Modified guanidines as potential chiral superbases. 3. Preparation of 1,4,6-triazabicyclooctene systems and 1,4-disubstituted 2-iminoimidazolidines by the 2-chloro-1,3-dimethylimidazolinium chloride-induced cyclization of guanidines with a hydroxyethyl substituent

Article abstract of DOI:10.1021/jo000746f

Simple preparation methods of modified guanidines have been explored as potential chiral superbases. Thus, 3,7,8-trisubstituted and 3,6,7,8-tetrasubstituted 1,4,6-triazabicyclooctene systems were prepared from (1S,2S)-1,2-diphenylethylenediamine through stepwise 2-chloro-1,3-dimethylimidazolinium chloride (DMC)-induced cyclizations of protected thioureas to the corresponding 2-iminoimidazolidines and then of 2-(2-hydroxyethylimino)imidazolidines to the bicyclic systems. Linear guanidines with a 2-hydroxyethyl functional group were prepared by the reaction of carbodiimides with 2-amino alcohols. Reaction of linear-type guanidines with DMC followed by base treatment afforded 1,4-disubstitued 2-iminoimidazolidines. Furthermore, another type of 1,4,6-triazabicyclooctene was also prepared through double DMC-induced cyclization of guanidines with two 2-hydroxyethyl substituents.

Full text of DOI:10.1021/jo000746f

J . Org. Chem. 2000, 65, 7779-7785
7779
Mod ified Gu a n id in es a s P oten tia l Ch ir a l Su p er ba ses. 3.
P r ep a r a tion of 1,4,6-Tr ia za bicycloocten e System s a n d
1,4-Disu bstitu ted 2-Im in oim id a zolid in es by th e
2-Ch lor o-1,3-d im eth ylim id a zolin iu m Ch lor id e-In d u ced Cycliza tion
of Gu a n id in es w ith a Hyd r oxyeth yl Su bstitu en t
Toshio Isobe,†,‡ Keiko Fukuda,‡ Kentaro Yamaguchi,§ Hiroko Seki,§ Tatsuhiro Tokunaga,§ and
Tsutomu Ishikawa*,†
Faculty of Pharmaceutical Sciences and Chemical Analysis Center, Chiba University, 1-33 Yayoi, Inage,
Chiba 263-8522, J apan, and Central Research Laboratory, Shiratori Pharmaceutical Co. Ltd.,
6-11-24 Tsudanuma, Narashino, Chiba 275-0016, J apan
benti@p.chiba-u.ac.jp
Received May 15, 2000
Simple preparation methods of modified guanidines have been explored as potential chiral
superbases. Thus, 3,7,8-trisubstituted and 3,6,7,8-tetrasubstituted 1,4,6-triazabicyclooctene systems
were prepared from (1S,2S)-1,2-diphenylethylenediamine through stepwise 2-chloro-1,3-dimeth-
ylimidazolinium chloride (DMC)-induced cyclizations of protected thioureas to the corresponding
2-iminoimidazolidines and then of 2-(2-hydroxyethylimino)imidazolidines to the bicyclic systems.
Linear guanidines with a 2-hydroxyethyl functional group were prepared by the reaction of
carbodiimides with 2-amino alcohols. Reaction of linear-type guanidines with DMC followed by
base treatment afforded 1,4-disubstitued 2-iminoimidazolidines. Furthermore, another type of 1,4,6-
triazabicyclooctene was also prepared through double DMC-induced cyclization of guanidines with
two 2-hydroxyethyl substituents.
In tr od u ction
key step. In addition 1,4-disubstituted 2-iminoimidazo-
lidines 30-35 have also been prepared by the similar
DMC-induced cyclization.
