Synthesis of carbocyclic hydantocidins via regioselective and diastereoselective phosphine-catalyzed [3 + 2]-cycloadditions to 5-methylenehydantoins

Article abstract of DOI:10.1021/jo050827h

The phosphine-catalyzed [3 + 2]-cycloaddition of 5-methylenehydantoins 4 with the ylides 5, derived from addition of tributylphosphine to the 2-butynoic acid derivatives, 6a-d, gives spiro-heterocyclic products. The camphor sultam derivative 6b gives optically active products. Noteable was that the ylides derived from ethyl 2-butynoate and the 3-(2-butynoyl)-1,3-oxazolidin-2-one derivatives 6c and 6d gave spiro-heterocyclic products with reverse regioselectivities. The N,N-dibenzylprotected cycloadduct has been converted to carbocyclic hydantocidin and 6,7-diepi-carbocyclic hydantocidin.

Full text of DOI:10.1021/jo050827h

Synthesis of Carbocyclic Hydantocidins via Regioselective and
Diastereoselective Phosphine-Catalyzed [3 + 2]-Cycloadditions to
5-Methylenehydantoins
Tien Q. Pham,† Stephen G. Pyne,*,† Brian W. Skelton,‡ and Allan H. White‡
Department of Chemistry, University of Wollongong, Wollongong, New South Wales, 2522, Australia, and
Department of Chemistry, University of Western Australia, Crawley, Western Australia, 6009, Australia
spyne@uow.au.edu
Received April 24, 2005
The phosphine-catalyzed [3 + 2]-cycloaddition of 5-methylenehydantoins 4 with the ylides 5, derived
from addition of tributylphosphine to the 2-butynoic acid derivatives, 6a-d, gives spiro-heterocyclic
products. The camphor sultam derivative 6b gives optically active products. Noteable was that the
ylides derived from ethyl 2-butynoate and the 3-(2-butynoyl)-1,3-oxazolidin-2-one derivatives 6c
and 6d gave spiro-heterocyclic products with reverse regioselectivities. The N,N-dibenzylprotected
cycloadduct has been converted to carbocyclic hydantocidin and 6,7-diepi-carbocyclic hydantocidin.
Introduction
Hydantocidin (1) is a naturally occurring spironucleo-
side that was first isolated from the culture broth of
Streptomyces hygroscopicus SANK 635841 and later from
other strains of Streptomyces including Tu-24742 and
A1491.3 Structurally, it features a spirohydantoin at-
tached to D-ribofuranose at the anomeric position. How-
ever biologically, it exhibits potent nonselective herbicidal
activities against annual weeds and perennial weeds1
with an efficacy similar to that of glyphosate.4 In contrast,
the phytotoxin showed low toxicity toward micro-organ-
isms, fungi, fish, and mice. In mice it had a LD50 > 1000
mg/kg.1
Further studies showed that hydantocidin acted as a
proherbicide, being phosphorylated at the 5′ position in
vivo.4 In the phosphorylated form (2), it strongly binds
to its target enzyme, adenylatesuccinate synthetase
(Adss).5-7 This is an enzyme involved in de novo purine
synthesis in plants that converts inosine monophosphate
(IMP) to adenosine monophosphate (AMP), an enzyme
system that no current herbicide targets. It was also
shown that hydantocidin was a competitive inhibitor of
IMP synthesis with a Ki of 22 nM, which is 1000 times
stronger than its competitor.7 X-ray crystallographic
analysis of the Adss-inhibitor complex of phosphorylated
hydantocidin 2 established that 2 bound to the same
active site and in the same way as AMP.6,8 Adss is also
the site of action for several antibiotics, including hada-
cidin and alanosine,9 suggesting that derivatives of
hydantocidin that inhibit this enzyme may also have use
in therapeutic applications.
The fermentation yield of hydantocidin from Strepto-
myces was low,1 and thus there was a drive for the
† University of Wollongong.
‡ University of Western Australia.
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T. J. Antibiot. 1991, 44, 293-300.
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10.1021/jo050827h CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/14/2005
J. Org. Chem. 2005, 70, 6369-6377
6369

Pham et al.
SCHEME 1
synthesis of optically active hydantocidin and its 15 other
possible stereoisomers around its four stereogenic cen-
ters.10-15 However, these studies showed that only the
natural configuration of hydantocidin showed any phy-
totoxic activity. Furthermore, deoxy derivatives of hy-
dantocidin, that is, compounds without the hydroxyl
groups, also revealed a dramatic decrease in activity,
signifying the importance of the hydrogen bonds to the
hydroxyl groups.5,16,17 N-Acetyl derivatives of hydantoci-
din were found to have no biological activity and there-
fore further illustrated the importance of hydrogen
bonding to the hydantoin ring.5 Herbicidal activity,
however, was maintained when the oxygen in the furan
ring was replaced with a carbon to form the carbocyclic
analogue (3).18
Many of the synthetic strategies for the synthesis of
hydantocidin and its analogues10,12,15,19,20 have revolved
around the use of sugar derivatives to generate the
desired stereochemistry of the hydroxyl groups in the
furan ring. By use of this strategy, hexofuranose,21-24
hexopyranose,25-27 and tetrofuranose28 analogues have
been generated. One problem associated with this strat-
egy is that anomerization at the spiro carbon (C5) can
occur during the synthesis; however, carbocyclic ana-
logues do not suffer from this detriment.18,29 Other
analogues of hydantocidin have involved modification of
the hydantoin ring,30 and it has been shown that thio-
hydantocidins, where the C2 carbonyl is replaced with a
thiocarbonyl, can be produced14,31 and used without the
loss of herbicidal activity.31
We report here a new strategy for the synthesis of
carbocyclic hydantocidin (3) and its 3′,4′-diepimer using
a phosphine-catalyzed [3 + 2]-cycloaddition of ethyl
2-butynoate 6a (6, X ) OEt) with N,N′-diprotected-5-
methylenehydantoins (4) to generate the key spiro-
heterocyclic system of these target molecules (Scheme 1).
The phosphine-catalyzed [3 + 2]-cycloaddition of ethyl
buta-2,3-dienoate or ethyl butynoate with electron-
deficient alkenes has been established as a useful method
for preparing substituted cyclopentenes32-45 both in ra-
cemic and enantio-enriched forms. However, only a few
examples of preparing spiro-heterocyclic derivatives us-
ing this method have been reported.36,41-45 Indeed, prior
to our initial communication,42 the phosphine-catalyzed
[3 + 2]-cycloaddition reactions of 5-methylenehydantoins
had not been described.42,43
(10) Mio, S.; Ichinose, R.; Goto, K.; Sugai, S.; Sato, S. Tetrahedron
1991, 47, 2111-20.
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1997, 53, 5813-5824.
Results and Discussion
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39, 3129-3132.
