Fusicoccin synthesis by intramolecular [4+4] photocycloaddition of 2-pyridones: Stereocontrol of the cycloaddition and elaboration of the pentacyclic product

Article abstract of DOI:10.1055/s-2001-15066

Intramolecular photocycloaddition of a three-carbon tethered pyrindinone-pyridone system yields the 5-8-5 ring system of the fusicoccin/ophiobolin/ceroplastol families. The stereoselectivity of the cycloaddition was found to be dependent on nitrogen substitution; N-methylation led to exclusively trans products while an absence of nitrogen substitution resulted in solvent-dependent stereoselectivity. Solvent and concentration effects for this cycloaddition were consistent with a hydrogen-bonded dimer that enforces a pro-cis conformation in nonpolar solvents and at higher concentrations. The cis-isomer, a fusicoccin synthesis intermediate, underwent a Cope rearrangement at ambient temperature but could be trapped efficiently as the mono epoxide, yielding a product with six new stereogenic centers. A four-step transformation of an amide carbonyl to a methyl group was achieved using a carbamoyl group to activate the amide for cleavage.

Full text of DOI:10.1055/s-2001-15066

PAPER
1185
Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-
Pyridones: Stereocontrol of the Cycloaddition and Elaboration of the
Pentacyclic Product
F
usicoccin Synthe
e
sis by Intram
v
olecular [4
i
ntocycloaddition ofF
2-Pyridones . McGee, Jr.,1 Taleb H. Al-Tel,2 Scott McN. Sieburth*
Department of Chemistry, State University of New York, Stony Brook, New York 11794–3400, USA
Fax +1(631)6328882; E-mail: scott.sieburth@sunysb.edu
Received 5 March 2001; revised 29 March 2001
Dedicated to Howard Zimmerman on the occasion of his 75th birthday
Abstract: Intramolecular photocycloaddition of a three-carbon
sugar
tethered pyrindinone–pyridone system yields the 5-8-5 ring system
of the fusicoccin/ophiobolin/ceroplastol families. The stereoselec-
tivity of the cycloaddition was found to be dependent on nitrogen
substitution; N-methylation led to exclusively trans products while
an absence of nitrogen substitution resulted in solvent-dependent
stereoselectivity. Solvent and concentration effects for this cycload-
dition were consistent with a hydrogen-bonded dimer that enforces
a pro-cis conformation in nonpolar solvents and at higher concen-
trations. The cis-isomer, a fusicoccin synthesis intermediate, under-
went a Cope rearrangement at ambient temperature but could be
trapped efficiently as the mono epoxide, yielding a product with six
new stereogenic centers. A four-step transformation of an amide
carbonyl to a methyl group was achieved using a carbamoyl group
to activate the amide for cleavage.
OAc
HO
O
H
O
H
OHC
H
O
7
H
H
11
H
12
3
OH
H
H
OH
OCH3
OH
fusicoccin A
ophiobolin A
ceroplastol
O
O
N
N
hν
+
N
ref. 3
Keywords: fusicoccin, higher-order cycloadditions, photochemis-
try, stereoselectivity, solvent effects
N
2 trans
N
O
O
O
1
3 cis
4
56 : 44
Scheme 1 Representative natural products with a 5-8-5 ring system,
2-pyridone photodimers, and the photodimer carbon skeleton
Among the cyclooctane-containing natural products,
more than 60 members have a tricyclic 5-8-5 carbon skel-
eton, divided largely among three families: the fusicoc-
cins, the ophiobolins, and the ceroplastols (Scheme 1).
These families are differentiated as di- or sesterterpenes
and by their stereochemistry, but have a number of obvi-
ous structural similarities. For example, all of these sub-
stances have methyl groups (or oxidized methyl groups) at
C-3, C-7 and C-11 (fusicoccin numbering). Several of
these structures have been successfully prepared by total
synthesis.3 In this report we describe the use of 2-pyridone
photocycloaddition to assemble the central features of the
fusicoccins.4
Intramolecular photoreaction of 5, pyridones tethered
head-to-tail by a three-carbon chain (Scheme 2), forms
cycloadducts 6 and 7 with fused 5-8 carbon rings. A ste-
reogenic center on the tether at C-12 such as a tert-bu-
tyldimethylsilyloxy group, controls formation of the
adjacent stereocenter, leading to anti-isomers as the only
observed products. This cycloaddition yields, however, a
mixture of cis and trans products similar to that formed by
intermolecular reactions (Scheme 1).
Adapting this intramolecular photochemistry to give all
three carbon rings of the fusicoccins required only that
one of the pyridones carry a cyclopentane ring (a pyrindi-
none), 8. Moreover, only two additional appendages
would be required in a fusicoccin A precursor, the me-
thoxymethyl group at C-3 and the side chain at C-14. Nev-
ertheless, for intramolecular photochemistry of 8 to be a
useful solution to the challenges of a fusicoccin synthesis,
additional goals needed to be met, the most important ear-
ly objective being a cis-selective photocycloaddition. The
cis relationship of the methyl groups of fusicoccin A
would be ideally addressed with a cis cycloaddition of 8
to give 9. The chemistry of 9 was also anticipated to be
challenging: despite decades of study of the 2-pyridone
photodimerization, few successful manipulations of 2-
pyridone photoproducts had been reported. The initial ob-
The carbon skeleton of the simplest 2-pyridone photodi-
mer consists of a cycloocta-1,5-diene (4), with two one-
carbon substituents, the bridging lactam carbonyls. These
lactams can be trans (2) or cis (3), with the former typical-
ly dominating the product mixture. The exclusively head-
to-tail regiochemistry of the cycloaddition results in a ter-
pene-like product that overlaps intriguingly with the cy-
clooctane of a variety of natural products, including those
in Scheme 1.
Synthesis 2001, No. 8, 18 06 2001. Article Identifier:
1437-210X,E;2001,0,08,1185,1196,ftx,en;C01901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

1186
K. F. McGee, Jr. et al.
PAPER
jectives, therefore, were to devise a way to gain cis selec- conformation (Figure 1). At the same time, the C-3 me-
tivity for the photocycloaddition and then to demonstrate thoxymethyl group of 8 blocks one face of the pyridone to
that the amide carbonyl groups could be reduced to meth- which it is attached. These two stereogenic centers would
yl groups in this densely functionalized system.
thereby synergistically enforce the same stereochemistry
at C-11, but would not play a role in the cis/trans outcome.
The cis selectivity of 8 was paramount. To evaluate the
anticipated cis selectivity outlined in Figure 1, only the
cyclopentane ring was required. We therefore prepared
and tested the photochemistry of 10, containing a single
stereogenic center.
O
O
N
N
N
hν
O
+
O
ref. 6
N
N
N
12
OTBS
66:34
OTBS
O
O
OTBS
O
O
5
6 trans-anti
7 cis-anti
O
O
N
N
N
N
R
OTBS
OTBS
OTBS
O
14
R
N
N
5
8
pro-cis
pro-cis
OMe
O
hν
O
H
11
12
O
O
N
N
N
N
12
OTBS
O
N
N
OTBS
OTBS
OMe
3
O
O
8
9
5
8
pro-trans
pro-trans
(disfavored)
OMe
H
OMe
O
N
Scheme 2 Pyridone [4+4] cycloadditions are generally trans-selec-
tive but fusicoccin synthesis would be best served by a cis-selective
reaction of 8
O
N
Pyridone photodimerizations, and their intramolecular
counterparts, yield either mixtures of trans and cis prod-
ucts (Schemes 1 and 2) or exclusively trans products.5
When this investigation began, cis-selective dimeriza-
tions of 2-pyridones had only been observed for reactions
performed in micelles.6 General conditions for trans se-
lectivity have been described,7 but no equivalent proce-
dure had been developed for cis-selective reactions.
Nevertheless, the product mixture formed by 5 indicated
that the relative energies of the pro-cis and pro-trans con-
formations (Figure 1) leading to [4+4] products 6 and 7
must be nearly identical in energy. It seemed reasonable,
therefore, that a small change in their relative energies
could lead to cycloadditions with high cis selectivity.
OTBS
10
Figure 1 Introduction of the cyclopentane ring, changing 5 to 8 and
10, was expected to destabilize the pro-trans conformation, resulting
in a cis-selective cycloaddition
Synthesis of the pyrindinone-pyridone 10 began with a
two-step conversion of cyclopentanone to pyrindinone 11,
using a modification of the procedure of Paine9
(Scheme 3). O-Benzylation of 11 using Tieckleman's con-
ditions,10,11 followed by reduction of nitrile 12, gave the
aldehyde 13. Coupling of aldehyde 13 with the magne-
sium acetylide 14,8 followed by derivatization with tert-
butyldimethylchlorosilane, gave silyl ether 15. Hydroge-
nation/hydrogenolysis of 15 with palladium-on-carbon
produced bis-2-pyridone 16. Treatment of 16 with excess
iodomethane and potassium carbonate in methanol gave
N,N'-dimethyl 10.
Comparing the pro-cis and pro-trans conformations of 8
with those of 5 (Figure 1) suggested that one new interac-
tion would be present in the pro-trans conformation. We
have proposed8 that the polar pyridone carbonyls, at least
in hydrogen-bonding solvents, carry a solvation-enhanced
steric bulk. This would lead to a steric interaction (shown
by the large arrow) for the pro-trans conformation of 8, an
interaction not found for 5, whereas inspection of the pro-
cis conformations of 5 and 8 reveal no additional interac-
tions. Destabilizing the pro-trans conformation would
lead to enhanced production of the cis-isomer.
One of the mono-N-methyl bis-2-pyridones was also pre-
pared (Scheme 4), to evaluate the effect of nitrogen sub-
stitution (vide infra). Treatment of nitrile 11 with DIBAL
led to its reduction to the aldehyde 17. Using an excess of
the acetylide 14, in part to deprotonate the acidic pyridone
proton of 17, led to alcohol 18 in modest yield. Alcohol 18
was then N-methylated, converted to the tert-butyldimeth-
ylsilyl ether, and hydrogenated/hydrogenolyzed to give
19.
