lit.21c mp 190-193 °C for (+)-18); IR (KBr)
3387, 1686, 1601, 1508, 1230 cm-1; 1H NMR (D2O) δ 1.30 (ddd,
J ) 5.0, 5.9, 6.8 Hz, 1H), 1.44 (ddd, J ) 5.0, 8.5, 8.8 Hz, 1H),
1.65 (dddd, J ) 6.8, 7.9, 8.8, 10.8 Hz, 1H), 1.89 (ddd, J ) 5.9,
7.9, 8.5 Hz, 1H), 3.90 (d, J ) 10.8 Hz, 1H); 13C NMR (D2O) δ
16.8, 20.2, 24.5, 56.0, 175.3, 178.5. Anal. Calcd for C6H9NO4‚
0.8H2O: C, 41.52; H, 6.15; N, 8.07. Found: C, 41.47; H, 6.33;
N, 8.00.
1,3-Dih yd r o-R-[2-(m eth oxyca r bon yl)cyclop r op yl]-1,3-
d ioxo-2H-isoin d ole-2-a cetic Acid Meth yl Ester (r a c-22).
To a solution of diacid rac-21 (0.15 g, 0.52 mmol) in methanol
(30 mL) was added concentrated H2SO4 (10 drops). The
reaction mixture was heated at reflux for 3.75 h, cooled to rt,
concentrated to ∼5 mL, and transferred to a separatory funnel
using ethyl acetate (25 mL). The organic solution was washed
sequentially with saturated sodium bicarbonate solution,
water, and brine. The organic solution was dried and concen-
trated. The resultant colorless oil was purified by column
chromatography (SiO2, hexanes-ethyl acetate ) 2:1) to give
rac-22 as a colorless oil, which upon agitation gave a colorless
amorphous solid (0.14 g, 85%): mp 98-101 °C; IR (KBr) 3062,
1
2952, 1716, 1386, 1178 cm-1; H NMR (CDCl3) δ 1.45 (ddd, J
) 5.3, 7.9, 8.8 Hz, 1H), 1.53 (ddd, J ) 5.5, 5.8, 7.0 Hz, 1H),
1.82 (ddd, J ) 5.9, 7.9, 8.5 Hz, 1H), 2.45 (dddd, J ) 6.9, 8.7,
8.7, 10.6 Hz, 1H), 3.61 (s, 3H), 3.78 (s, 3H), 4.95 (d, J ) 10.6
Hz, 1H), 7.70-7.77 (AA′BB′, 2H), 7.82-7.89 (AA′BB′, 2H); 13
C
NMR (CDCl3) δ 14.5, 17.8, 21.1, 51.7, 52.5, 53.3, 123.7, 131.9,
134.3, 167.4, 169.3, 172.0; GC/MS m/z 317. Anal. Calcd for
C
16H15NO6: C, 60.56; H, 4.76; N, 4.41. Found: C, 60.45; H,
4.83; N, 4.39.
Alter n a tive P r ep a r a tion of r a c-22 by Sh a r p less Oxi-
d a tion a n d Ester ifica tion . To a biphasic mixture of diene
rac-19 (0.1250 g, 0.4975 mmol) and sodium periodate (0.89 g,
4.1 mmol) in carbon tetrachloride (1.00 mL), acetonitrile (1.00
mL), and distilled water (1.50 mL) was added RuCl3‚3H2O (3.4
mg, 0.013 mmol, 2.6 mol %) (CAUTION: the reaction becomes
exothermic!). After the mixture was stirred at rt for 2.5 h, CH2-
Cl2 and brine were added to the dark solution, followed by
additional water to dissolve the remaining NaIO3. The pink
organic phase was removed, and the aqueous phase was
extracted with CH2Cl2 followed by ethyl acetate. The organic
extracts were combined, dried, and concentrated in vacuo to
Deu ter a ted CCG-III (d -18). Acidic hydrolysis of d -22
(0.120 g, 0.377 mmol) followed by generation of the free-base
by treatment with propylene oxide was carried out in a fashion
similar to the preparation of rac-18 to give d -18 (0.0472 g, 76%,
based upon 0.25 waters of hydration) as an off-white powder:
1
mp 168-169 °C; IR (KBr) 3423, 1701, 1514, 1230 cm -1; H
NMR (D2O) δ 1.42 (br t, J ) 8.7 Hz, 1H), 1.58-1.69 (m, 1H),
1.88 (br t, J ) 8.0 Hz, 1H), 3.90 (d, J ) 10.6 Hz, 1H); 13C NMR
(D2O) δ 16.5 (t, J CD ) 23.5 Hz), 20.3, 24.3, 56.1, 175.3, 178.7.
Compound d -18 was found to contain 80% d-incorporation by
1H NMR spectral integration. Anal. Calcd for C6H8DNO4‚1/
4H2O: C, 43.77; H, 5.20; N, 8.51. Found: C, 43.67; H, 5.47; N,
8.25.