Synthesis of N,N′-Diprotected-5-methylenehydan-
toins. Surprisingly, with the exception of N,N′-dibenzyl-
5-methylenehydantoin (9),46,47 the literature is devoid of
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Org. Chem. 2000, 1831-1840.
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S. Tetrahedron 1995, 51, 12563-12572.
(19) Matsumoto, M.; Kirihara, M.; Yoshino, T.; Katoh, T.; Terashima,
Shiro Tetrahedron Lett. 1993, 34, 6289-6292.
(20) Harrington, P. M.; Jung, M. E. Tetrahedron Lett. 1994, 35,
5145-5148.
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Xu, J.-F.; Lao, X.-F. Chem. Commun. 1997, 79-81.
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(35) O’Donovan, B. F.; Hitchcock, P. B.; Meidine, M. F.; Kroto, H.
W.; Taylor, R.; Walton, D. R. M. Chem. Commun. 1997, 81-82.
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Commun. 1997, 2267-2268.
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Lilley, P. M.; Watkin, D. J.; Johnson, L. N.; Oikonomakos, N. G.; Fleet,
G. W. J. Tetrahedron Lett. 1995, 36, 2149-2152.
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N.; Crook, S.; de Q. Lilley, P. M.; Watkin, D. J.; Tsitsanou, K. E.;
Zographos, S. E. Tetrahedron 1996, 52, 10721-10736.
(23) Burton, J. W.; Son, J. C.; Fairbanks, A. J.; Choi, S.-m. S.; Taylor,
H.; Watkin, D. J.; Winchester, B. G.; Fleet, George W. J. Tetrahedron
Lett. 1993, 34, 6119-6122.
(37) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Am.
Chem. Soc. 1997, 119, 3836-3837.
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K.; Wouters, R.; Linden, I. V. d.; Biesmans, I.; Lesage, A. S. J.; Skelton,
B. W.; White, A. H. J. Org. Chem. 2002, 67, 227-233.
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Tetrahedron Lett. 2002, 43, 5953-5956.
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Tetrahedron: Asymmetry 1996, 7, 387-390.
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D.; Platt, F. M.; Tsitsanou, K. E.; Zographos, S. E.; Oikonomakos, N.
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Brennan, P. J.; Nash, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
1996, 7, 391-394.
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(46) Hess, W. C. J. Am. Chem. Soc. 1934, 56, 1421.
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6370 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of Carbocyclic Hydantocidins
TABLE 1. Tributylphosphine-Catalyzed [3 +
2]-Cycloaddition Reactions of 5-Methylenehydantions
with Ethyl 2-Butynonate (6a)
SCHEME 2
entry
hydantoin
products (yield, %)b [ratio A:B]c
1
2
3
4
5
9
18 + 19 (81) [>98:<2] + 26 (6)
18 + 19 (82) [80:20]
9a
10
16
17
20 + 21 (86) [83:17]
22 + 23 (43) [80:20]
24 + 25 (57) [78:22] + 27 (7)
a Ethyl 2,3-butadienoate and Ph3P were used in this reaction.
b Total yield of regioisomers A and B after purification by column
chromatography. c Ratio determined by 1H NMR on the crude
reaction mixture (see discussion for details).
+ 2]-cycloaddition reactions of the 5-methylenehydanto-
ins 9, 10, 16, and 17 with the ylide 5 (X ) OEt) that was
generated in situ from the reaction of ethyl 2-butynoate
6a and tributylphosphine (TBP) are shown in Table 1.
The reaction of 5-methylenehydantoin 9 with ethyl
2-butynoate (2 equiv) and TBP (0.1 equiv) in benzene
solution at room temperature (RT) for 15 h gave es-
sentially a single regioisomer (18) from 1H NMR analysis
of the crude reaction mixture. Column chromatography
gave diastereomerically pure and racemic 18 in 81%
yield, based on the moles of 9, along with a small amount
(6%) of the tricyclic product 26 (Table 1, entry 1). The
structure of 26 was determined from single-crystal X-ray
analysis (Supporting Information), which showed that
this compound arises from a further cycloaddition reac-
tion on the regioisomer 19 that could not be isolated from
the crude reaction mixture. An analogous tricyclic prod-
uct that could be formed from the reaction of 18 with the
ylide 5 (X ) OEt) was not detected. The related tri-
phenylphosphonium ylide of 5 (X ) OEt) was generated
in situ from ethyl buta-2,3-dienoate49 (2 equiv) and
triphenylphosphine (TPP, 0.1 equiv) and reacted with 9
to give an 80:20 mixture of the two regioisomers 18 and
19 that were readily separated by column chromatogra-
phy (Table 1, entry 2). Pure 18 and 19 (both racemic)
were obtained in yields of 65 and 17%, respectively. Soon
after our initial communication on this work, Lu’s group43
reported that the TPP-catalyzed [3 + 2]-cycloaddition
reaction of ethyl buta-2,3-dienoate and 9 in toluene gave
a 65:35 mixture of 18 and 19 in 96% yield, while tert-
butyl buta-2,3-dienoate gave a 74:26 mixture of the tert-
butyl ester analogues of 18 and 19, respectively. They
also reported that the combination of tert-butyl-2-bu-
tynoate/TBP and 9 gave a much enhanced regioselectivity
of >97:3. While these two independent studies have been
performed using different reaction solvents and concen-
trations (0.27 M in our case and 0.1 M in Lu’s43) and ester
groups, they both show that the regioselectivity is better
using the alkyne/TBP system rather than the allene/TPP
system as a precursor to the ylide 5 or its triphenylphos-
phonium analogue. In our studies, the amount of 19
formed in Table 1, entry 1, is underestimated since at
least 6% of this compound is formed but reacts with
excess ylide to form the tricyclic compound 26.
methods for the synthesis of usefully diprotected, N,N′-
diprotected-5-methylenehydantoins. Compound 9 and its
previously unreported N,N′-diPMB analogue (10) were
prepared from the base-catalyzed reactions of cystine
hydantoin (8)47 and the appropriate arylmethyl bromide
(Scheme 2). The former compound was isolated pure after
column chromatography in 83% yield while the latter in
only 64% due to concomitant formation of the mono-N3-
protected-5-methylenehydantoin 11 in 15% yield. At-
tempts to prepare N,N′-diacetyl-protected hydantoins
from serine hydantoin (12)46,48 or S-methylcystein hy-
dantoin (not shown)46,47 were not successful due to the
lability of the N3-acetyl group to column chromatography,
even though 1H NMR analysis of the crude reaction
mixtures showed both nitrogens had been acetylated
(Scheme 2). For example, serine hydantoin 12 upon
acetylation with an excess amount of acetic anhydride
in DMF at 45 °C for 24 h gave, after evaporation of all
volatiles, a sample that showed resonances for N,N′-
diacetyl-5-methylenehydantoin; however, after column
chromatography only the N1-acetyl-5-methylenehydan-
toin 13 could be isolated in modest yield (34%). The
position of the acetyl group in 13 was unequivocally
determined by X-ray crystallographic analysis (Support-
ing Information). This structure was not unexpected
considering that the N3-nitrogen is flanked by two
electron-withdrawing carbonyl groups that makes the
N3-acetyl group more labile toward acid- or base-
catalyzed hydrolysis. The N,N′-diboc-protected-5-meth-
ylenehydantoin 14 was more stable but could only be
isolated in 32% yield. High yields (91-92%) of the N3-
benzyl, N1-acetyl, and N1-Boc-5-methylenehydantoins 16
and 17 could be obtained directly from N3-benzyl serine
hydantoin 1511 by base-catalyzed N- and O-acylation with
concomitant elimination of the O-acylated group as
shown in Scheme 2.