Notably, the C-3 and the C-12 substituent stereochemistry
of 8 were expected to work in concert. For both 5 and 8,
the bulky silyloxy group can be pseudo-equatorial when
the pyridones are aligned in any cycloaddition-conducive
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-Pyridones
1187
O
O
BnBr
Ag2CO3
1. Na, HCO2Et
63%
HN
CN
NC
CONH2
95%
2.
11
79%
ref. 9
BrMgC2
N
OBn
OBn
CHO
OBn
86%
1.
N
N
DIBAL
92%
14
CN
2. TBSCl
87%
12
13
BnO
N
O
N
R
OBn
R
O
N
N
H2, Pd-C
63%
OTBS
OTBS
15
Scheme 5 Photocycloaddition of 10 yields exclusively the trans-
isomer 21 and the X-ray structure of 21
16 R = H
K2CO3
MeI, 79%
10 R = CH3
tions, changing the reaction solvent did not alter the trans/
cis stereoselectivity.
Scheme 3 Synthesis of cyclopentane-annulated bis-2-pyridones 10
and 16
In view of the intransigent stereochemical outcome of
pyridone 10 photochemistry, we turned our attention to
the effect of pyridone nitrogen substitution. N-Methyla-
tion has been routinely used in all of our 2-pyridone pho-
tochemistry for several reasons. Photodimerization of
pyridones lacking nitrogen substitution often leads to
products that are highly insoluble.13–15 Tethered pyridones
without nitrogen substitution have been used for molecu-
lar self assembly,16 because nitrogen-unsubstituted pyri-
dones strongly associate through hydrogen bonding.
Nitrogen-unsubstituted 2-pyridones therefore tend to be
very polar and of low solubility. Nevertheless, the ready
availability of intermediate 16 made evaluation of its
properties straightforward.
O
excess
HN
14
DIBAL
78%
CHO
11
35%
17
BnO
O
N
HN
1. MeI, K2CO3
(80%)
2. TBSCl (20%)
O
O
HN
N
3. H2, Pd-C
(91%)
OH
OTBS
18
19
The stereoselectivity of 16 proved to be highly responsive
to the reaction solvent,17 the first substantial solvent de-
pendency found for any 2-pyridone photocycloaddition.
In addition, the stereoselectivity was also affected by the
concentration of 16.18 These effects are illustrated in
Scheme 6 and tabulated in the Table. For polar solvents
like methanol or DMSO, a high percentage of the trans
photoproduct 22 was produced (1–10% cis), whereas in
benzene or toluene, the cis-isomer 23 is essentially the
only product observed (>99% cis). Increasing the polarity
of the solvent from benzene (ET=34.3)19 to chlorobenzene
(ET=36.8) and trifluoromethylbenzene (ET=38.5) de-
creases the cis selectivity to 95% and 80%, respectively.
Use of dichloromethane (Et=40.7) yields mostly the
trans-isomer (25% cis).
Scheme 4 Preparation of mono-N-methyl bis-2-pyridone 19
The proposed cis-selective photocycloaddition was tested
with 10 (Scheme 5). To our delight, the cycloaddition was
not only rapid (3–4 h) but also gave a single product (pro-
ton NMR)! The product was not, however, fully consis-
tent with the anticipated cis product 20. We have found
empirically that proton and carbon NMR spectra provide
evidence of the cis/trans stereochemistry. For trans-iso-
mers, the proximity of the amides to the alkenes results in
a dispersion of the alkene chemical shifts, whereas for the
cis-isomers the alkene chemical shifts are similar. In the
case of 21, the 13C chemical shifts for the alkenes are
spread over more than 30 ppm. X-ray crystallography
confirmed that, despite the expectations outlined above,
only the trans-isomer 21 had formed.12 While this was the
most trans-selective photocycloaddition we have ob-
served for a three-atom tethered pyridone, the desired cis-
selective cycloaddition was clearly not in hand. In keep-
ing with all previously studied pyridone photocycloaddi-
If hydrogen-bonding solvents are used, the cis selectivity
is much lower. Diethyl ether, although less polar
(ET=34.5) than chlorobenzene, leads to a 67% cis product
mixture. THF (ET=37.4) and ethyl acetate (ET=38.1) both
produce a 50–80% cis mixture.
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

1188
K. F. McGee, Jr. et al.
PAPER
pyridones similar to 16 and found that they formed hydro-
gen-bonded dimers and trimers.16 In the 1H NMR spectra
of 16 in chloroform, THF and benzene, the two different
hydrogen-bonding protons were visible as broad but well
defined singlets near 14 ppm, consistent with the observa-
tions of Wuest for his self-assembling bis-2-pyridones.16
A hydrogen-bonded dimer of 16, with four hydrogen
bonds, aligns the pyridones of each molecule in the same
direction. Folding this dimer puts both molecules in a pro-
cis conformation that leads to cis photoproducts. The cis
photoproducts, moreover, likely template other molecules
of 16 into a pro-cis conformation.
Scheme 6 Solvent and concentration dependence for the photocy-
cloaddition of 16. Dark bars indicate non-hydrogen-bonding solvents
These selectivities were determined using a 25 mM start-
ing concentration of 16. With highly cis-selective solvents
like chlorobenzene, decreasing the concentration by two
orders of magnitude fails to alter the percentage of cis-iso-
mer formed. Changing the concentration in THF or ethyl
acetate, however, leads to substantial changes. Low con-
centrations (i.e. 0.05 mM) yield mostly the trans-isomer,
whereas high concentrations (50 mM) yield mostly the
cis-isomer.
Scheme 7 A hydrogen bonded dimer of 16 yields cis selectivity in
nonpolar solvents and at high concentrations
Nitrogen substitution on both pyridones would, of course,
make the hydrogen-bonded dimers of Scheme 7 impossi-
ble, but would a single N-methyl group be sufficient to
eliminate formation of the cis-isomer? This question was
addressed with the mono-N-methyl 19 (Scheme 4). Inter-
estingly, the presence of single methyl group completely
eliminated the solvent dependency of the cycloaddition;
photoreaction of 19 gave only the trans product, whether
the reaction solvent was methanol or benzene. While the
reason for the high trans selectivity of the nitrogen-substi-
tuted pyridones 10 and 19 remains obscure, the excellent
cis selectivity of 16 set the stage for transformations of the
functionally dense 23.
These concentration and solvent polarity responses are
consistent with a hydrogen-bonded dimer of 16
(Scheme 7). Wuest has investigated head-to-tail tethered
Table Percent cis-23 Formed by Photocycloaddition of 16 as a
Function of Solvent and Concentration
Solvent
C6H6
ET
50 mM
25 mM
>9 %
6 %
5.0 mM 0.5 mM
34.3
34.5
35.5
36.8
37.4
38.1
38.5
40.7
45.1
55.4
Et2O
One problem remained with this cis-selective reaction, a
surprising instability of the product 23. Many multiply
bridged 1,5-dienes with the alkenes in close proximity, in-
cluding the cis-pyridone dimers, undergo a facile Cope re-
arrangement.7 The unusual direction of this
rearrangement has been noted previously. The parent cis-
1,2-divinylcyclobutane, on warming to 120°C, rearranges
to 1,5-cyclooctadiene.20 In contrast, the 1,5-cyclooctadi-
ene of 23 rearranges quantitatively to the divinylcyclobu-
tane 24 overnight at ambient temperature (Scheme 8).
This is the most facile rearrangement of a pyridone photo-
product that we are aware of, and may reflect either a
more strained product, with the added substitution of the
MTBE
PhCl
90 %
95 %
53 %
7 %
THF
57 %
7 %
42 %
67 %
27 %
31 %
EtOAc
PhCF3
CH2Cl2
DMSO
MeOH
80 %
25 %
<2 %
10 %
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PAPER
Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-Pyridones
1189
cyclopentane ring, or stabilization of a polar transition
state: early heterolytic cleavage of the C-6–C-7 bond
(Scheme 7) in 23 would create an iminium/enolate zwit-
terion, shown in an extreme form as 26.21–23 The alkyl sub-
stitution at C-6 would stabilize positive charge at this po-
sition, lowering the energy of this transition state and
consequently the rate of reaction. Whatever the cause of
the rearrangement facility, this unstable product would
somehow need to be stabilized or intercepted. In earlier
work on the taxol problem,24 we had found that hydroge-
nation of an alkene stabilized the [4+4] adduct and we ex-
pected that removal of one alkene of 23 would have the
same result.
16
toluene
0 °C
hν
O
O
O
O
7
HN
HN
O
HN
HN
HN
HN
6
25 °C
O
O
O
O
0 °C
24
23
25
OTBS
OTBS
?
OTBS
84% from 16
O
O
O
NH
O
NH
HN
O
HN
OTBS
After much experimentation, it was discovered that di-
methyldioxirane (DMDO)25,26 was an ideal reagent for
capturing 23. Irradiation of 16 in toluene for three hours at
ice bath temperature served to convert all of 16 to photo-
product. Addition to a cold dimethyldioxirane solution
and stirring for an additional 2 hours at 0°C led to a single
and stable product 25, isolated in 84% overall yield from
O
HN
OTBS
O
NH
26
24
25
OTBS
Scheme 8 cis-Product 23 undergoes a facile Cope rearrangement,
but can be efficiently intercepted by epoxidation with dimethyldio-
xirane. An early bond cleavage in 23 would lead to zwitterionic 26.
1
16 (Scheme 8). With only one olefin proton in the H
different isocyanates gave nitrogen adduct 30 in good to
NMR spectrum, epoxidation had occurred at the disubsti-
tuted and not the trisubstituted alkene. This selectivity
excellent yields.
may be due to the steric sensitivity of DMDO27 and the Interestingly, in each of these reactions a single isocya-
shielding of the trisubstituted alkene by the nearby sily- nate product was found, having reacted only once and
loxy group. Approach of the DMDO was assumed to have with only one of the two amides. The differences in the
occurred from the least hindered face of the alkene. These amide environments are rather subtle, making a prediction
assignments were confirmed by X-ray crystallography of of the reaction site tenuous. The single derivatization is
a more advanced intermediate (see Figure 2). The site of easier to understand. An approach of the isocyanate to the
this epoxidation was ideal for fusicoccin A, situated anion of 25 that minimizes steric interactions would be
where a trans-1,2-diol is located in the natural product nearly orthogonal to the plane of the amide (Scheme 9).