Due to their strongly basic character,1 guanidines can
be considered as superbases2 and, although chiral
guanidines are expected to have potential as asymmetric
reagents, their limited use3 in asymmetric synthesis as
chiral auxiliaries is due mainly to the absence of simple
preparation methods. In the preceding papers4 we re-
ported the preparation of modified guanidines containing
a 2-iminoimidazolidine ring as potential chiral super-
bases. In this paper we present the preparation of three
kinds of bicyclic guanidines, 3,7,8-trisubstituted 11,
3,6,7,8-tetrasubstituted 20, and 3,6,8-trisubstituted 1,4,6-
triazabicyclooctene systems 41 and 44 by the 2-chloro-
1,3-dimethylimidazolinium chloride (DMC)5-induced cy-
clization of hydroxyethyl-substituted guanidines as the
Resu lts a n d Discu ssion
P r ep a r a tion of 3-Su bstitu ted (7S,8S)-7,8-Dip h en -
yl-1,4,6-tr ia za bicyclo[3.3.0]oct-4-en es (3,7,8-Tr isu b-
stitu ted Bicyclic Gu an idin es) 11. 3-Substituted (7S,8S)-
7,8-diphenyl-1,4,6-triazabicyclo[3.3.0]oct-4-enes (3,7,8-
trisubstituted bicyclic guanidines) 11 were prepared from
2-amino alcohols 1 through eight-step sequences as
shown in Scheme 1, in which DMC played important
roles in both the dehydrosulfination and the chlorination
reactions. The results obtained in each step are given in
Table 1.
† Faculty of Pharmaceutical Sciences, Chiba University.
‡ Shiratori Pharmaceutical Co. Ltd.
Optically active tert-butyldimethylsilyl (TBDMS)-
protected hydroxyethyl isothiocyanates 4 were prepared
from the corresponding 2-amino alcohols 1 by the DMC-
induced dehydrosulfide reaction5c of triethylammonium
dithiocarbamates 3 after protection of the hydroxy group
in 1 through steps 1-3. Treatment of 4 with monoethoxy-
§ Chemical Analysis Center, Chiba University.
(1) Yamamoto, Y.; Kojima, S. The Chemistry of Amidines and
Imidates; Patai, S.; Rappoport, Z., Eds.; J ohn Wiley & Sons Inc.: New
York, 1991; Vol. 2, pp 485-526.
(2) Costa, M.; Chiusoli, G. P.; Taffurelli, D.; Dalmonego, G. J . Chem.
Soc., Perkin Trans. 1 1998, 1541-1546.
(3) (a) For the nitroaldol (Henry) reaction, see Chinchilla, R.; Najera,
C.; Sanchez-Agullo, P. Tetrahedron: Asymmetry 1994, 5, 1393-1402.
(b) For the Strecker reaction, see Iyer, M. S.; Gigstad, K. M.; Namdev,
N. D.; Lipton, M. J . Am. Chem. Soc. 1996, 118, 4910-4911. Corey, E.
J .; Grogan, M. J . Org. Lett. 1999, 1, 157-160. (c) For Michael reaction,
see Alcazar, V.; Moran, J . R.; deMendoza, J . Tetrahedron Lett. 1995,
36, 3941-3944. Ma, D.; Cheng, K. Tetrahedron: Asymmetry 1999, 10,
713-719. Howard-J ones, A.; Murphy, P. J .; Thomas, D. A. Caulkett,
P. W. R. J . Org. Chem. 1999, 64, 1039-1041.
(4) (a) Isobe, T.; Fukuda, K.; Ishikawa, T. J . Org. Chem. 2000, 65,
7770-7773. (b) Isobe, T.; Fukuda, K.; Tokunaga, T.; Seki, H.; Yamagu-
chi, K.; Ishikawa, T. J . Org. Chem. 2000, 65, 7774-7778.
(5) (a) Isobe, T.; Ishikawa, T. J . Org. Chem. 1999, 64, 5832-5835.
(b) Isobe, T.; Ishikawa, T. J . Org. Chem. 1999, 64, 6984-6988. (c) Isobe,
T.; Ishikawa, T. J . Org. Chem. 1999, 64, 6989-6992.
carbonylated (1S,2S)-1,2-diphenylethylenediamine4b
5
afforded thiourea derivatives 6 (step 4), which were
subjected to the DMC-induced cyclization4b to give pro-
tected 2-iminoimidazolidines 7 smoothly (step 5).
We have shown that DMC can be used for the chlori-
nation of primary alcohols.5a Application of this reaction
to 2-hydroxyethyl-substituted guanidines 8 was expected
to produce cyclized guanidines 10 through spontaneous
intramolecular displacement of chlorinated compounds
9. Treatment of 7 with DMC in boiling acetonitrile
10.1021/jo000746f CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/21/2000

7780 J . Org. Chem., Vol. 65, No. 23, 2000
Isobe et al.