The related PMB analogue (10) of 9 gave a 83:17
mixture of regioisomeric cycloaddition products, 20 and
21, respectively (Table 1, entry 3). Diastereomerically
pure 20 could be isolated in 68% yield after column
[3 + 2]-Cycloaddition Reactions of 5-Methylene-
hydantoins. The results of the phosphine-catalyzed [3
(48) Meanwell, N. A.; Roth, H. R.; Smith, E. C. R.; Wedding, D. L.;
Wright, J. J. K. J. Org. Chem. 1991, 56, 6897-904.
(49) Lang, R. W.; Hansen, H.-J. Org. Synth. 1984, 62, 202-209.
J. Org. Chem, Vol. 70, No. 16, 2005 6371

Pham et al.
SCHEME 3. Compounds 18-27 are Racemic
SCHEME 4
TABLE 2. Tributylphosphine-Catalyzed [3 +
2]-Cycloaddition Reactions of 5-Methylenehydantions
with the Chiral 2-Butanoyl Compounds 6b and 6c and
Achiral 6d
chromatography. The N1-acetyl and N1-Boc-N3-benzyl-
5-methylenehydantoins 16 and 17 also reacted with the
ylide derived from 6a to give 22 and 24 as the major
regioisomers, respectively (Table 1, entries 4 and 5). In
the latter reaction the tricyclic compound 27 was also
isolated in 7% yield and had similar NMR spectral data
to those of 26. Compound 27 was thus assumed to have
a similar structure and relative stereochemistry to 26.
In general, type A regioisomers 18, 20, 22, and 24
showed olefinic proton resonances upfield (δ 6.40-6.69)
of the corresponding resonances for type B regioisomers
19, 21, 23, and 25 (δ 7.02-7.20). Integration of these
olefinic resonances, on the crude reaction mixtures, was
used to determine the regioselectivities of the reactions
reported in Table 1. The structures of 18 and 19 were
determined by extensive 2D NMR studies and from
single-crystal X-ray analysis of the derivatives, 48 and
50, of 18.
To prepare enantiomerically enriched versions of these
cycloadducts, the corresponding cycloadditions reactions
with the chiral (1S)-camphor sultam50 and the (4S)-
benzyl-2-oxazolidinone,50 2-butynoyl derivatives, 6b and
6c, respectively, were examined (Scheme 4 and Table 2).
The TBP-catalyzed cycloaddition reaction between 9 and
the chiral (1S)-camphor sultam 2-butynoyl derivative 6b
gave a single regioisomeric product (28b) (Table 2, entry
1) but as a 1:1 mixture of diastereomers. These were
readily separated by column chromatography into their
pure (1R)- ([R]D22 -25 (c 1.7, CHCl3)) and (1S)- ([R]D22 -10
(c 1.7, CHCl3)) diastereomers in a combined yield of 74%.
The absolute stereochemistry of these diastereomers was
determined by single-crystal X-ray analysis of (1R)-28b
(see Supporting Information). In contrast, TBP-catalyzed
cycloaddition reaction between 9 and the chiral (4S)-
benzyl-2-oxazolidinone 2-butynoyl derivative 6c gave a
mixture of regioisomeric products, 28c and 29c, in a ratio
of 11:89, respectively. Surprisingly, the regioisomer 29c,
2-butanoyl
products
entry derivative 6 hydantoin yielda
(Ratio A [de]:B [de])b
1
2
3
4
5
6b
6c
6c
6c
6d
9
74% 28b (100 [0]:0)
9
54%b 28c + 29c (11 [0]:89 [98%])
32%c 30c + 31c (18 [0]:82 [98%])
43% 32c + 33c (5 [0]:95 [98%])
42% 28d + 29d (20:80)
10
17
9
a Total yield of regioisomers A and B after purification by
column chromatography. b Ratio determined by 1H NMR on the
crude reaction mixture (see discussion for details). c 17% of (4S)-
benzyl-2-oxazolidinone was also isolated. d 12% of (4S)-benzyl-2-
oxazolidinone was also isolated.
a type-B regioisomer, was the major product. Diastereo-
merically pure 29c could be obtained after purification
of the crude reaction mixture by column chromatography,
while 28c was isolated as a 1:1 mixture of diastereomers
(Table 2, entry 2). Similar regiochemical results were
obtained from the reactions of 6c with the 5-methylene-
hydantoins 10 and 17 (Table 2, entries 3 and 4), with
31c and 33c being formed as the major regioisomers,
respectively, and as single diastereomers. The reaction
between 9 and the achiral analogue 6d51 of 6c also
favored the formation of regioisomer B (29d) over regio-
isomer A (28d) (29d:28d ) 80:20, Table 2, entry 5). Thus
the reactions of 5-methylenehydantoins with the ylides
generated from 6a and 6b favor regioisomeric products
of the type A, while ylides derived from the 2-oxazolidi-
none 2-butynoyl derivatives 6c and 6d favor regioiso-
meric products of the type B. In the case of 6c, these
type-B products are obtained as single diastereomers.
The relatively low yields of these cycloadducts were likely
due to the instability of the COX group (compare with
Scheme 5).
(50) Fonquerna, S.; Moyano, A.; Pericas, M. A.; Riera, A. Tetrahe-
dron: Asymmetry 1997, 8, 1685-1691.
(51) Evans, D. A.; Miller, S. J.; Lectka, T.; von Matt, P. J. Am. Chem.
Soc. 1999, 121, 7559-7573.
6372 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of Carbocyclic Hydantocidins
SCHEME 5a
SCHEME 6a
a Reagents and conditions: (a) Sm(OTf)3, MeOH, reflux, 12 h,
70%. (b) CAN, MeCN, RT, 45 min. (c) 10% HCl, 100 °C, 30 min,
microwave reactor, 100%.
a Reagents and conditions: (a) HPLC separation (Supporting
Information). (b) Sm(OTf)3, MeOH, reflux, 12 h, 20% (38), 37%
(39).