(Scheme 1).
This trajectory requires that one end of the isocyanate be
directed toward the other amide. If that amide is nitrogen-
substituted, sterics might preclude such an approach. The
first isocyanate reaction would therefore be expected to
slow or prevent a second isocyanate reaction.
With the stable, cis-cycloadduct 25 now in hand, the next
objective was reduction of the amide carbonyl groups to
methyl groups. At the start of this project, few reactions of
2-pyridone dimers were known. Paquette had reported the
most substantial transformations, alkene hydrogenation, Identification of the site of the isocyanate reaction, near
amide reduction to tertiary amines, and quaternization of the trisubstituted alkene, was conclusively determined by
the amines,14,35 but in no case had photodimer amide X-ray crystallography of the isopropyl derivative
bonds been opened, hydrolytically or reductively. In our (Figure 2).31 This structure also confirmed the cis stereo-
recent work with [4+4] adduct 27, however, Grieco's chemistry of the cycloaddition, the relative stereochemis-
cleavage procedure for secondary amides28 had worked try of the silyloxy substituent, and the site and stereo-
extremely well; Boc-activated amide 28 formed rapidly, chemistry of the epoxidation. In addition, an
and reductive opening with lithium borohydride to 29 pro- intramolecular hydrogen bond was found between the car-
ceeded smoothly.29,30 Despite this precedent, intermediate bamoyl nitrogen and the imide carbonyl oxygen with an
25 proved to be impervious to derivatization with a Boc H–O bond length of 1.94 Å. This proton was clearly visi-
group, a tosylate group, or even a mesylate group. Pre- ble in the proton NMR spectrum of 30, as a well defined,
sumably this is due, in part, to the neopentyl nature of the albeit broad, singlet at =8.1.
nitrogens in 25. In addition, while one face of the second-
With successful introduction of a carbamoyl-activating
ary amide of 27 is blocked by an alkene, the amides in 25
group, reductive cleavage of the imide carbonyl of 30 was
are buttressed on one side by an amide group, which pres-
anticipated to be straightforward. Carbamoyl-activated
ents a greater steric hurdle. We turned, therefore, to the
amides have been opened with a variety of nucleophiles,
use of an isocyanate, a compact, unencumbered functional
including hydride.32 While reduction of a -lactam acti-
group. Scheme 9 shows a Chem3D model of the expected
vated with a carbamoyl group closely related to 30 had not
been reported, the reactivities of a broad series of related
approach of methyl isocyanate to an amide nitrogen in 25.
This transformation proved quite successful. Following
amide and carbamate systems appeared to be sufficient
treatment with sodium hydride, introduction of several
precedent.
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

1190
K. F. McGee, Jr. et al.
PAPER
Figure 2 Crystal structure of isocyanate derivative of 25 showing
intramolecular hydrogen bond
action with additives, including LiCl, ZnCl2 and MgBr2,
failed to positively impact the yield of 31.
The reduction of the amide carbonyl dramatically altered
the chemical shift of the C-12 carbinol proton geminal to
the silyloxy group. In 30 (and earlier compounds) this pro-
ton is visible in the 1H NMR spectra at =4.8 0.3, anom-
alously far downfield, due to the anisotropy of the nearby
amide carbonyl. Reduction of this carbonyl to give 31 is
accompanied by a change in the chemical shift of this pro-
ton to the more typical 3.4 ppm, an upfield movement of
1.4 ppm.
Scheme 9 Activation of the secondary amides of the [4+4] adducts
allows for a facile amide opening. While 25 was inert to the standard
reagents, an isocyanate adduct was readily formed. A molecular mo-
del shows approach of an isocyanate to the amide.
Treatment of 30, R=Ph, with NaBH4, following Katigiri's
procedure, did not lead to any product formation. Lithium
borohydride, on the other hand, led almost exclusively to
the loss of the carbamoyl group and regeneration of 25!
Attack of the hydride on the urea-like carbonyl over the
imide-like carbonyl was unexpected. Consideration of the
phenyl group electronegativity as well as the conjugation
of the nitrogen lone pair into the aromatic ring, made it
clear that an aliphatic group would be a better choice as a
nitrogen substituent. The isopropyl carbamoyl group was
selected for further experimentation, with the expectation
that it might also provide a degree of steric protection for
the urea carbonyl carbon.
Reduction of 30, R=i-Pr, did lead to the desired cleavage
mode, yielding 31, however, competitive cleavage of the
carbamoyl group remained problematic. Although by-
product 25 was easily recycled, minimizing its production
was obviously the best alternative. The ratio of 25 and 31,
the only products formed, was eventually found to cor-
relate with the initial concentration of lithium borohy-
dride. When the concentration of LiBH4 was held at 0.4 M
and the concentration of 30 at 40 mM, a consistent 64%
yield of 31 was achieved, whereas higher or lower con-
centrations of LiBH4 led to reduced yields (Scheme 10).
We are not aware of any similar reports of the effect of
LiBH4 concentration on a reduction outcome.
It was possible that the 25/31 ratio is related to the confor-
mation of the carbamoyl group and perhaps chelation of
lithium by the two carbonyls. Attempts to modulate the re-
Scheme 10 Lithium borohydride reduction of 30 was a competition
between carbonyl reductions a and b. The yield of 31 correlated with
the initial concentration of lithium borohydride.
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-Pyridones
1191
cycloaddition, presumably generalizable to related sys-
tems, and the first reduction of an amide to a methyl group
in a polycyclic pyridone photoproduct.
2-Oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-
carbonitrile (11)9
To a flask charged with finely cut sodium metal (2.24 g, 97.5 mmol)
in Et2O (175 mL) at 0°C was added dropwise a solution of cyclo-
pentanone (10.5 mL, 119 mmol) and ethyl formate (10 mL, 124
mmol) in Et2O (100 mL) over the course of 40 min. After stirring
overnight, the brown slurry was filtered, the residue washed with
Et2O (2 150 mL), and dried in vacuo to give 8.35 g (63%) of the
sodium salt of 2-formyl cyclopentanone as a tan solid.
1H NMR (DMSO-d6): = 8.88 (s, 1 H), 2.25 (t, J=7.5 Hz, 2 H), 1.88
(t, J=7.5 Hz, 2 H), 1.57 (pentet, J=7.5 Hz, 2 H).
13C NMR (DMSO-d6): =195.0, 174.2, 106.0, 39.8, 26.4, 19.8.
IR (KBr): =2949, 2836, 1638, 1489, 1353 cm–1.
MS (EI): m/z (%)=112 (15), 84 (39), 55 (100).
This salt (8.35 g, 62.3 mmol) and 2-cyanoacetamide (11.5 g, 137
mmol) were suspended in toluene (300 mL) and stirred vigorously
as a 1 M solution of AcOH–piperdine (1:1) in CH2Cl2 (27 mL) was
added. The mixture was heated to reflux for 2 h, cooled to 0°C,
acidified with AcOH to pH 5 and concentrated in vacuo. The resi-
due was washed with toluene (2 100 mL), dried in vacuo, and pu-
rified by flash chromatography (MeOH–CH2Cl2, 1:4) to give 7.9 g
(79%) of 11 as yellow solid; Rf 0.7 (MeOH–CH2Cl2, 1:9).
Scheme 11 Two-step reduction of the hydroxymethyl to a methyl
group
1H NMR (CDCl3): = 7.76 (s, 1 H), 7.44 (br s, 1 H, NH), 3.02 (t,
J=7.5 Hz, 2 H), 2.79 (t, J=7.5 Hz, 2 H), 2.20 (pentet, J=7.5 Hz, 2
H).
13C NMR (CDCl3): =164.0, 158.0, 145.2, 122.0, 116.0, 100.0,
31.8, 29.3, 23.0.
IR (KBr): =3002, 2949–2553, 2225, 1649, 1596, 1393, 771 cm–1.
Successful reduction of the amide carbonyl set the stage
for conversion of the alcohol in 32 to a methyl group. The
neopentyl setting of this alcohol, with the surrounding
functionality, was anticipated to provide multiple reaction
pathways. Nevertheless, treatment of 31 with methanesul-
fonyl chloride produced the mesylate 32 without difficul-
ty. This mesylate, when heated to 110°C in DMF
containing NaI and zinc powder,33,34 gave a clean conver-
sion to 33 in a gratifying 90% yield (Scheme 11).
MS (EI): m/z (%)=160 (M+, 82), 159 (100), 131 (38), 104 (40), 77
(36), 52 (35).
2-(Benzyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-
carbonitrile (12)
Attaining product 33 fulfilled the objectives of developing
a cis-selective cycloaddition and demonstrating that the
photoproduct amides could be readily reduced to methyl
groups. The limitations of product 33, with its rather rigid
bridged cyclooctane and without the additional function-
ality required for the natural product, meant that it had
reached the end of its usefulness as a fusicoccin model.
The successful completion of the objectives set out at the
beginning, however, provides a firm platform from which
to build a total synthesis, and progress in this arena will be
provided in due course. Notably, the six steps from 10 to
33, Scheme 12, includes the first cis-selective pyridone
To a suspension of 11 (1.3 g, 8.12 mmol) and benzyl bromide (2.8
g, 16 mmol) in toluene (43 mL) and protected from light, was added
AgCO3 (1.12 g, 4.06 mmol), and the mixture was stirred for 4 d. The
mixture was filtered through Celite, the filtrate concentrated in vac-
uo, and purified by flash chromatography (CH2Cl2–hexanes, 1:1) to
give 12 (1.94 g, 95%) as colorless crystals; mp 62–64°C; Rf 0.5
(CH2Cl2–hexanes, 1:1).