Ta ble 2. Rea ction of 8a w ith DMC in CH2Cl2 a t r t in
Step 7 in Sch em e 1
Sch em e 1
F igu r e 1. Possible imino- 12 and amino-type isomers 13 of
3,7,8-trisubstituted bicyclic guanidines based on a diphenyl-
substituted ring (A).
methoxide (MeONa) gave 3-substituted 7,8-diphenyl-
1,4,6-triazabicyclooctenes as 3,7,8-trisubstituted bicyclic
guanidines 11 (step 8).
Simple chlorination5a of the hydroxyl group in 8 in the
step 7 was also observed in addition to desired cyclization
when the reaction was carried out at room temperature.
The results, when 8a derived from (S)-phenylalaninol
(1a ) was used as a substrate, are shown in Table 2. The
product ratio of a chlorinated product 9a and bicyclic
guanidine 10a was dependent upon both the amount of
Et3N used and reaction time. Thus, the reaction using a
limited amount of Et3N (1.5 mol equiv) at room temper-
ature for 1 h produced 9a in slightly higher yield (run 1
in Table 2). Alternatively, 10a resulted mainly given on
treatment with excess of Et3N for longer periods (30 h)
(run 3 in Table 2).
Ta ble 1. Resu lt of Ea ch Step in Sch em e 1 for th e
P r ep a r a tion of 3,7,8-Tr isu bstitu ted Bicyclic
Gu a n id in es 11
In bicyclic systems 11 two isomers6 of an imino-type
12 and an amino-type 13 based on a diphenyl-substituted
ring (A) are theoretically possible as discussed in the Part
24b of this series (Figure 1). X-ray crystallographic
analysis of the (3R)-phenyl derivative 11c (See Support-
ing Information) suggested that these systems preferred
an imino isomer such as 12 in a solid state.
P r ep a r a tion of (3S,7S,8S)-3-Ben zyl-7,8-d ip h en yl-
6-m eth yl-1,4,6-tr ia za bicyclo[3.3.0]oct-4-en e (3,6,7,8-
Tetr asu bstitu ted Bicyclic Gu an idin e) (20). (3S,7S,8S)-
3-Benzyl-7,8-diphenyl-6-methyl-1,4,6-triazabicyclo [3.3.0]-
oct-4-ene (20) was prepared as a representative of 3,6,7,8-
tetrasubstituted bicyclic guanidines by N-methylation
before construction of bicyclic systems (Scheme 2). Treat-
ment of the tert-butoxycarbonyl (Boc)-protected 2-imino-
imidazolidine 147 with methyl iodide in the presence of
(6) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J . Am. Chem. Soc. 1998, 120, 6433-6442.
(7) 14 was prepared from (1S,2S)-1,2-diphenylethylenediamine by
three sequential reactions of thioamidation with an isothiocyanate 4a ,
protection with Boc group, and the DMC-induced cyclization according
to a similar procedure shown in Scheme 1 (see Supporting Informa-
tion).
(MeCN) in the presence of triethylamine (Et3N) after
selective deprotection of the TBDMS group afforded the
desired bicyclic systems 10 in moderate yields (steps 6
and 7). Removal of the ethoxycarbonyl group with sodium

Modified Guanidines as Potential Chiral Superbases. 3.
J . Org. Chem., Vol. 65, No. 23, 2000 7781
Sch em e 2
Sch em e 3
Ta ble 3. P r ep a r a tion of 1,4-Disu bstitu ted
2-Im in oim id a zolid in es 30-35 th r ou gh Lin ea r -Typ e
Gu a n id in es 24-29
base gave an N-methylated product 15. Introduction of
a methyl group on the ring nitrogen was deduced by
inspection of its NMR spectra including HMBC experi-
ments (see Supporting Information). Furthermore, this
deduction was supported by chemical evidence that an
aziridine 21 was formed as an alternative product in the
DMC-induced cyclization of a guanidine 18 derived from
15 (vide infra).