SCHEME 7
The reaction of ethyl acrylate with ylide 5 (R ) OEt)
is known to give an 89:11 mixture of diethyl 3-cyclopro-
pene-1,3-dicarboxylate and diethyl 2-cyclopropene-1,2-
dicarboxylate, respectively.32 Thus the regiochemical
sense of this reaction is similar to that of the reactions
of 6a with 9. Treatment of methyl acrylate with the ylide
6c gave essentially a 1:1 mixture of the two possible
regioisomers 34 and 35 in low yield (39%) (Scheme 5).
Products arising from cleavage of the chiral auxiliary (HX
and MeO2CH2CH2X), presumably by TBP, were also
isolated. Diastereomers 36 and 37 (Scheme 5) were
formed in a ratio of 82:18 and could be separated by
preparative high-performance liquid chromatography
(HPLC), while 34 was a 54:46 mixture of diastereomers.
Diastereomers 36 and 37 were readily converted to the
known dimethyl esters (R)-38 and (S)-39, respectively.52
because of the volatility of these diesters, their isolated
yields were low (20-37%). Chiral gas chromatography
(GC) analysis (Supporting Information) indicated that
these diesters were isolated in >98% enantiomeric excess
(ee), and the sign of their optical rotations confirmed their
absolute stereochemistries.52
relative structure could be unequivocally determined by
X-ray crystallographical structural analysis (Supporting
Information), confirming the above regiochemical assign-
ments of our B-type regioisomeric cycloaddition products.
Microwave-assisted acid hydrolysis of 41 using 1N HCl
at 100 °C for 30 min gave the known amino diacid 44.41
23
Its optical rotation ([R]D -12 (c 1.05, H2O)) matched
To determine the absolute stereochemistry of 31c, the
chiral auxiliary was removed by treatment with samari-
um(III) triflate in methanol53 to give the methyl ester 40
in 70% yield. (Scheme 6). Treatment of 40 with ceric
ammonium nitrate in acetonitrile/water gave the desired
closely in magnitude to that of the S enantiomer (ee 88%)
of this compound ([R]D23 +11 (c 0.4, H2O)),41 and the sign
of the rotation indicated that 44 had the R stereochem-
istry.
The difference in regiochemical outcomes between the
ylides generated from 6a and 6c,d with methyl acrylate,
9, and 10 suggests that electronic effects are responsible
for the reversal of regiochemistry rather than steric
effects. On the basis of steric considerations only, transi-
tion state A would be expected to be less sterically
crowded and favored over transition state B for both
ylides (Scheme 7). Preliminary semiemperical calcula-
tions (AM1, PC Spartan Pro) on the ylides 5a (R ) OEt)
24
N,N-dideprotected derivative 43 [([R]D -33 (c 0.45,
CHCl3)] in 26% yield plus the monodeprotected/benzylic
oxidation products, the amides 41 (62%) and 42 (11%).
Compound 42 formed single crystals from which its
(52) Suemune, H.; Tanaka, M.; Obaishi, H.; Sakai, K. Chem. Pharm.
Bull. 1988, 36, 15-21.
(53) Evans, D. A.; Scheidt, K. A.; Downey, C. W. Org. Lett. 2001, 3,
3009-3012.
J. Org. Chem, Vol. 70, No. 16, 2005 6373

Pham et al.
SCHEME 8. All Compounds are Racemica
and 5d (R ) N-oxazolidinone) suggest that the magnitude
of the frontier molecular orbital coefficient of the highest-
occupied molecular orbital of 5d is significantly larger
at the γ-position than that in 5a, consistent with a
reversing of the observed regiochemical outcomes.
The absolute stereochemistry of the major B-type
regioisomeric cycloaddition product 36, formed in Scheme
5, can be rationalized as arising from the endo transition
state C (Scheme 7). The ylide 5d (R ) chiral N-
oxazolidinone) would be expected to have the enolate
oxygen and the phosphonium cation in an electrostati-
cally favorable syn-periplanar arrangement, while the
endo and exo cyclic carbonyl groups in the ylide would
be expected to have an anti-periplanar arrangement to
minimize unfavorable dipolar interactions. The stereo-
chemistry observed in cycloadduct 31c, however, suggests
that the related exo-transition state D (Scheme 7) may
be favored. Indeed, exo-selective Diels-Alder reactions
of cyclic exocyclic-methylene dienophiles related to 9, 10,
and 17 are well documented,54 and it has been suggested
that dipole-dipole interactions between the diene and
dienophile are responsible for this selectivity.54b
Synthesis of Carbocylic Hydantocidin and its
6,7-Diepimer. Deconjugation of 18 was effected by
deprotonation with potassium bistrimethylsilylamide
under an argon atmosphere, followed by a low-temper-
ature quench with acetic acid of the resulting enolate
(Scheme 8). This gave a 3:2 mixture of the epimeric esters
45 and 46, respectively, that were readily separated by
column chromatography. Intersestingly, deprotonation
with potassium bistrimethylsilylamide under a nitrogen
atmosphere gave rise to the ketone 51 (42% yield) and
the R-hydroxy ester 52 (37% yield) as a single diastere-
omer (Scheme 9). These compounds presumably arise
from the reaction of the enolate anion with traces of
molecular oxygen. Cis-dihydroxylation of 45 and 46 using
catalytic osmium tetroxide gave the respective diols 47
(74%) and 48 (60%) as single diastereomers; the diol 47
was converted to the acetonide 49 under standard condi-
tions (Scheme 8). The facial selectivity of these dihy-
droxylation reactions appears to be controlled by the ester
group, with both products 47 and 48 arising from
dihydroxylation from the most hindered face of the alkene
moiety and syn to the ester group. Attempts to convert
49 to the target molecule by selectively reducing the ester
group in this compound were thwarted due to competing
reduction of the hydantoin carbonyl. For example, at-
tempts to reduce the ester group in 49 with lithium
borohydride gave the alcohol 50 in 71% yield and the diol
product (structure not shown) from reduction of the
hydantoin ring and the ester group. The relative stereo-
chemistry of the compounds shown in Scheme 8 was
based on the single-crystal X-ray structures of 48 and
50 (Supporting Information). In contrast, deconjugation
of 28b was highly diastereoselective, and the resulting
product 53 was converted to 54, the chiral methyl ester
analogue of 49 (Scheme 10). The overall yield for this
process was low, presumably due to the lability of the
chiral auxiliary. Compounds 49 (racemic) and 54 had
a Reagents and conditions: (a) (i) KN(TMS)2, THF, -78 °C, 10
min, (ii) HOAc, -78 °C to RT, 99%. (b) K2OsO4‚2H2O, NMO,
acetone/H2O (4:1), RT,
5 days, 74% (47), 60% (48). (c)
MeC(OMe)2Me, p-TsOH, DCM, RT, 8 h, 94%. (d) LiBH4, MeOH,
Et2O, RT, 1 h, 71%.
SCHEME 9. All Compounds are Racemica
a Reagents and conditions: (a) (i) KN(TMS)2, THF, -78 °C, 1
h, (ii) HOAc, -78 °C to RT, 42% (51), 37% (52).
identical NMR spectral characteristics, except for their
ester resonances.