1H NMR (CDCl3): =7.64 (s, 1 H), 7.49–7.27 (m, 5 H), 5.47 (s, 2
H), 2.96 (t, J=7.5 Hz, 2 H), 2.87 (t, J=7.5 Hz, 2 H), 2.14 (pentet, J
=7.5 Hz, 2 H).
13C NMR (CDCl3): =168.6, 138.2, 135.9, 131.4, 129.5, 128.9,
127.9, 127.8, 116.0, 102.0, 68.2, 34.7, 29.4, 23.0.
IR (KBr): =2950–2931, 2220, 1600–1570, 1451–1409, 1248,
1054, 737, 692 cm–1.
O
MS (EI): m/z (%)=250 (31), 91 (100).
Exact Mass (M+): m/z Calcd 250.1107, Found 250.1106.
O
O
HN
NH
O
H
N
H
N
HN
2-(Benzyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-
carbaldehyde (13)
six steps
O
OTBS
OTBS
To a solution of 12 (500 mg, 2 mmol) in CH2Cl2 (20 mL) at –78°C
was added dropwise DIBAL (4 mL of a 1 M solution, 4 mmol) over
10 min. After stirring for 1 h, the solution was quenched with 10%
HCl and stirred for 30 min while warming to r.t. The mixture was
washed with a sat. solution of Rochelle's salt, and the aqueous solu-
10
33
Scheme 12 The short sequece of 10
selective cycloaddition and the first conversion of a pyridone photop-
roduct amide to a methyl group.
34 includes the first cis-
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

1192
K. F. McGee, Jr. et al.
PAPER
tion was extracted with CH2Cl2 (3 50 mL). The combined organ-
ics were washed with brine and concentrated in vacuo to give 13
(467.4 mg, 92%) as a yellow solid; Rf 0.8 (EtOAc–hexanes, 1:4).
1H NMR (CDCl3): =10.39 (s, 1 H), 7.92 (s, 1 H), 7.46–7.26 (m, 5
H), 5.50 (s, 2 H), 3.04–2.81 (m, 4 H), 2.20–2.04 (m, 2 H).
13C NMR (CDCl3): = 189.2, 170.7, 138.1, 136.8, 132.8, 130.4,
128.5, 128.0, 127.9, 116.5, 68.0, 34.8, 29.5, 23.0.
(MeOH–CH2Cl2, 1:9) to give 16 (335.4 mg, 62%) as a colorless
foam; Rf 0.45 (MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): =14.2 (br s, 1 H, NH), 13.8 (br s, 1 H, NH),
7.44 (s, 1 H), 7.30 (t, J=7.5 Hz, 1 H), 6.32 (d, J=10 Hz, 1 H), 6.05
(d, J=7.5 Hz, 1 H), 5.08 (d, J=5.0 Hz, 1 H), 2.89–2.79 (m, 4 H),
2.68–2.63 (m, 2 H), 2.17–2.04 (m, 4 H), 0.93 (s, 9 H), 0.08 (s, 3 H),
–0.05 (s, 3 H).
13C NMR (CDCl3): =166.2, 163.6, 150.6, 147.5, 141.6, 134.4,
132.5, 119.2, 116.2, 105.7, 68.4, 37.9, 30.8, 30.3, 29.8, 25.9, 22.9,
18.2, –4.5.
1-[2-(Benzyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl]-3-
[6-(benzyloxy)pyridin-2-yl]prop-2-yn-1-ol
To a solution of 6-benzyloxy-2-ethynylpyridine8 (2.07g, 9.87
mmol) in THF (23 mL) at 0°C was added dropwise a solution of
ethylmagnesium bromide (9.87 mL of a 1 M solution, 9.87 mmol)
over 15 min. The resulting maroon solution gradually turned yellow
and was stirred for 30 min. A solution of aldehyde 13 (1.25 g, 4.93
mmol) in THF (23 mL) was added dropwise. After 5 min sat. NH4Cl
was added and the mixture was stirred for an addition 10 min. The
aqueous phase was extracted with EtOAc (3 30 mL), the com-
bined organics were dried (Na2SO4), concentrated in vacuo, and pu-
rified by flash chromatography (EtOAc–hexanes, 1:4) to give the
title compound (1.95 g, 86%) as a tan foam; Rf 0.2 (EtOAc–
hexanes, 1:4).
1H NMR (CDCl3): =7.72 (s, 1 H), 7.54–7.28 (m, 11 H), 7.03 (d,
J=7.5 Hz, 1 H), 6.75 (d, J=7.5 Hz, 1 H), 5.64 (d, J=5.0 Hz, 1 H),
5.48 (s, 2 H), 5.35 (s, 2 H), 3.19 (d, J=7.5 Hz, 1 H, OH), 2.97–2.85
(m, 4 H), 2.19–2.10 (m, 2 H).
13C NMR (CDCl3): =163.3, 162.6, 159.9, 139.6, 138.6, 137.4,
137.0, 133.1, 129.7, 128.5, 128.4, 128.2, 127.9, 127.6, 121.0, 120.0,
111.6, 87.9, 85.1, 67.9, 67.5, 61.0, 34.0, 30.0, 23.3.
MS (EI): m/z (%)=325 (36), 279 (36), 160 (61), 75 (100).
Exact Mass (M+): m/z Calcd 401.2273, found 401.2260.
Anal. Calcd for C22H32N2O3Si: C 65.96, H 8.05, N 6.99, Found C
65.04, H 7.99, N 6.89.
3-[{1-[tert-Butyl(dimethyl)silyl]oxy}-3-(1-methyl-6-oxo-1,6-
dihydropyridin-2-yl)propyl]-1-methyl-1,5,6,7-tetrahydro-2H-
cyclopenta[b]pyridin-2-one (10)
To a solution of 16 (257 mg, 0.64 mmol) in MeOH (15 mL) was
added K2CO3 (1.77 g, 12.83 mmol) and MeI (1.05 g, 7.38 mmol)
and then heated to reflux for 15 h. The reaction was cooled, diluted
with Et2O, filtered, and the residue was washed with CH2Cl2 (3
15 mL). The combined organics were concentrated in vacuo and
partitioned between H2O and CH2Cl2. The organics were concen-
trated in vacuo and purified by flash chromatography (MeOH–
CH2Cl2, 1:9) to give 10 (217.7 mg, 79%) as a colorless solid; Rf
0.65 (MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): = 7.40 (br s, 1 H), 7.27 (dd, J=6.9, 9.0 Hz, 1
H), 6.65 (d, J=9.0 Hz, 1 H), 6.20 (d, J=6.9 Hz, 1 H), 5.01 (dd,
J=3.0, 6.3 Hz, 1 H), 3.54 (s, 3 H), 3.47 (s, 3 H), 2.98 (t, J=7.5 Hz,
2 H), 2.76 (t, J=7.2 Hz, 2 H), 2.72–2.65 (m, 2 H), 2.15–2.08 (m, 4
H), 0.91 (s, 9 H), 0.04 (s, 3 H), –0.08 (s, 3 H).
MS (EI): m/z (%)=463 (MH+, 100), 353 (23), 256 (58), 254 (35),
216 (22), 91 (80).
Exact Mass (MH+): m/z Calcd 463.2021, Found 463.2018.
13C NMR (CDCl3): =163.8, 161.3, 150.8, 148.1, 136.6, 132.3,
130.8, 118.2, 116.2, 107.5, 68.8, 58.1, 35.1, 32.4, 32.2, 31.4, 30.5,
29.3, 25.3, 18.1, –4.6, –5.0.
2-(Benzyloxy)-3-(3-[6-(benzyloxy)pyridin-2-yl]-1-{[tert-butyl-
(dimethyl)silyl]oxy}prop-2-ynyl)-6,7-dihydro-5H-cyclopen-
ta[b]pyridine (15)
To
a solution of 1-[2-(benzyloxy)-6,7-dihydro-5H-cyclopen-
2-Oxo-2,5,6,7-tetrahydro-1H-cyclopenta[b]pyridine-3-carbox-
aldehyde (17)
ta[b]pyridin-3-yl]-3-[6-(benzyloxy)pyridin-2-yl]prop-2-yn-1-ol
(1.10 g, 2.38 mmol) in MeCN (51 mL) was added imidazole (1.69
g, 23.8 mmol) and tert-butyldimethylchlorosilane (1.79 g, 11.9
mmol). After stirring at r.t. for 18 h, the mixture was diluted with
Et2O and filtered. The filtrate was concentrated in vacuo, and puri-
fied by flash chromatography (EtOAc–hexanes, 1:4) to provide 15
(1.19 g, 87%) as an oil; Rf 0.6 (EtOAc–hexanes, 1:4).
1H NMR (CDCl3): =8.02 (s, 1 H), 7.66 (d, J=7.1 Hz, 1 H), 7.55
(d, J=6.9 Hz, 1 H), 7.50–7.35 (m, 9 H), 7.09 (d, J=7.2 Hz, 1 H),
6.82 (d, J=8.2 Hz, 1 H), 6.18 (s, 1 H), 5.63 (AB quartet, JAB=12.5
To a solution of 11 (100 mg, 0.62 mmol) in CH2Cl2 (6 mL) at –78°C
was added dropwise DIBAL (1.25 mL of a 1 M solution, 1.25
mmol) over 25 min. After 1 h, the reaction was quenched with 10%
HCl, and stirred for an additional 1 h while warming to r.t. The mix-
ture was washed with sat. Rochelle's salt, and the aqueous phase
was then extracted with CH2Cl2 (3 75 mL). The combined organ-
ics were washed with brine, concentrated in vacuo, and purified by
flash chromatography (MeOH–CH2Cl2, 1:9) to give 17 (80 mg,
78%) as a yellow viscous liquid; Rf 0.6 (MeOH–CH2Cl2, 1:9).