Displacement5a of the oxygen function in 15 by a
chlorine atom using DMC was investigated on O-depro-
tected product 16, but complete recovery of 16 was
observed. The presence of Boc and methyl groups on the
ring nitrogens of 16 could be acting to block the approach
of the reagent because smooth displacement was observed
in the case of ethoxycarbonylated 8 (see Scheme 1). Thus,
both protecting groups on 15 were removed before
cyclization. Stepwise deprotection of N- and O-functions
in 15 with tetra-n-butylammonium fluoride (TBAF) fol-
lowed by 30% trifluoroacetic acid (TFA) in dichloro-
methane (CH2Cl2) or simultaneous deprotection with TFA
afforded 18.
Treatment of 18 with DMC led to only conversion into
the corresponding chlorine-substituted product 19, de-
spite smooth cyclization to bicyclic systems 10 from the
protected guanidines 8 as mentioned above (see Scheme
1), indicating undesired formation of hydrochloride salt
of a guanidyl function. Thus, base treatment after
chlorination of 18 with DMC without isolation of an
intermediate 19 afforded expectedly 3,6,7,8-tetrasubsti-
tuted bicyclic guanidine 20 in 67% yield (Scheme 2).
Alternative cyclization of 19 involving participation of
the external nitrogen leading an aziridine 21 was ob-
served as a reaction path (18%). However, aziridine
cyclization did not occur when protected guanidines 8
were used as substrates in the DMC-induced cyclization.
These facts suggest that cyclization paths could be
controlled by the electronic character of substituents on
guanidyl nitrogen atoms.
P r ep a r a tion of Lin ea r -typ e Gu a n id in es 24-29
w ith a 2-Hyd r oxyeth yl Gr ou p a n d 1,4-Disu bstitu ted
2-Im in oim id a zolid in es 30-35. Linear-type guanidines
24-29 with a 2-hydroxyethyl function and the corre-
sponding cyclized guanidines 30-35 were prepared as
shown in Scheme 3 and Table 3. The linear-type
guanidines 24-29, which could be also used as chiral
superbases, were synthesized by reaction of carbodiim-
ides with 2-amino alcohols 1. We used di[(S)-1-phenyl-
ethyl]carbodiimide8 (22) and commercially available di-
isopropylcarbodiimide (23) as carbodiimide substrates.
Heating carbodiimides 22 or 23 and amino alcohols 1
in toluene at 60 °C gave 24-29 in moderate to good yields
(step 1 in Table 3). In some cases 1,4-disubstituted
imidazolidinones 36, the hydrolyzed products of the
(8) Chinchilla, R.; Najera, C.; Sanchez-Agullo, P. Tetrahedron:
Asymmetry 1994, 7, 1393-1402.

7782 J . Org. Chem., Vol. 65, No. 23, 2000
Isobe et al.
Sch em e 4
F igu r e 2. One of three possible biguanidium chlorides formed
by the reaction of a linear-type guanidine 37 and DMC.
Sch em e 5
39 in 79% combined yield along with bicyclic guanidine
41 (15% yield). After O-deprotection, the mixture was
subjected to the second DMC-induced cyclization followed
by base treatment to afford 41 in 72% yield.
Alternatively, the same type of the bicyclic guanidine
44 was directly prepared from a protected guanidine 4211
in good overall yield by the DMC-induced cyclization of
a linear-type guanidine 43 with two free 2-hydroxyethyl
functions (Scheme 5).
2-iminoimdazolidines, were obtained as coproducts in
runs 1 (11%), 2 (12%), 3 (63%), and 6 (19%). On the other
hand the cyclized guanidine 34 (10%) was also formed,
together with the urea derivative (11%) in the case of
run 5. Stirring a solution of 24-29 in MeCN with DMC
at room temperature in the presence of Et3N followed by
base treatment afforded 1,4-disubstituted 2-iminoimida-
zolidines 30-35 in good to excellent yields9 (step 2 in
Table 3).