An alternative and more successful approach to the
target compounds is shown in Scheme 11. Acid-catalyzed
hydrolysis of the ester group of 45 smoothly gave the
carboxylic acid 55 in quantitative yield. Attempts at a
base-catalyzed hydrolysis with sodium hydroxide/metha-
nol/water gave 55 as a 5:1 mixture of epimers. Chemose-
lective reduction of the acid group of 55 to give 56 was
achieved in high yield (95%) using a borane-dimethyl
sulfide complex. Cis-dihydroxylation of 56 gave a 2:1
(54) (a) Roush, W. R.; Essenfeld, A. P.; Warmu, J. S.; Brown, B. B.
Tetrahedron Lett. 1989, 30, 7305-7309. (b) Roush, Brown, B. B. J.
Org. Chem. 1992, 57, 3380-3387. (c) Mattay, J.; Mertes, J.; Mass, G.
Chem. Ber. 1989, 122, 327-330. (d) Pyne, S. G.; Dikic, B.; Skelton, B.
W.; White, A. H. Chem. Commun. 1991, 1505-1506.
6374 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of Carbocyclic Hydantocidins
SCHEME 10a
“Cieplak effect” in which the developing vacant C-O σ*
bonds would prefer to overlap with the more electron rich
R-C-H σ bond rather than the more electron poor
R-C-CO2Et σ bond.55 A number of methods were at-
tempted to reductively remove the N-benzyl protecting
groups in the corresponding acetonide derivatives of 57
and 58 (not shown). Catalytic hydrogenolysis or Birch-
type reductions were unsuccessful. The former resulted
in recovered starting material, and the latter gave mono-
deprotection and/or reduction of the aromtatic rings to
dihydrobenzenes and/or reduction of the hydantoin car-
bonyls. The most successful method proved to be benzylic
bromination of a mixture of triacetates 59 and 60 with
NBS/AIBN in a solution of chlorobenzene at reflux tem-
perature, followed by hydrolysis on the intermediate
benzylbromide with water.56 Treatment of a 2:1 mixture
of 59 and 60, respectively, with 3 equiv of NBS at 125
°C in a sealed tube for 14 h, followed by the addition of
water, gave the fully debenzylated compounds 63 (31%
yield) and 64 (15%) along with their mono-debenzylated
products 61 (25% yield) and 62 (11% yield). All four
compounds were readily separated by flash column
chromatography. The structure of 63 was unequivocally
established by single-crystal X-ray crystallography (Sup-
porting Information). Acid-catalyzed hydrolysis of the
individual triacetates 63 and 64 gave pure samples of
6,7-diepi-carbocyclic hydantocidin 65 and carbocyclic
hydantocidin 3, respectively, in high yields (95-99%).
The latter had spectral properties identical to those
reported in the literature.18,29
a Reagents and conditions: (a) (i) KN(TMS)2, THF, -78 °C, 1
h, (ii) HOAc, -78 °C to RT, 90% (a) K2OsO4‚2H2O, NMO, acetone/
H2O (4:1), RT, 5 days, 37% (+46% recovered 53). (c) MeC(OMe)2Me,
p-TsOH, DCM, RT, 8 h, 53%.
SCHEME 11. All Compounds are Racemica
In conclusion, we have developed a synthesis of car-
bocyclic hydantocidins using a phosphine-catalyzed [3 +
2]-cycloaddition reaction of ethyl 2-butynoate with N,N′-
dibenzyl-5-methylenehydantoin to generate the key spiro-
heterocyclic system of these target molecules. We have
also demonstrated the potential of obtaining chiral ver-
sions of these molecules using chiral auxiliaries on the
2-butynoate. Clearly other N-protecting groups on the
hydantoin ring need to be investigated in the future to
allow more efficient access to the final structures.
Experimental Section
All 1H NMR and 13C NMR were determined in CDCl3
solution at 300 and 75 MHz, respectively, unless otherwise
noted.
Ethyl 1,3-Dibenzyl-2,4-dioxo-1,3-diazaspiro[4.4]non-7-
ene-7-carboxylate (18), Ethyl 1,3-Dibenzyl-2,4-dioxo-1,3-
diazaspiro[4.4]non-6-ene-6-carboxylate (19), and Diethyl
1,3-Dibenzyl-2,5-dioxo-2′,3′,3a′,6′-tetrahydro-6a′H-spiro-
[imidazolidine-4,1′-pentalene]-4′,6a′-dicarboxylate (26).
Procedure A. To a solution of compound 9 (134 mg, 0.46
mmol) in dry benzene (1 mL) under a N2 atmosphere was
added ethyl 2-butynoate (103 mg, 0.92 mmol) followed by
tributylphosphine (9 mg, 0.046 mmol). The reaction mixture
was allowed to stir at ambient temperature for 15 h and was
then concentrated and then partitioned between diethyl ether
and water. The organic extract was dried (MgSO4), concen-
trated, and purified by column chromatography (30% EtOAc/
Pet. Spirits.) to give compound 18 as a colorless oil (150 mg,
81%) and compound 26 as a white solid (14 mg, 6%).
a Reagents and conditions: (a) 10% HCl, MeCN, 90 °C, 15 h,
99% (b) BH3‚DMS, THF, 0°C, 6 h, 95%. (c) K2OsO4‚2H2O, NMO,
acetone/H2O (4:1), RT, 5 days, 37% (+46% recovered 53). (d) Ac2O,
pyridine, MeCN, RT, 10 h, 91%. (e) (i) NBS, C6H5Cl, 125 °C, 14 h,
(ii) H2O. (f) 10% HCl, THF, reflux, 4 h, 95-99%.
mixture of the diols 57 and 58, respectively, that could
not be readily separated nor could their respective
triacetates, 59 and 60. This reduced diastereoselectivity
is consistent with the ester group being responsible for
the direction of dihydroxylation in the reactions of
compounds 45 and 46. One explanation for this is the
(55) Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540-4552.
Katagiri, N.; Ito, Y.; Kitano, K.; Toyota, A.; Kaneko, C. Chem. Pharm.
Bull. 1994, 42, 2653-2655.
(56) Baker, S. R.; Parsons, A. F.; Wilson, M. Tetrahedron Lett. 1998,
39, 331-332.
J. Org. Chem, Vol. 70, No. 16, 2005 6375

Pham et al.