Hz,
AB=12.5 Hz, 2 H), 5.48 (s, 2 H), 3.05 (t, J=7.5 Hz, 2 H),
1H NMR (CDCl3): =10.1 (s, 1 H), 7.70 (s, 1 H), 3.00 (t, J=7.5 Hz,
2 H), 2.78 (t, J=7.5 Hz, 2 H), 2.19–2.10 (m, 2 H).
13C NMR (CDCl3): = 189.2, 165.6, 145.0, 140.0, 133.0, 121.3,
31.9, 29.2, 22.9.
2.98 (t, J=7.2 Hz, 2 H), 2.26–2.17 (m, 2 H), 1.11 (s, 9 H), 0.41 (s, 3
H), 0.31 (s, 3 H).
13C NMR (CDCl3): =163.3, 162.0, 159.4, 140.1, 138.6, 137.9,
137.3, 132.7, 129.6, 128.5, 128.4, 128.3, 128.0, 127.6, 121.2, 120.7,
111.4, 89.4, 84.2, 67.8, 67.6, 60.2, 34.2, 30.2, 26.0, 23.5, 18.5, –4.2,
–4.6.
3-{3-[6-(Benzyloxypyridin-2-yl]-1-hydroxyprop-2-ynyl}-
1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one (18)
Exact Mass (MH+): m/z Calcd 577.2886, Found 577.2886.
To a solution of 6-(benzyloxy)-2-ethynylpyridine8 (1.5 g, 7.17
mmol) in THF (10 mL) was added dropwise ethylmagnesium bro-
mide (7.17 mL of a 1 M solution, 7.17 mmol) over 10 min, and the
resulting mixture was allowed to stir for an additional 30 min. A
solution of 17 (390 mg, 2.39 mmol) in THF (10 mL) was added
dropwise. The reaction was quenched with sat. NH4Cl and the aque-
ous phase was extracted with CH2Cl2 (3 50 mL). The combined
organics were washed with brine, dried (Na2SO4), concentrated in
vacuo, and purified by flash chromatography (MeOH–CH2Cl2, 1:9)
3-[1-{[tert-Butyl(dimethyl)silyl]oxy}-3-(6-oxo-1,6-dihydropyri-
din-2-yl)propyl]-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-
2-one (16)
To a solution of 15 (774 mg, 1.34 mmol) in EtOH (8 mL) and EtO-
Ac (11 mL) was added 10% Pd/C (77 mg) and then placed under
one atmosphere of H2. After 5 h, the mixture was filtered through
Celite, concentrated in vacuo and purified by flash chromatography
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-Pyridones
1193
to give 18 (260 mg, 35%) as a light orange foam; Rf 0.45 (MeOH–
Exact Mass (MH+): m/z Calcd 415.2418. Found 415.2416.
CH2Cl2, 1:9).
(1S*,3aR*,6S*,6aS*,10aS*)-1-{[tert-butyl(dimethyl)silyl]oxy}-
4,12-dimethyl-2,3,8,9-tetrahydro-1H,4H,7H-3a,6-etheno-
6a,10a-(iminomethano)dicyclopent[b,e]azocine-5,11(6H)-dione
(21)
A solution of 10 (442 mg, 1.03 mmol) in MeOH (21 mL, 0.05 M)
was irradiated for 4 h with a Hanovia 450 W medium pressure mer-
cury lamp housed in a water-cooled quartz jacket fitted with a pyrex
filter. The reaction mixture was concentrated in vacuo to give 432.5
mg (98%) of 21 as a tan foam; Rf 0.8 (MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): =7.66 (s, 1 H), 7.49–7.29 (m, 6 H), 7.05 (d,
J=7.5 Hz, 1 H), 6.72 (d, J=7.5 Hz, 1 H), 5.73 (s, 1 H), 5.31 (s, 2 H),
3.43 (s, 1 H, OH), 3.00–2.88 (m, 2 H), 2.72 (t, J=7.5 Hz, 2 H), 2.19–
2.04 (m, 2 H).
MS (EI): m/z (%)=373 (MH+, 20), 357 (86), 251 (68), 161 (100), 91
(42).
Exact Mass: m/z Calcd for (MH+) 373.1541. Found 373.1552.
1H NMR (CDCl3): =6.15 (t, J =7.5 Hz, 1 H), 6.06 (dd, J =7.5 Hz,
2.5 Hz, 1 H), 4.62 (s, 1 H), 3.07 (d, J =2.5 Hz, 1 H), 3.05 (s, 3 H),
3.04 (s, 3 H), 2.85–2.16 (m, 6 H), 2.01–1.80 (m, 5 H), 0.88 (s, 9 H),
0.09 (s, 3 H), 0.03 (s, 3 H).
13C NMR (CDCl3): =177.1, 175.0, 152.1, 142.5, 128.6, 119.3,
74.1, 73.6, 71.4, 68.6, 58.1, 41.0, 34.2, 32.6, 31.9, 31.0, 28.7, 25.8,
23.1, 18.0, –4.6, –4.9.
3-{3-[6-(Benzyloxy)pyridin-2-yl]-1-hydroxyprop-2-ynyl}-1-
methyl-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-one
To a solution of 18 (260 mg, 0.7 mmol) in MeOH (15 mL) was add-
ed K2CO3 (966 mg, 6.99 mmol) and MeI (495.4 mg, 3.49 mmol),
and then heated to reflux for 18 h. The reaction mixture was diluted
with Et2O, filtered, and the filtrate was concentrated in vacuo. The
product was purified by flash chromatography (MeOH–
CH2Cl2, 1:9) to provide the title compound (215.3 mg, 80%) as a
off-white solid; Rf 0.65 (MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): =7.65–7.29 (m, 7 H), 7.13 (d, J=7.5 Hz, 1 H),
6.74 (d, J=7.5 Hz, 1 H), 5.74 (s, 1 H), 5.36 (s, 2 H), 4.02 (s, OH),
3.52 (s, 3 H), 2.94 (t, J=7.5 Hz, 2 H), 2.81 (t, J=7.5 Hz, 2 H), 2.25–
2.13 (m, 2 H).
MS (DCI): m/z (%)=429 (MH+, 8), 176 (11), 124 (22).
Exact Mass (MH+): m/z Calcd 429.2572, Found 429.2573.
(1S*,3aR*,6S*,6aS*,10aS*)-1-{[tert-Butyl(dimethyl)silyl]oxy}-
12-methyl-2,3,8,9-tetrahydro-1H,4H,7H-3a,6-etheno-6a,10a-
(iminomethano)dicyclopent[b,e]azocine-5,11(6H)-dione
A solution of 19 (10 mg, 0.024 mmol) in benzene-d6 (0.96 mL,
0.025 M) was irradiated for 3 h with a Hanovia 450 W medium pres-
sure mercury lamp in a water-cooled quartz jacket fitted with a py-
rex filter. The reaction mixture was concentrated in vacuo to give
9.5 mg (95%) of the title compound as a tan foam.
1H NMR (benzene-d6): =7.19 (s, 1 H, NH), 6.13 (s, 1 H), 5.89 (d,
J=7.5 Hz, 1 H), 5.64 (t, J=7.5 Hz, 1 H), 5.19 (d, J=7.5 Hz, 1 H),
2.65 (d, J=5.0, 1 H), 2.51 (s, 3 H), 2.24–1.97 (m, 4 H), 1.77–1.71
(m, 2 H), 1.53–1.50 (m, 2 H), 1.32 (m, 2 H), 0.96 (s, 9 H), 0.14 (s,
3 H), 0.12 (s, 3 H).
13C NMR (CDCl3): =177.7, 175.6, 151.6, 141.6, 128.6, 121.5,
74.3, 72.6, 68.6, 67.9, 59.2, 40.9, 35.5, 33.9, 32.0, 28.5, 25.8, 23.2,
18.0, –4.6, –4.8.
MS (DCI): m/z (%)=415 (MH+, 8), 283 (100), 176 (11), 110 (13).
Exact Mass (MH+): m/z Calcd 415.2424. Found 415.2416.
13C NMR (CDCl3): =164.5, 163.2, 158.0, 149.6, 145.0, 138.6,
137.0, 136.6, 128.4, 128.1, 127.9, 126.0, 121.0, 120.7, 120.3, 116.4,
111.6, 100.4, 86.8, 67.8, 62.6, 31.0, 29.2, 22.9.
3-{3-[6-(Benzyloxy)pyridin-2-yl]-1-[tert-butyl(dimethyl)silyl-
oxy]prop-2-ynyl}-1-methyl-1,5,6,7-tetrahydro-2H-cyclopen-
ta[b]pyridin-2-one
To a solution of 3-{3-[6-(benzyloxy)pyridin-2-yl]-1-hydroxyprop-
2-ynyl}-1-methyl-1,5,6,7-tetrahydro-2H-cyclopenta[b]pyridin-2-
one (215.3 mg, 0.56 mmol) in MeCN (8 mL) was added imidazole
(381 mg, 5.6 mmol) and tert-butyldimethylchlorosilane (422 mg,
2.8 mmol). The mixture was stirred for 18 h, diluted with Et2O and
filtered. The filtrate was concentrated in vacuo and purified by flash
chromatography (MeOH–CH2Cl2, 1:19) to provide the title com-
pound (56.1 mg, 20%) as a yellow foam; Rf 0.75 (MeOH–
CH2Cl2, 1:19).
1H NMR (CDCl3): =7.69 (s, 1 H), 7.50–7.29 (m, 6 H), 7.03 (d,
J=7.5 Hz, 1 H), 6.69 (d, J=8.3 Hz, 1 H), 5.92 (s, 1 H), 5.34 (s, 2 H),
3.50 (s, 3 H), 2.88 (t, J=7.5 Hz, 2 H), 2.80 (t, J=7.5 Hz, 2 H), 2.18–
2.06 (m, 2 H), 0.96 (s, 9 H), 0.28 (s, 3 H), 0.19 (s, 3 H).