P r ep a r a tion of 6-Su bstitu ted (3S,8S)-3,8-Diben -
zyl-1,4,6-tr ia za bicyclo[3.3.0]oct-4-en es (3,6,8-Tr isu b-
stitu ted Bicyclic Gu a n id in es) 41 a n d 44. 6-Substi-
tuted (3S,8S)-3,8-dibenzyl-1,4,6-triazabicyclo[3.3.0]oct-4-
enes 41 and 44 were prepared as an alternative type of
bicyclic guanidine from hydroxyethyl-substituted guani-
dines by a similar DMC-induced cyclization. 6-[(S)-1-
Phenylethyl] derivative 41 was derived from linear
guanidine 3710 (Scheme 4). Production of highly polar
substances, one possible compound of which appeared to
correspond to biguanidinium salt 40 (Figure 2), was
observed when 37 was treated with DMC in a prelimi-
nary experiment. Therefore, we preprotected the strongly
basic guanidyl nitrogen using methanesulfonic acid
(MSA) resulting in salt formation. Subsequent treat-
ments with DMC and potassium hydroxide afforded an
inseparable 1:1 mixture of isomeric guanidines 38 and
Con clu sion s
It was found that guanidines with a 2-hydroxyethyl
function can be easily converted into cyclized guanidines
by treatment with DMC. Although limited synthesis of
these specialized guanidines were described in the present
paper, preparation methods based upon the DMC-
induced cyclization should be widely applicable to the
preparation of similar types of guanidines with different
substituents by use of appropriate 2-amino alcohols. In
addition, successful preparation of cyclic guanidines
induced by DMC resulted in uncovering further utility
of DMC5 as a reagent in organic synthesis.
Modified guanidines may be promising basic catalysts
for green chemistry12 because of their recycling potential,
easy handling, and expected safety.13 We have examined
their possibility as chiral auxiliaries in asymmetric
synthesis and reported their application to alkylative
esterification14 of benzoic acid with racemic phenylethyl
(11) This guanidine was prepared by reaction of a symmetrical
carbodiimide derived from (S)-phenylalaninol (1a ) with propylamine
(see Supporting Information).
(12) Anastas, P. T.; Warner, J . C. Green Chemistry: Theory and
Practice; Oxford University Press: Oxford, 1998.
(9) In these reaction schemes (5S)-3-[(S)-1-phenylethyl]-2-[(S)-1-
phenylethylimino]-1,3-diazabicyclo[3.3.0]octane, which had been pre-
pared in the Part 14a in this series, was obtained from di[(S)-1-
phenylethyl]carbodiimide in 61% overall yield when (S)-prolinol was
used as the 2-amino alcohol unit (see Supporting Information).
(10) This guanidine was prepared by the reaction of an unsym-
metrical carbodiimide derived from a protected amino alcohol 2a and
(S)-phenylethylisothiocyanate with (S)-phenylalaninol (1a ) (see Sup-
porting Information).
(13) Although there are no data on the toxicity of modified guanidines
prepared here, the presence of guanidyl functions including an
2-iminoimidazolidine ring in a range of pharmaceutical products such
as clonidine, a cardiovascular drug, allows us to deduce that they are
likely to be nontoxic (see Greenhill, J . V.; Lue, P. Progress in Medicinal
Chemistry;Ellis, G. P.; Luscombe, D. K., Eds; Elsevier Science Publish-
ers: New York, 1993; Vol. 30, Chapter 5).
(14) Isobe, T.; Fukuda, K.; Ishikawa, T. Tetrahedron Asymmetry,
1998, 9, 1729-1735.

Modified Guanidines as Potential Chiral Superbases. 3.
J . Org. Chem., Vol. 65, No. 23, 2000 7783
(4S,5S)-2-[(S)-1-Ben zyl-2-(ter t-bu tyld im eth ylsilyloxy)eth -
ylim in o]-4,5-diph en yl-1-eth oxycar bon ylim idazolidin e (7a).
A mixture of 6a (4.53 g, 7.67 mmol), Et3N (2.32 g, 23.0 mmol),
and DMC (1.56 g, 9.20 mmol) in MeCN (100 mL) was refluxed
for 13 h, poured into water, and extracted with CH2Cl2. The
residue obtained from the organic extract was purified by
column chromatography (SiO2, hexanes-EtOAc ) 5:1) gave
7a (3.76 g, 88%) as a colorless oil; IR (neat) νmax 3380, 1710,
bromide. Their utilities as chiral superbases for asym-
metric synthesis15 will be reported elswhere.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. 1H (300 MHz) and
13C NMR (75 MHz) spectra were recorded in CDCl3 with TMS
as an internal reference unless otherwise stated. UV spectra
were measured in MeOH. Organic extract was dried over
MgSO4 or Na2SO4 and evaporated under reduced pressure.