Procedure B. Compound 9 (400 mg, 1.37 mmol) was
dissolved in benzene (5 mL), and then ethyl 2,3-butadienoate49
(307 mg, 2.74 mmol), followed by triphenylphosphine (36 mg,
0.137 mmol), were then added to the solution. The reaction
mixture was allowed to stir at ambient temperature for 24 h
before it was concentrated and then partitioned between
diethyl ether and water. The organic extract was dried
(MgSO4), concentrated in vacuo, and then purified by column
chromatography (30% EtOAc/Pet. Sp.) to give 2 regioisomers,
18 (361 mg, 65%) and 19 (94 mg, 17%) as oils. Spectral data
for 18 and 19 were comparable to those reported in the
literature.43 26: white solid (6%), mp 118-120 °C. 1H NMR δ
0.92 (t, 7.2 Hz, 3H), 1.28 (t, 7.2 Hz, 3H), 1.56-1.76 (m, 1H),
1.69-1.76 (m, 1H), 1.93-2.08 (m, 1H), 2.19-2.31 (m, 1H), 2.64
(dd, J ) 2.7, 20.7 Hz), 3.78 (q, J ) 7.2 Hz, 2H), 3.99 (d, J )
16.8 Hz, 1H), 4.11 (dt, J ) 2.4, 20.7 Hz), 4.14-4.22 (m, 2H),
4.25-4.29 (m, 1H), 4.68 (d, J ) 14.4 Hz, 1H), 4.86 (d, J ) 14.4
Hz, 1H), 5.08 (d, J ) 16.8 Hz, 1H), 6.54 (m, 1H), 7.20-7.52
(m, 5H). 13C NMR δ 13.9 (CH3), 14.3 (CH3), 29.9 (CH2), 35.1
(CH2), 39.8 (CH2), 43.0 (CH2), 44.8 (CH2), 51.7 (CH), 60.4 (CH2),
61.7 (CH2), 68.1 (C), 74.0 (C5), 126.0 (CH), 127.3 (CH), 127.7
(CH), 128.4 (CH), 128.5 (CH), 128.8 (CH), 135.9 (C), 137.4 (C),
138.2 (CH), 138.4 (C), 156.2 (C), 163.7 (C), 172.0 (C), 172.9
(C). MS: (CI + ve) m/z 517 (M + 1). HRMS (EI + ve) calcd.
for C30H32N2O6 (M+): 516.2260. Found: 516.2235.
(5RS,7SR)-1,3-Dibenzyl-2,4-dioxo-1,3-diazaspiro[4.4]-
non-8-ene-7-carboxylic Acid (55). Compound 45 (1.14 g,
2.82 mmol) in CH3CN (10 mL) was added to 10% HCl (10 mL).
The mixture was heated to 90 °C for 15 h before it was cooled
to RT and then extracted into ethyl acetate (2 × 50 mL). The
combined organic extract was dried (MgSO4) and concentrated
in vacuo to give 55 as a white solid (1.05 g, 99%), mp 140-
144 °C. 1H NMR δ 2.39 (dd, J ) 6.3, 14.4 Hz, 1H), 2.53 (dd, J
) 9.0, 14.4 Hz, 1H), 3.86 (ddt, J ) 2.4, 6.4, 9.0 Hz, 1H), 4.43
(d, J ) 15.9 Hz, 1H), 4.60 (d, J ) 15.9 Hz, 1H), 4.71 (s, 2H)
5.32 (dd, J ) 2.4, 5.4 Hz, 1H), 6.13 (dd, J ) 2.4, 5.4 Hz, 1H),
7.27-7.43 (m, 10H). 13C NMR δ 33.7 (CH2), 42.8 (CH2), 43.6
(CH2), 49.3 (CH), 76.3 (C), 127.7 (CH), 127.9 (CH), 128.2 (CH),
128.5 (CH), 128.5 (CH), 128.7 (CH), 131.0 (CH), 135.9 (C),
136.4 (CH), 137.3 (C), 155.6 (C), 174.3 (C), 177.7 (C). MS: (CI
+ ve) m/z 377 (M + 1). HRMS (CI + ve) Calcd. for C22H20N2O4
(M+): 376.1423. Found: 376.1406.
tography (460 mg, 63%) and therefore could not be analyzed
by NMR. MS: (CI + ve) m/z 397 (M + 1). HRMS (CI + ve)
Calcd. for C22H25N2O5 (MH+): 397.1763. Found: 397.1765.
(5RS,6RS,7SR,8RS)-6-(Acetyloxy)-8-[(acetyloxy)methyl]-
1,3-dibenzyl-2,4-dioxo-1,3-diazaspiro[4.4]non-7-yl acetate
(59) and (5RS,6SR,7RS,8RS)-6-(Acetyloxy)-8-[(acetyloxy)-
methyl]-1,3-dibenzyl-2,4-dioxo-1,3-diazaspiro[4.4]non-7-
yl Acetate (60). A solution of a mixture of triols 57 and 58
(300 mg, 0.757 mmol) in CH3CN (5 mL), pyridine (3 mL), and
acetic anhydride (5 mL) was stirred at RT for 10 h. After this
time, all volatiles were removed in vacuo. The resulting residue
was purified by column chromatography (30% EtOAc/Pet. Sp.)
to give compound 59 and its diepimer 60 as clear oils in a ratio
of 2:1, respectively (determined by 1H NMR integration of their
respective acetate resonances) (359 mg, total yield 91%). 59:
1H NMR δ 1.54 (dd, J ) 12.0, 13.8 Hz, 1H), 1.85 (dd, J ) 7.8,
13.8 Hz, 1H), 1.94 (s, 3H,), 1.99 (s, 3H), 2.25 (s, 3H,), 2.63 (m,
1H), 3.86 (dd, J ) 6.0, 11.1 Hz, 1H), 4.08 (dd, J ) 8.7, 11.1
Hz, 1H), 4.31 (d, J ) 16.2 Hz, 1H), 4.69 (ABq, J ) 7.5 Hz,
2H), 4.99 (d, J ) 16.2 Hz, 1H), 5.26 (d, J ) 4.2 Hz, 1H), 5.64
(t, J ) 4.2 Hz, 1H), 7.23-7.41 (m, 10H). 13C NMR δ 20.0 (CH3),
20.6 (CH3), 21.0 (CH3), 33.8 (CH2), 37.6 (CH), 42.8 (CH2), 44.6
(CH2), 61.3 (CH2), 68.6 (C), 72.4 (CH), 76.8 (CH), 126.9 (CH),
127.3 (CH), 128.3 (CH), 128.6 (CH), 128.8 (CH), 128.8 (CH),
135.7 (C), 137.8 (C), 156.5 (C), 169.1 (C), 169.2 (C), 170.5(C),
175.9 (C). MS: (CI + ve) m/z 523 (M + 1). HRMS (CI + ve)
Calcd. for C28H31N2O8 (MH+): 523.2080. Found: 523.2076.