(1S*,3aR*,6S*,6aS*,10aS*)-1-{[tert-Butyl(dimethyl)silyl]oxy}-
2,3,8,9-tetrahydro-1H,4H,7H-3a,6-etheno-6a,10a-(iminometh-
ano)dicyclopent[b,e]azocine-5,11(6H)-dione (22)
A solution of 16 (50 mg, 0.12 mmol) in 3:7 CH2Cl2–MeOH (2.5
mL) was irradiated for 3 h with a Hanovia 450 W medium pressure
mercury lamp in a water-cooled quartz jacket fitted with a pyrex fil-
ter. The reaction mixture was concentrated in vacuo to give 22 (47
mg, 94%) as colorless crystals; mp 189–191°C; Rf 0.4 (MeOH–
CH2Cl2, 1:9).
1H NMR (CDCl3–MeOH-d4): =6.01 (d, J=10 Hz, 1 H), 5.88 (dd,
J=10 Hz, 7.5 Hz, 1 H), 5.64 (s, 1 H), 4.51 (t, J=5 Hz, 1 H), 2.77 (d,
J=7.5 Hz, 1 H), 2.25–2.14 (m, 2 H), 1.86–1.54 (m, 8 H), 0.63 (s, 9
H), –0.14 (s, 3 H), –0.21 (s, 3 H).
3-[1-{[tert-Butyl(dimethyl)silyloxy}-3-(6-oxo-1,6-dihydropyri-
din-2-yl)propyl]-1-methyl-1,5,6,7-tetrahydro-2H-cyclopen-
ta[b]pyridin-2-one (19)
To a solution of 3-{3-[6-(benzyloxy)pyridin-2-yl]-1-[tert-butyl(di-
methyl)silyloxy]prop-2-ynyl}-1-methyl-1,5,6,7-tetrahydro-2H-cy-
clopenta[b]pyridin-2-one (56.1 mg, 0.112 mmol) in EtOAc (4 mL)
and EtOH (2 mL) was added 5% Pd/C (5.6 mg) and placed under
one atmosphere of H2. After 3 h, the mixture was filtered through
Celite, concentrated in vacuo, and purified by flash chromatography
(MeOH–CH2Cl2, 1:9) to provide 19 (41.9 mg, 91%) as a colorless
foam; Rf 0.50 (MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): =11.7 (br s, 1 H, NH), 7.44 (s, 1 H), 7.28–7.25
(m, 1 H), 6.29 (d, J=7.5 Hz, 1 H), 6.04 (d, J=7.5 Hz, 1 H), 5.03 (t,
J=5.0 Hz, 1 H), 3.48 (s, 3 H), 2.88 (t, J=7.5 Hz, 2 H), 2.77 (t, J=7.5
Hz, 2 H), 2.67–2.51 (m, 2 H), 2.18–1.90 (m, 4 H), 0.88 (s, 9 H), 0.02
(s, 3 H), –0.09 (s, 3 H).
13C NMR (CDCl3–MeOH-d4): =179.9, 178.5, 152.6, 140.3, 130.4,
120.6, 73.4, 69.6, 69.2, 66.0, 59.0, 40.9, 34.1, 33.4, 28.2, 25.3, 23.4,
17.6, –4.2, –4.6.
IR (KBr): =3170–3054, 2952–2859, 1662, 1448, 1130, 856, 799,
777 cm–1.
MS (EI): m/z (%)=325 (100), 279 (81), 222 (40), 160 (75), 75, (65).
Exact Mass (MH+): m/z Calcd 401.2258. Found 401.2260.
13C NMR (CDCl3): =164.6, 161.3, 149.4, 148.0, 141.2, 132.7,
131.2, 118.3, 117.0, 104.3, 68.5, 35.6, 32.5, 32.2, 30.5, 28.5, 25.9,
22.4, 18.1, –4.7, –5.0.
Anal. Calcd for C22H32N2O3Si: C 65.96, H 8.05, N 6.99; Found C
66.03, H 8.07, N 6.90.
MS (EI): m/z (%)=415 (MH+, 61), 283 (100).
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

1194
K. F. McGee, Jr. et al.
PAPER
(1S*,3aS*,6S*,6aR*,10aS*)-1-{[tert-Butyl(dimethyl)silyl]oxy}-
2,3,8,9-tetrahydro-1H,4H,7H-3a,6-etheno-6a,10a-(iminometh-
ano)dicyclopent[b,e]azocine-5,11(6H)-dione (23)
A solution of 16 (50 mg, 0.12 mmol) in benzene-d6 (2.5 mL) at 5°C
was irradiated for 3 h with a Hanovia 450 W medium pressure mer-
cury lamp in a water-cooled quartz jacket fitted with a pyrex filter.
over 1 h, the reaction was quenched with 1 N HCl, washed with
brine and the aqueous layer was extracted with CH2Cl2 (3 15 mL).
The combined organics were dried (NaSO4) and concentrated in
vacuo. The residue was purified by flash chromatography (MeOH–
CH2Cl2, 1:9) to give the title compound (27.5 mg, 76%) as a color-
less solid; Rf 0.65 (MeOH–CH2Cl2, 1:9).
1H NMR (C6D6): =9.88 (br s, 1 H, NH), 9.51 (br s, 1 H, NH), 6.14
(br s, 1 H), 5.75 (t, J=7.5 Hz, 1 H), 5.62 (d, J=7.5 Hz, 1 H), 5.10 (br
s, 1 H), 2.80 (d, J=7.5 Hz, 1 H), 2.42 (br s, 1 H), 1.98–1.66 (m, 9
H), 0.96 (s, 9 H), 0.10 (s, 3H ), –0.08 (s, 3 H).
1H NMR (CDCl3): =8.08 (d, J=7.5 Hz, 1 H, NH), 6.10 (s, 1 H),
5.67 (s, 1 H, NH), 4.81 (t, J=6.3 Hz, 1 H), 3.93 (dd, J=5, 7.5 Hz, 1
H), 3.43 (t, J=5 Hz, 1 H), 3.34 (br s, 1 H), 3.10 (d, J=2.5 Hz, 1 H),
2.50–1.60 (m, 10 H), 1.14 (s, 3 H), 1.12 (d, J=1.8 Hz, 3 H), 0.87 (s,
9 H), 0.09 (s, 3 H), 0.04 (s, 3 H).
(5aR*,6R*,8aS*,12aS*,12bS*)-6-{[tert-Butyl(dimethyl)silyl]-
oxy}-2,3,7,8,12a,12b-hexahydro-1H,6H-cyclopenta[b]cyclo-
penta[2,3]pyrido[2',3':3,4]cyclobuta[1,2-d]pyridine-
5,10(4H,9H)-dione (24)
An NMR tube containing a 0.025 M solution of 16 (100 mg, 0.4
mmol) in benzene-d6 was irradiated for 3 h with a Hanovia 450 W
medium pressure mercury lamp fitted with a pyrex filter. The reac-
tion mixture was then placed in a 45°C water bath overnight to give
24 in quantitative yield; Rf 0.5 (MeOH–CH2Cl2, 1:9).
1H NMR (C6D6): =11.32 (br s, 1 H, NH), 9.06 (br s, 1 H, NH), 5.89
(d, J=10 Hz, 1 H), 5.68 (dd, J=5, 10 Hz, 1 H), 5.29 (t, J=6.7 Hz, 1
H), 3.34 (d, J=10 Hz, 1 H), 2.59 (dd, J=5, 10 Hz, 1 H), 2.36–2.24
(m, 2 H), 1.92–1.22 (m, 8 H), 0.91 (s, 9 H), 0.08 (s, 3 H), 0.05 (s, 3
H).
13C NMR (CDCl3): = 173.2, 164.6, 138.0, 135.3, 122.7, 108.8,
74.4, 67.9, 59.6, 40.4, 37.6, 34.9, 33.5, 31.6, 31.1, 29.7, 25.7, 22.1,
–4.81, –4.50.
13C NMR (CDCl3): =175.9, 169.9, 152.4, 150.1, 119.6, 73.9, 68.7,
65.5, 65.2, 56.2, 52.7, 44.7, 42.5, 35.0, 32.9, 28.7, 25.6, 23.4, 22.7,
22.6, 22.4, 17.8, –4.8, –5.0.
MS (FAB): m/z (%)=502 (MH+, 100), 417 (25), 359 (52), 85 (91).
Exact Mass (MH+): m/z Calcd 502.2737. Found 502.2750.
(1aR,1bR*,4R*,4aR*,8aR*,9S*,9S*)-4-{[tert-Butyl(dimethyl)si-
lyl]oxy}-N-ethyl-1a,3,4,7,8,9a-hexahydro-10,13-dioxo-
2H,6H,9H-1b,9:8a,4a-bis(iminomethano)dicyclopen-
ta[3,4:6,7]cyclooct[1,2-b]oxirene-12-carboxamide (30, R=Et)
Following the procedure for 30 (R=i-Pr) using ethyl isocyanate
gave the title compound as a colorless solid (92%); Rf 0.65
(MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): =8.17 (br s, 1 H, NH), 6.11 (br s, 1 H), 5.31 (br
s, 1 H, NH), 4.83 (t, J=6.25 Hz, 1 H), 3.44 (t, J=3.2 Hz, 1 H), 3.36
(s, 1 H), 3.28 (t, J=6.25 Hz, 2 H), 3.12 (d, J=2.5 Hz, 1 H), 2.48–
1.95 (m, 10 H), 1.14 (t, J=6.25 Hz, 3 H), 0.88 (s, 9 H), 0.11 (s, 3 H),
0.05 (s, 3 H).
MS (DCI): m/z (%)=401 (MH+, 30), 325 (20), 279 (39), 269 (100).
Exact Mass (MH+): m/z Calcd 401.2260. Found 401.2263.
MS (FAB+): m/z (%)=510 (MNa+, 31), 488 (MH+, 12), 392 (3), 219
(5), 165 (7).