Columns for chromatography contained silica gel 60 (SiO2)
(70-230 mesh ASTM; Merck) or NH-type silica gel (NH-SiO2)
(Chromatorex NH-DM1020; Fuji Silysia Chemical Ltd.), and
TLC proceeded on silica gel GF254 (Merck).
1640, 1130 cm-1; UV λmax 207.2 (ꢀ 35400) nm; [R]22 -37.5 (c
D
1.00, CHCl3); 1H NMR δ 0.09 (s, 3H), 0.10 (s, 3H), 0.93 (t, J )
7.1 Hz, 3H), 0.96 (s, 9H), 3.00 (dd, J ) 13.4, 7.1 Hz, 1H), 3.07
(dd, J ) 13.4, 8.6 Hz, 1H), 3.67 (dd, J ) 9.9, 3.1 Hz, 1H), 3.81
(dd, J ) 9.9, 4.4 Hz, 1H), 3.94 (q, J ) 7.1 Hz, 2H), 4.31 (br s,
1H), 4.75 (s, 2H), 7.11 (d, J ) 6.4 Hz, 2H), 7.21-7.35 (m, 13H);
13C NMR δ -5.5, -5.4, 13.8, 18.3, 25.9, 37.4, 54.9, 61.8, 62.9,
70.0, 73.9, 125.7, 126.07, 126.10, 127.2, 127.5, 128.2, 128.5,
128.7, 129.6, 138.6, 142.7, 144.7, 153.1; HRFABMS m/z
558.3156 (M + H+, C33H44N3O3Si requires m/z 558.3152).
A Typ ica l P r oced u r e for P r ep a r a tion of O-Dep r o-
tected 2-Im in oim id a zolid in es 8 (step 6 in Ta ble 1):
(4S,5S)-2-[(S)-1-Ben zyl-2-h yd r oxyeth ylim in o]-4,5-d ip h en -
yl-1-eth oxyca r bon ylim id a zolid in e (8a ). A 1 M solution of
TBAF in THF (8.78 mL, 8.78 mmol) was dropped to a solution
of 7a (3.76 g, 6.75 mmol) in THF (17 mL), and the whole was
stirred at room temperature for 1.5 h. The reaction mixture
was poured into 5% NaOH aqueous solution and extracted
with CH2Cl2. The residue obtained from the organic extract
was purified by column chromatography (SiO2, hexane-EtOAc
) 1:1) gave 8a (2.87 g, 96%) as a colorless viscous oil; IR (neat)
A Typ ica l P r oced u r e for P r otection of 2-Am in o Alco-
h ols 1 (st ep 1 in Ta b le 1): (S)-1-Ben zyl-2-(ter t-b u t yld i-
m eth ylsilyloxy)eth yla m in e (2a ). A solution of TBDMSCl
(16.0 g, 106 mmol) in CH2Cl2 (96 mL) was dropped to a stirred
solution of (S)-phenylalaninol (1a ) (16.1 g, 106 mmol), Et3N
(21.5 g, 213 mmol), and 4-(dimethylamino)pyridine (2.60 g,
21.3 mmol) in CH2Cl2 (160 mL). The whole was stirred at room
temperature for 21 h, poured into water, and extracted with
CH2Cl2. The residue obtained from the organic extract was
purified by column chromatography (SiO2, CHCl3 to CHCl3-
MeOH ) 50:1) gave 2a (28.2 g, quant) as colorless oil; UV λmax
208.0 (ꢀ 8100) nm; [R]23 -3.6 (c 1.00, CHCl3); 1H NMR δ 0.06
D
(s, 6H), 0.91 (s, 9H), 1.40 (br s, 2H), 2.50 (dd, J ) 13.4, 8.2 Hz,
1H), 2.79 (dd, J ) 13.4, 5.3 Hz, 1H), 3.05-3.13 (m, 1H), 3.44
(dd, J ) 9.7, 6.6 Hz, 1H), 3.58 (dd, J ) 9.7, 4.4 Hz, 1H), 7.19-