60: 1H NMR δ 1.68 (s, 3H), 1.96 (m, 2H), 2.00 (s, 3H), 2.03 (s,
3H), 3.07 (m, 1H), 4.03 (apparent d, J ) 4.8 Hz, 2H), 4.35 (d,
J ) 16.2 Hz, 1H), 4.71 (ABq, J ) 9.3 Hz, 2H), 4.87 (d, J )
16.2 Hz, 1H), 5.01 (dd, J ) 7.2, 8.1 Hz), 5.28 (d, J ) 7.2 Hz,
1H), 7.23-7.41 (m, 10H). 13C NMR δ 20.0 (CH3), 20.4 (CH3),
20.6 (CH3), 30.1 (CH2), 40.8 (CH), 42.4 (CH2), 43.0 (CH2), 63.3
(CH2), 70.0 (CH), 71.2 (Cspiro), 71.3 (CH), 127.0 (CH), 127.6
(CH), 127.7 (CH), 127.8 (CH), 128.0 (CH), 128.4 (CH), 136.0
(C), 136.8 (CH), 155.9 (C), 169.1 (C), 170.2 (C), 170.5 (C), 171.6
(C). MS: (CI + ve) m/z 523 (M + 1). HRMS: (CI + ve) Calcd.
for C28H31N2O8 (MH+) 523.2080, Found 523.2076.
(5RS,6RS,7SR,8RS)-6,7-Di(acetyloxy)-8-[(acetyloxy)-
methyl]-3-benzyl-1,3-diazaspiro[4.4]nonane-2,4-dione
(61),
(5RS,6SR,7RS,8RS)-6,7-Di(acetyloxy)-8-[(acetyl-
oxy)methyl]-3-benzyl-1,3-diazaspiro[4.4]nonane-2,4-di-
one (62), (5RS,6RS,7SR,8RS)-6,7-Di(acetyloxy)-8-[(acetyl-
oxy)methyl]-1,3-diazaspiro[4.4]nonane-2,4-dione (63), and
(5RS,6SR,7RS,8RS)-6,7-Di(acetyloxy)-8-[(acetyloxy)-
methyl]-1,3-diazaspiro[4.4]nonane-2,4-dione (64). To a
sealed tube, under a N2 atmosphere, was added a mixture of
compounds 59 and 60 (500 mg, 0.96 mmol), freshly redistilled
chlorobenzene (20 mL), recrystallized N-bromosuccinamide
(511 mg, 2.87 mmol), and azobisisobutyronitrile (47 mg, 0.287
mmol). The reaction tube was sealed and heated to 125 ïC with
stirring for 14 h where it was then cooled on ice before it was
filtered. The filtrate was concentrated in vacuo to give a brown
residue, which was redissolved in ethyl acetate (20 mL) and
then washed with water (2 × 20 mL). The organic extract was
dried and solvent removed in vacuo to give an oily residue that
was purified by column chromatography (50% EtOAc/Pet. Sp
to 90% EtOAc/Pet. Sp.) to give 61 (103 mg, 25%), and its 6,7-
diepimer 62 (45 mg, 11% as oils and compound 63 (101 mg,
31%) and its 6,7-diepimer 64 (50 mg, 15%) were isolated as
white solids. 61: 1H NMR δ 1.84 (dd, J ) 9.9, 13.5 Hz, 1H),
1.91 (s, 3H), 2.03 (s, 3H), 2.14 (s, 3H), 2.55 (dd, J ) 9.0 Hz,
13.5 Hz, 1H), 2.63 (m, 1H), 4.01 (dd, J ) 6.3, 11.1 Hz, 1H),
4.15 (dd, J ) 8.1, 11.1 Hz, 1H), 4.63 (s, 2H), 5.15 (d, J ) 3.6
Hz, 1H), 5.62 (t, J ) 3.6 Hz, 1H), 6.20 (br s, 1H), 7.23-7.38
(m, 5H). 13C NMR δ 20.0 (CH3), 20.6 (CH3), 20.7 (CH3), 36.9
(CH2), 37.1 (CH), 42.4 (CH2), 61.8 (CH2), 65.8 (C), 73.6 (CH),
75.6 (CH), 127.9 (CH), 128.3 (CH), 128.6 (CH), 135.7 (C), 156.6
(C), 169.3 (C), 169.4 (C), 170.7 (C), 174.9 (C). MS: (CI + ve)
m/z 433 (M + 1). HRMS (CI + ve) Calcd. for C21H25N2O8
(MH+): 433.1603. Found: 433.1603. 62: 1H NMR δ 1.70 (dd,
J ) 9.0, 14.1 Hz), 1.91 (s, 3H), 2.06 (s, 3H), 2.07 (s, 3H), 2.53
(5RS,8SR)-1,3-Dibenzyl-8-(hydroxymethyl)-1,3-
diazaspiro[4.4]non-6-ene-2,4-dione (56). To a solution of
55 (900 mg, 2.39 mmol) in THF (20 mL) at 0 °C was added
dropwise a 2 M solution of borane.methyl sulfide in THF (1.32
mL, 2.64 mmol). Stirring was continued for 6 h before water
(10 mL) was added. After 10 min, the THF was removed in
vacuo and the remaining residue was extracted into ethyl
acetate (2 × 50 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo to give an oily residue.
Purification by column chromatography (50% EtOAc/Pet. Sp.
to 60% EtOAc/Pet. Sp.) gave the title compound 56 as a
colorless oil (822 mg, 95%). 1H NMR (CD3CN) δ 1.76 (dd, J )
6.3, 14.1 Hz, 1H), 2.30 (dd, J ) 8.4, 14.1 Hz, 1H), 2.98 (m,
1H), 3.44 (dd, J ) 2.1, 5.4 Hz), 4.43 (d, J ) 16.2 Hz), 4.52 (d,
J ) 16.2 Hz), 4.64 (s, 2H), 5.36 (dd, J ) 2.4, 5.4 Hz, 1H), 6.08
(dd, J ) 2.4, 5.4 Hz, 1H), 7.21-7.39 (m, 10H). 13C NMR δ 34.0
(CH2), 42.4 (CH2), 43.2 (CH2), 47.4 (CH), 64.8 (CH2), 76.7 (C),
127.4 (CH) 127.7 (CH), 127.8 (CH), 128.2 (CH), 128.4 (CH),
128.5 (CH), 129.2 (CH), 136.0 (C), 137.5 (C), 140.8 (CH), 155.7
(C), 174.9 (C). MS: (CI + ve) m/z 363 (M + 1). HRMS (CI +
ve) m/z Calc. for C22H23N2O3: 363.1708. Found: 363.1705.