(1aR*,1bR*,4R*,4aR*,8aR*,9S*,9aS*)-4-{[tert-Butyl(dimeth-
yl)silyl]oxy}-1a,3,4,7,8,9a-hexahydro-2H,6H,9H-1b,9:8a,4a-
bis(iminomethano)dicyclopenta[3,4:6,7]cyclooct[1,2-b]oxirene-
10,13-dione (25)
An NMR tube containing a 25 mM solution of 16 (45 mg, 0.11
mmol) in benzene-d6 and cooled in ice was irradiated for 3 h with a
Hanovia 450 W medium pressure mercury lamp fitted with a pyrex
filter. The resulting solution was mixed with dimethyldioxirane
(5.62 mL, 0.34 mmol) in acetone at 0°C. After stirring for 2 h, the
mixture was concentrated in vacuo, taken up in CH2Cl2, concentrat-
ed in vacuo again to give a yellow solid which was purified by flash
chromatography (MeOH–CH2Cl2, 1:9) to give 25 (41 mg, 84%) as
a colorless solid; Rf 0.55 (MeOH–CH2Cl2, 1:9).
Exact Mass (MNa+): m/z Calcd 510.2410. Found 510.2400.
(1aR,1bR*,4R*,4aR*,8aR*,9S*,9S*)-4-{[tert-Butyl(dimethyl)si-
lyl]oxy}-1a,3,4,7,8,9a-hexahydro-10,13-dioxo-N-phenyl-
2H,6H,9H-1b,9:8a,4a-bis(iminomethano)dicyclopen-
ta[3,4:6,7]cyclooct[1,2-b]oxirene-12-carboxamide (30, R=Ph)
Following the procedure for 30 (R=i-Pr) using phenyl isocyanate
gave the title compound as a light brown solid (79%); Rf 0.65
(MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): = 7.47 (br s, 1 H, NH), 7.88 (br s, 1 H, NH),
7.39–7.27 (m, 5 H), 6.04 (s, 1 H), 4.70 (s, 1 H), 3.39 (t, J=2.5 Hz, 1
H), 3.13 (s, 1 H), 2.90 (s, 1 H), 2.35–1.66 (m, 10 H), 0.88 (s, 9 H),
0.09 (s, 3 H), 0.03 (s, 3 H).
MS (FAB+): m/z (%)=558 (MNa+, 53), 536 (MH+, 30), 417 (9), 285
(15), 165 (13).
Exact Mass (MNa+): m/z Calcd 558.2399, Found 558.2399.
1H NMR (CDCl3): =8.31 (s, 1 H, NH), 8.18 (s, 1 H, NH), 6.02 (s,
1 H), 4.86 (d, J=5.0 Hz, 1 H), 3.38 (t, J=3.8 Hz, 1 H), 3.11 (d, J=5.0
Hz, 1 H), 2.88 (d, J=2.5 Hz, 1 H), 2.45 (m, 2 H), 2.25–2.09 (m, 4
H), 1.92–1.71 (m, 4 H), 0.88 (s, 9 H), 0.08 (s, 3 H), 0.03 (s, 3 H).
13C NMR (CDCl3): =176.7, 171.6, 149.9, 119.8, 73.9, 65.4, 64.7,
64.1, 56.8, 56.3, 52.9, 41.9, 34.7, 33.8, 29.1, 25.8, 23.8, 18.0, –4.6,
–4.8.
MS (FAB): m/z (%)=417 (MH+, 100), 359 (60), 285 (93), 78 (62).
Exact Mass (MH+): m/z Calcd 417.2209. Found 417.2204.
(1aR,1bR*,4R*,4aR*,8aR*,9S*,9S*)-4-{[tert-butyl(dimethyl)si-
lyl]oxy}-N-cyclohexyl-1a,3,4,7,8,9a-hexahydro-10,13-dioxo-
2H,6H,9H-1b,9:8a,4a-bis(iminomethano)dicyclopen-
ta[3,4:6,7]cyclooct[1,2-b]oxirene-12-carboxamide (30, R=cy-
clohexyl)
Following the procedure for 30 (R=iso-propyl) using cyclohexyl
isocyanate gave the title compound as a colorless solid (87%); Rf
0.65 (MeOH–CH2Cl2, 1:9).
1H NMR (CDCl3): =8.15 (d, J=7.5 Hz, 1 H, NH), 6.09 (s, 1 H),
5.49 (s, 1 H, NH), 4.80 (d, J=5.0 Hz, 1 H), 3.63 (m, 1 H), 3.42 (t,
J=5.0 Hz, 1 H), 3.33 (s, 1 H), 3.09 (d, J=2.5 Hz, 1 H), 2.47 (s, 2 H),
2.28–1.15 (m, 18 H), 0.86 (s, 9 H), 0.09 (s, 3 H), 0.04 (s, 3 H).
13C NMR (CDCl3): =175.9, 169.7, 152.4, 150.2, 119.6, 73.9, 68.7,
65.5, 65.2, 56.3, 52.8, 49.3, 44.8, 35.2, 32.9, 32.7, 28.8, 25.6, 25.5,
24.6, 24.5, 23.4, 17.8, –4.8, –5.0.
(1aR,1bR*,4R*,4aR*,8aR*,9S*,9S*)-4-{[tert-Butyl(dimethyl)-
silyl]oxy}-1a,3,4,7,8,9a-hexahydro-N-(1-methylethyl)-10,13-
dioxo-2H,6H,9H-1b,9:8a,4a-bis(iminomethano)dicyclopen-
ta[3,4:6,7]cyclooct[1,2-b]oxirene-12-carboxamide (30, R=i-Pr);
Typical Procedure
To a 0°C solution of 25 (30 mg, 0.072 mmol) in THF (2.0 mL) was
added NaH (60% in mineral oil, 12.1 mg, 0.3 mmol) and the reac-
tion mixture was allowed to warm to r.t. over the course of 1 h. The
flask was cooled to 0°C and isopropyl isocyanate (35.4 L, 0.36
mmol) was added dropwise over two min. After warming to r.t.
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Fusicoccin Synthesis by Intramolecular [4+4] Photocycloaddition of 2-Pyridones
1195
MS (FAB) m/z (%): 542 (MH+, 100), 417 (22), 359 (54), 85 (83).
Exact Mass (MH+): m/z Calcd 542.3066, Found 542.3050.
1.75 (m, 4 H), 1.23 (s, 3 H), 1.07 (d, J=6.3 Hz, 6 H), 0.87 (s, 9 H),
0.02 (s, 6 H).
13C NMR (CDCl3): =169.7, 162.8, 155.8, 136.1, 125.3, 81.9, 70.0,
60.7, 55.7, 51.1, 42.3, 41.7, 37.3, 32.7, 30.1, 29.7, 29.5, 25.6, 23.3,
21.3, 17.8, 16.4, –4.7, –4.9.
MS (FAB+): m/z (%)=488 (M – H+, 82.4), 386 (100).
Exact Mass (M – H+): m/z Calcd 488.2943, Found 488.2944.
N-[(1aR*,1bR*,4R*,4aS*,8aR*,9S*,9aS*)-4-{[tert-Butyl(di-
methyl)silyl]oxy}-1a,3,4,4a,6,7,8,9a-octahydro-4a-(hydroxy-
methyl)-10-oxo-2H-1b,9-(iminomethano)dicyclopen-
ta[3,4:6,7]cyclooct[1,2-b]oxiren-8a(9H)-yl]-N'-(1-methylethyl)-
urea (31)
To a –10°C solution of 30 (R=iso-propyl, 10 mg, 0.019 mmol) in
THF (400 L) was added dropwise LiBH4 (100 L, 2 M in THF)
over 1.5 min. After stirring at –5°C for 2 h, the mixture was warmed
to r.t. and stirred for an additional 4.5 h. The reaction was quenched
with 1 N HCl, extracted with CH2Cl2, concentrated in vacuo, and
purified by flash chromatography (MeOH–CH2Cl2, 1:9) to give 31
(6.4 mg, 64%) as a colorless solid; Rf 0.45 (MeOH–CH2Cl2, 1:9).
Acknowledgment
This work was supported by the National Institutes of Health
(GM45214). We thank Professor Joseph Lauher for the use of
ChemRay® for depiction of the X-ray structures.
1H NMR (CDCl3): =6.90 (br s, 1 H, NH), 5.54 (s, 1 H), 5.45 (br s,
1 H, NH), 5.08 (br s, 1 H, NH), 4.14 (br s, 1 H, OH), 4.08 (d, J=5.4
Hz, 1 H), 3.81 (d, J=4.2 Hz, 1 H), 3.74 (d, J=11.4Hz, 1 H), 3.70 (m,
1 H), 3.44 (br s, 1 H), 3.29 (m, 2 H), 2.70 (m, 2 H), 2.44 (m, 2 H),
2.19 (m, 1 H), 1.87 (m, 1 H), 1.67 (s, 4 H), 1.09 (dd, J=4, 6.6 Hz, 6
H), 0.85 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H).
MS (FAB): m/z (%)=506 (MH+, 100), 421 (53), 404 (26), 374 (81),
272 (35).
Exact Mass (MH+): m/z Calcd 506.3030, Found 506.3050.
References
(1) Current address: Albany Molecular Research, Inc., Albany,
NY 12203, USA.
(2) Current address: An-Najah National University, Nablus,
Palestine.
(3) (a) Kato, N.; Kataoka, H.; Ohbuchi, S.; Tanaka, S.;
Takeshita, H. J. Chem. Soc., Chem. Commun. 1988, 354.
(b) Rowley, M.; Tsukamoto, M.; Kishi, Y. J. Am. Chem. Soc.
1989, 111, 2735. (c) Boeckman, R. K. Jr.; Arvanitis, A.;
Voss, M. E. J. Am. Chem. Soc. 1989, 111, 2737. (d) Kato,
N.; Takeshita, H.; Kataoka, H.; Ohbuchi, S.; Tanaka, S. J.
Chem. Soc., Perkin Trans. 1 1989, 165. (e) Paquette, L. A.;
Wang, T.-Z.; Vo, N. H. J. Am. Chem. Soc. 1993, 115, 1676.
(f) Jamison, T. F.; Shambayati, S.; Crowe, W. E.; Schreiber,
S. L. J. Am. Chem. Soc. 1994, 116, 5505. (g) Okamoto, H.;
Arita, H.; Kato, N.; Takeshita, H. Chem. Lett. 1994, 2335.