1
give a white foam (0.1378 g) whose crude H NMR spectrum
was consistent with that of the previously prepared diacid rac-
21. The crude diacid was esterified with methanol/H2SO4 in a
fashion similar to that described above. The residue was
purified by column chromatography (SiO2, hexanes-ethyl
acetate ) 2:1) to give rac-22 as a faint yellow oil (0.1300 g,
(-)-2-(2′-Ca r boxycyclop r op yl)glycin e (-)-18. Acidic hy-
drolysis of (+)-22 (0.126 g, 0.397 mmol) followed by generation
the free-base by treatment with propylene oxide was carried
out in a fashion similar to the preparation of rac-18 to give
1
82%) that gelatinized on standing. The H NMR spectrum of
this product was identical with that previously obtained.
Deu ter a ted Diester (d -22). The Sharpless oxidation/
esterification of diene d -19 (0.3781 g, 1.4987 mmol) was carried
out in a fashion similar to that described above for 19.
Purification of the residue by column chromatography (SiO2,
hexanes-ethyl acetate ) 2:1) gave d -22 as a colorless oil which
solidified upon agitation (0.2649 g, 56%): mp 90-96 °C; IR
(KBr) 3056, 2951, 1717, 1386, 1173 cm-1;1H NMR (CDCl3) δ
1.44 (dd, J ) 7.8, 8.8 Hz, 1H), 1.82 (dd, J ) 7.8, 8.5 Hz, 1H),
2.45 (ddd, J ) 8.5, 8.8, 10.9 Hz, 1H), 3.61 (s, 3H), 3.78 (s, 3H),
4.95 (d, J ) 10.9 Hz, 1H), 7.70-7.77 (AA′BB′, 2H), 7.82-7.89
(AA′BB′, 2H); 13C NMR (CDCl3) δ 14.6 (t, J CD ) 24.8 Hz), 18.2,
21.5, 51.9, 52.6, 53.4, 123.3, 131.5, 133.8, 166.6, 168.6, 171.3;
GC/MS m/z 318. The product d -22 was found to contain 80%
(-)-18 as a tan solid (0.049 g, 78%): mp >145 °C dec; [R]20
)
D
-7.9 (c 0.328, H2O) (lit.21c [R]20 ) +20.4 (c 0.5, H2O). The H
1
D
NMR spectrum of (-)-18 was identical to that of rac-18.
Ben zoin d olizid in e (23). A flame-dried vial was charged
with the diester rac-22 (0.0578 g, 0.182 mmol), KHMDS (40
mg, 0.19 mmol), and a stirbar. The vial was stoppered and
cooled to -78 °C, and freshly distilled dry THF (0.40 mL) was
added via a syringe. The solution was stirred for 30 min and
then warmed to 0 °C over a period of 1 h. The vial was then
recooled to -78 °C, and the reaction was quenched by the
addition of a solution of acetic acid (30 µL) in THF (1 mL).
The solution was diluted with ethyl acetate and washed with
3006 J . Org. Chem., Vol. 69, No. 9, 2004

Reactivity of (Bicyclo[5.1.0]octadienyl)iron(1+) Cations
water. The organic phase was dried and filtered through silica
gel, the filter bed was washed with ethyl acetate, and the
combined organic phases were concentrated. The residue was
purified by preparative TLC (SiO2, hexanes-ethyl acetate )
2:1) to afford rac-23 as an off-white foam (0.0299 g, 52%). This
was identified as an 8:1 mixture of diastereomers by 1H
spectroscopy:. mp > 70 °C dec; IR (KBr) 3422, 2953, 1721,
1438, 1401, 1151 cm-1; 1H NMR (CDCl3, major diastereomer)
δ 2.59-2.71 (m, 2H), 2.84 (ddd, J ) 2.9, 13.1, 19.8 Hz, 1H),
3.80 (s, 3H), 3.84 (s, 3H), 6.29 (dd, J ) 2.9, 4.7 Hz, 1H), 7.47-
7.61 (m, 3H), 7.78-7.82 (m, 1H), signal for OH not observed;
13C NMR (DEPT, CDCl3, major diastereomer) δ 25.9 (CH2),
47.4 (CH), 52.95 (CH3), 52.98 (CH3), 84.4 (C), 120.6 (CH), 122.7
(CH), 124.0 (CH), 126.9 (C), 129.8 (C), 130.0 (CH), 132.8 (CH),
NO6‚0.5H2O: C, 58.89; H, 4.94; N, 4.29. Found: C, 58.81; H,
4.63; N, 4.21.
Ack n ow led gm en t. Financial support for this work
was provided by the National Institutes of Health
(Grant No. GM-42641), the Department of Education
(Grant No. P200A000228), and the Marquette Univer-
sity Integrative Neuroscience Research Center.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
and/or 13C NMR spectra of 11c,d , 13a ,b, 20b, and (-)-24. This
material is available free of charge via the Internet at
http://pubs.acs.org.
145.2 (C), 163.3 (C), 163.4 (C), 172.7 (C). Anal. Calcd for C16H15
-
J O030259A
J . Org. Chem, Vol. 69, No. 9, 2004 3007