(5RS,6SR,7RS,8RS)-1,3-Dibenzyl-6,7-dihydroxy-8-(hy-
droxymethyl)-1,3-diazaspiro[4.4]nonane-2,4-dione (57)
and Its Diepimer (5RS,6RS,7SR,8RS)-1,3-Dibenzyl-6,7-
dihydroxy-8-(hydroxymethyl)-1,3-diazaspiro[4.4]nonane-
2,4-dione (58). Compound 56 (670 mg, 1.85 mmol) was
dihydroxylated in the same manner as 45 in the synthesis of
47 (Supporting Information). After it was stirred for 3 days
at RT, the reaction produced a mixture of cis diols, 57 and 58,
as foams, which could not be separated by column chroma-
6376 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of Carbocyclic Hydantocidins
(dd, J ) 9.3 Hz, 14.1 Hz), 2.96 (m, 1H), 4.14 (dd, J ) 5.1, 11.4
Hz, 1H,), 4.18 (dd, J ) 4.8, 11.4 Hz, 1H), 4.63 (ABq, J ) 14.7
Hz, 2H), 5.16 (dd, J ) 6.0, 8.1 Hz, 1H), 5.28 (d, J ) 6.0 Hz,
1H), 6.78 (br s, 1H), 7.26-7.38 (m, 5H). 13C NMR δ 20.2 (CH3),
20.6 (CH3), 20.8 (CH3), 33.8 (CH2), 40.5 (CH), 42.3 (CH2), 63.8
(CH2), 66.9 (C), 71.9 (CH), 76.8 (CH), 127.9 (CH), 128.4 (CH),
128.6 (CH), 135.8 (C), 156.4 (C), 169.8 (C), 170.4 (C), 170.9
(C), 172.0 (C). MS: (CI + ve) m/z 433 (M + 1). HRMS (CI +
ve) Calcd. for C21H25N2O8 (MH+): 433.1603. Found: 433.1603.
63: White solid mp 163-165 ïC. 1H NMR δ 1.89 (dd, J ) 13.8,
17.7 Hz, 1H), 2.04 (s, 3H), 2.06 (s, 3H), 2.16 (s, 3H), 2.60 (dd,
J ) 9.0 Hz, 17.7 Hz), 2.62 (m, 1H), 4.03 (dd, J ) 5.7, 11.1 Hz,
1H), 4.17 (dd, J ) 8.1, 11.1 Hz, 1H), 5.14 (d, J ) 3.6 Hz, 1H),
5.64 (t, J ) 3.6 Hz, 1H), 5.87 (br s, 1H), 7.89 (br s, 1H). 13C
NMR δ 20.2 (CH3), 20.6 (CH3), 20.7 (CH3), 37.0 (CH) 37.4
(CH2), 61.8 (CH2), 66.9 (C), 73.5 (C(H), 75.7 (CH), 156.7 (C),
169.6 (C), 169.7 (C), 170.8 (C), 176.4 (C). MS: (CI + ve) m/z
343 (M + 1). HRMS (CI + ve) Calcd. for C14H19N2O8 (MH+):
343.1141. Found: 343.1131. 64: 1H NMR δ 1.76 (dd, J ) 8.4,
14.4 Hz, 1H), 2.08 (s, 3H), 2.09 (s, 3H), 2.10 (s, 3H), 2.63 (dd,
J ) 10.2, 14.4 Hz, 1H), 2.90 (m, 1H), 4.14 (dd, J ) 5.7, 11.4
Hz, 1H), 4.22 (dd, J ) 5.4, 11.4 Hz, 1H), 5.22 (dd, J ) 5.4, 8.4
Hz, 1H), 5.32 (d, J ) 5.4 Hz), 7.24 (br s, 1H), 8.73 (br s, 1H).
13C NMR δ 20.58 (CH3), 20.6 (CH3), 20.8 (CH3), 33.9 (CH2),
40.0 (CH), 64.1 (CH2), 67.6 (C), 72.5 (CH), 77.3 (CH), 156.4
(C), 170.2 (C), 170.5 (C), 171.2 (C), 173.1 (C). MS: (CI + ve)
m/z 343 (M + 1). HRMS (CI + ve) Calcd. for C14H19N2O8
(MH+): 343.1141. Found: 343.1133.
(5RS,6SR,7RS,8RS)-6,7-Dihydroxy-8-(hydroxymethyl)-
1,3-diazaspiro[4.4]nonane-2,4-dione (3). Compound 64 (20
mg, 0.058 mmol) was treated in the same manner as compound
63 for the synthesis of 65. The reaction gave the title compound
3 as a yellow solid (12 mg, 95%) (mp 150 °C, literature
value18,29 158-160 °C) with spectral data identical to those
reported in the literature.18,29
Acknowledgment. We thank the University of
Wollongong for financial support and for a Ph.D.
scholarship to T.Q.P. Use of the ChemMatCARS Sector
15 at the Advanced Photon Source was supported by
the Australian Synchrotron Research Program, which
is funded by the Commonwealth of Australia under the
Major National Research Facilities Program. Chem-
MatCARS Sector 15 is also supported by the National
Science Foundation/Department of Energy under Grant
Nos. CHE9522232 and CHE0087817 and by the Illinois
Board of Higher Education. The Advanced Photon
Source is supported by the U.S. Department of Energy,
Basic Energy Sciences, Office of Science, under Contract
No. W-31-109-Eng-38.
Supporting Information Available: Full experimental
details and characterization data and spectral assignments for
all compounds, including chiral GC traces and conditions.
Copies of the 1H and 13C NMR spectra of compounds 3, 9-11,
13-20, 22, 24, 26, 27, (1R)-28b, (1S)-28b, 29c,d, 31c, 33c,
36-38, 40-43, 45-49, 50-52, 54-56, and 61-65 and crystal/
refinement data and the molecular projections of compounds
13, 26, (1R)-28b, 42, 48, 50, and 63. CCDC depositions:
181271 (42), 269432 (13), 269433 (26), 269434 (63), 269435
(28b), 269436 (48), 269437 (50), and 269438 (50, ethyl acetate
solvate). This material is available free of charge via the
Internet at http://pubs.acs.org.
(5RS,6RS,7SR,8RS)-6,7-Dihydroxy-8-(hydroxymethyl)-
1,3-diazaspiro[4.4]nonane-2,4-dione (65). To a solution of
compound 63 (35 mg, 0.102 mmol) in THF (1 mL) was added
10% HCl (1 mL). The reaction mixture was heated at reflux
for 4 h before all volatiles were removed under reduced
pressure to yield the title compound 65 as a white solid (22
ï
1
mg, 99%), mp 203-204 C. H NMR (CD3OD) δ 1.74 (dd, J )
9.6, 13.8 Hz), 2.14 (m, 1H), 2.32 (dd, J ) 9.6, 13.8 Hz, 1H),
3.58 (dd, J ) 6.0, 10.8 Hz, 1H), 3.76 (dd, J ) 7.8, 10.8 Hz,
1H), 4.04 (d, J ) 3.3 Hz, 1H), 4.14 (t, J ) 3.3 Hz, 1H). 13C
NMR (CD3OD) δ 37.0 (CH2), 42.3 (CH), 62.3 (CH2), 70.8 (C),
75.1 (CH), 79.2 (CH), 159.4 (C), 180.9 (C). MS: (CI + ve) m/z
217 (M + 1). HRMS (CI + ve) Calcd. for C8H12N2O5 (MH+):
217.0824. Found: 217.0823.
JO050827H
J. Org. Chem, Vol. 70, No. 16, 2005 6377