(h) Paquette, L. A.; Sun, L.-Q.; Friedrich, D.; Savage, P. B.
Tetrahedron Lett. 1997, 38, 195. (i) Kato, N.; Zhang, C.-S.;
Matsui, T.; Iwabuchi, H.; Mori, A.; Ballio, A.; Sassa, T. J.
Chem. Soc., Perkin Trans. 1 1998, 2473.
(4) (a) A portion of this work was the subject of a
communication: Sieburth, S. McN.; McGee, K. F. Jr.; Al-
Tel, T. H. Tetrahedron Lett. 1999, 40, 4007. (b) See also
Refs 17 and 18.
(5) Sieburth, S. McN. The Inter- and Intramolecular [4 + 4]
Photocycloaddition of 2-Pyridones and Its Application to
Natural Product Synthesis, In Advances in Cycloaddition,
Vol. 5; Harmata, M., Ed.; JAI: Greenwich CT, 1999, 85–
118.
N-[(1aR*,1bR*,4R*,4aS*,8aR*,9S*,9aS*)-4-{[tert-Butyl(di-
methyl)silyl]oxy}-1a,3,4,4a,6,7,8,9a-octahydro-4a-[(methyl-
sulfonyl)oxymethyl]-10-oxo-2H-1b,9-(iminomethano)dicyclo-
penta[3,4:6,7]cyclooct[1,2-b]oxiren-8a(9H)-yl]-N'-(1-methyl-
ethyl)urea (32)
To a solution of 31 (6.4 mg, 0.013 mmol) in CH2Cl2 (300 L) was
added Et3N (1.8 L, 0.13 mmol) followed by mesyl chloride (10.1
L, 0.13 mmol). The reaction mixture was washed with H2O, ex-
tracted with CH2Cl2 (3 15 mL), dried (Na2SO4), concentrated in
vacuo and purified by flash chromatography (MeOH–CH2Cl2, 1:9)
to give 32 (5.6 mg, 76%) as a brown oil; Rf 0.5 (MeOH–
CH2Cl2, 1:9).
1H NMR (CDCl3): =7.08 (br s, 1 H, NH), 5.47 (s, 1 H), 4.66 (br s,
2 H, NH), 4.32 (d, J=10 Hz, 1 H), 4.09 (d, J=5.4 Hz, 1 H), 3.93 (d,
J=10 Hz, 1 H), 3.78 (m, 1 H), 3.62 (m, 1 H), 3.33 (br s, 1 H), 3.26
(br s, 1 H), 3.06 (s, 3 H), 2.67 (m, 2 H), 2.44 (m, 2 H), 2.19 (m, 2
H), 1.72 (m, 4 H), 1.07 (dd, J=4, 6.3 Hz, 6 H), 0.85 (s, 9 H), 0.08
(s, 3 H), 0.07 (s, 3 H).
13C NMR (CDCl3): =169.7, 162.8, 156.8, 136.2, 121.3, 81.4, 78.8,
72.7, 66.3, 63.0, 60.4, 55.2, 52.4, 41.6, 40.0, 37.4, 36.5, 29.6, 25.6,
23.3, 23.1, 22.2, 17.7, –4.3, –4.8.
(6) Nakamura, Y.; Kato, T.; Morita, Y. Tetrahedron Lett. 1981,
22, 1025.
(7) See Sieburth, S. McN.; Lin, C.-H. J. Org. Chem. 1994, 59,
3597; and references cited therein.
(8) Sieburth, S. McN.; Hiel, G.; Lin, C.-H.; Kuan, D. P. J. Org.
Chem. 1994, 59, 80.
MS (FAB) m/z (%)=584 (MH+, 51), 488 (62), 386 (57).
Exact Mass (MH+): m/z Calcd 584.2848, Found 584.2825.
(9) Paine, J. B. III J. Heterocycl. Chem. 1987, 24, 351.
(10) Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.;
Tieckelmann, H. J. Org. Chem. 1967, 32, 4040.
(11) Chung, N. M.; Tieckelmann, H. J. Org. Chem. 1970, 35,
2517.
(12) Compound 21 crystallizes in the monoclinic space group
P21/n with a=10.541(3) Å, b=16.593(2) Å, c=26.791(6) Å,
=90.36(1)°, V=4686(2) Å3, and Z=4. Final least squares
refinement using 1622 unique reflections with I > 3 (I) gave
R1 (wR2)=0.060 (0.055)
N-[(1aR*,1bR*,4R*,4aS*,8aR*,9S*,9aS*)-4-{[tert-Butyl(di-
methyl)silyl]oxy}-1a,3,4,4a,6,7,8,9a-octahydro-4a-methyl-10-
oxo-2H-1b,9-(iminomethano)dicyclopenta[3,4:6,7]cyclooct[1,2-
b]oxiren-8a(9H)-yl]-N'-(1-methylethyl)urea (33)
To a solution of 32 (11.7 mg, 0.02 mmol) in DMF (18.2 mL) was
added NaI (15 mg, 0.1 mmol) and zinc powder (99.998%, 100
mesh, 13.1 mg, 0.2 mmol). The mixture was heated to 110°C over-
night. The mixture was cooled, diluted with Et2O, washed with
brine (3 20 mL) and concentrated in vacuo to give 33 (9.31 mg,
95 %) as a colorless solid; Rf 0.65 (MeOH–CH2Cl2, 1:9).
(13) Taylor, E. C.; Kan, R. O. J. Am. Chem. Soc. 1963, 85, 776.
(14) Paquette, L. A.; Slomp, G. J. Am. Chem. Soc. 1963, 85, 765.
(15) Meyers, A. I.; Singh, P. J. Org. Chem. 1970, 35, 3022.
1H NMR (CDCl3): =5.97 (s, 1 H), 5.51 (br s, 1 H, NH), 5.32 (br s,
1 H, NH), 4.23 (d, J=9 Hz, 1 H, NH), 3.83–3.78 (m, 1 H), 3.59 (br
s, 1 H), 3.13–3.10 (m, 2 H), 2.70–2.61 (m, 3 H), 2.27–2.16 (m, 4 H),
Synthesis 2001, No. 8, 1185–1196 ISSN 0039-7881 © Thieme Stuttgart · New York

1196
K. F. McGee, Jr. et al.
PAPER
(16) (a) Ducharme, Y.; Wuest, J. D. J. Org. Chem. 1988, 53,
5787. (b) Gallant, M.; Phan Viet, M. T.; Wuest, J. D. J. Am.
Chem. Soc. 1991, 113, 721. (c) Simard, M.; Su, D.; Wuest,
J. D. J. Am. Chem. Soc. 1991, 113, 4696. (d) Persico, F.;
Wuest, J. D. J. Org. Chem. 1993, 58, 95. (e) Gallant, M.;
Phan Viet, M. T.; Wuest, J. D. J. Org. Chem. 1991, 56,
2284. (f) Boucher, E.; Simard, M.; Wuest, J. D. J. Org.
Chem. 1995, 60, 1408.
(28) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J. Org. Chem. 1983,
48, 2424.
(29) Sieburth, S. McN.; Rucando, D.; Lin, C.-H. J. Org. Chem.
1999, 64, 954.
(30) For a related example that does not involve ring opening
when a Boc-activated lactam of a pyridone photodimer is
reduced see: Spivey, A. C.; Andrews, B. I.; Brown, A. D.;
Frampton, C. S. Chem. Commun. 1999, 2523.
(17) Sieburth, S. McN.; McGee, K. F. Jr.; Al-Tel, T. H. J. Am.
Chem. Soc. 1998, 120, 587.
(31) Compound 30 crystallizes from MeCN in the monoclinic
space group P21/c with a=15.126(4) Å, b=12.900(3) Å,
c=15.592(4) Å, =111.70(2)°, V=2826.9(5) Å3, and Z=4.
Final least squares refinement using 2229 unique reflections
with I > 3 (I) gave R1 (wR2)=0.069 (0.088)
(32) Katagiri, N.; Muto, M.; Nomura, M.; Higashikawa, T.;
Kaneko, C. Chem. Pharm. Bull. 1991, 39, 1112.
(33) Fujimoto, Y.; Tatsuno, T. Tetrahedron Lett. 1976, 3325.
(34) Matsumoto, T.; Terao, H.; Wada, M.; Imai, S. Bull. Chem.
Soc. Jpn. 1991, 64, 2762.
(18) Sieburth, S. McN.; McGee, K. F. Jr. Org. Lett. 1999, 1, 1775.
(19) Reichardt, C. Solvents and Solvent Effects in Organic
Chemistry, 2nd ed.; VCH: New York, 1988.
(20) Vogel, E. Liebigs Ann. Chem. 1958, 615, 1.
(21) Carpenter, B. K. Tetrahedron 1978, 34, 1877.
(22) Delbecq, F.; Anh, N. T. New J. Chem. 1983, 7, 505.
(23) Dollinger, M.; Henning, W.; Kirmse, W. Chem. Ber. 1982,
115, 2309.
(24) Sieburth, S. McN.; Chen, J.; Ravindran, K.; Chen, J.-l. J.
Am. Chem. Soc. 1996, 118, 10803.
(25) Murray, R. W. Chem. Rev. 1989, 89, 1187.
(26) Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 1989,
22, 205.
(35) (a) Paquette, L. A. US Patent 3 321 482, 1967. (b) Chem.
Abstr. 1968, 68, 49577. (c) Paquette, L. A. US Patent 3 318
899, 1967. (d) Chem. Abstr. 1968, 68, 49579. (e) Paquette,
L. A. US Patent 3 432 507, 1969. (f) Chem. Abstr. 1969, 70,
96834. (g) Paquette, L. A. US Patent 3 466 292, 1969.
(h) Chem. Abstr. 1970, 72, 12781. (i) Paquette, L. A. US
Patent 3 562 252, 1971. (j) Chem. Abstr. 1971, 75, 20454.
(27) Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem. 1995,
67, 811.
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