7.32 (m, 5H); 13C NMR δ -5.5, 18.2, 25.8, 40.4, 54.3, 67.4,
126.1, 128.3, 129.2, 139.1; HRFABMS m/z:266.1935 (M + H+,
ν
max 3350, 1710, 1635 cm-1; UV λmax 207.2 (ꢀ 28100) nm; [R]21
D
-22.9 (c 1.00, CHCl3); 1H NMR δ 0.89 (t, J ) 7.1 Hz, 3H),
2.94 (dd, J ) 13.7, 8.3 Hz, 1H), 3.08 (dd, J ) 13.7, 6.0 Hz,
1H), 3.75 (dd, J ) 11.3, 5.7 Hz, 1H), 3.81 (dd, J ) 11.3, 3.1
Hz, 1H), 3.86-3.96 (m, 2H), 4.10-4.16 (m, 1H), 4.77 (s, 2H),
7.10-7.35 (m, 15H); 13C NMR δ 13.7, 37.6, 57.1, 62.1, 65.8,
70.2, 73.2, 125.8, 125.9, 126.5, 127.4, 127.7, 128.5, 128.7, 128.8,
129.4, 138.1, 142.2, 143.9, 153.1, 154.3; HRFABMS m/z
444.2293 (M + H+, C27H30N3O3 requires m/z 444.2287).
A Typ ica l P r oced u r e for th e DMC-In d u ced Cycliza -
tion of P r otected Hyd r oxyeth ylgu a n id in es 8 (step 7 in
Ta ble 1): On th e (S)-Ben zyl Der iva tive 8a (r u n 2 in Ta ble
2). To a stirred mixture of 8a (2.87 g, 6.48 mmol) and DMC
(1.64 g, 9.72 mmol) in CH2Cl2 (30 mL) was added Et3N (0.98
g, 9.72 mmol) at room temperature, and then the whole was
stirred at room temperature for 7.5 h, poured into water, and
extracted with CH2Cl2. The residue obtained from the organic
extract was purified by column chromatography (SiO2, hex-
anes-EtOAc ) 1:3 to CHCl3-MeOH ) 20:1) gave two prod-
ucts. (i) (4S,5S)-2-[(S)-1-Ben zyl-2-ch lor oeth ylim in o]-4,5-
d ip h en yl-1-eth oxyca r bon ylim id a zolid in e (9a ). Obtained
as a less polar colorless oil (1.06 g, 35%); IR (neat) νmax 3360,
C
15H28NOSi requires m/z 266.1940).
A Typ ica l P r oced u r e for P r ep a r a tion of Isoth iocya n -
a tes 44b (step s 2 a n d 3 in Ta ble 1): (S)-1-Ben zyl-2-(ter t-
bu tyld im eth ylsilyloxy)eth ylisoth iocya n a te (4a ). A solu-
tion of 2a (8.01 g, 30.2 mmol), Et3N (7.33 g, 72.6 mmol), and
CS2 (2.30 g, 30.2 mmol) in CH2Cl2 (100 mL) was stirred at
room temperature for 2 h, and to the resulting solution was
dropped a solution of DMC (6.13 g, 36.3 mmol) in CH2Cl2 (30
mL). The whole was stirred at room temperature for 48 h and
evaporated. Purification of the residue by column chromatog-
raphy (SiO2, hexanes-EtOAc ) 20:1) gave 4a (8.91 g, 96%)
as colorless oil; IR (neat) νmax 2100, 1125, 830 cm-1; UV λmax
247.2 (ꢀ 1300), 204.0 (12100) nm; [R]22D -77.0 (c 1.00, CHCl3);
1H NMR δ 0.10 (s, 3H), 0.11 (s, 3H), 0.95 (s, 9H), 2.89 (dd, J
) 13.6, 7.9 Hz, 1H), 3.01 (dd, J ) 13.6, 5.7 Hz, 1H), 3.65 (dd,
J ) 10.1, 5.3 Hz, 1H), 3.70 (dd, J ) 10.1, 4.8 Hz, 1H), 3.81-
3.89 (m, 1H), 7.21-7.37 (m, 5H); 13C NMR δ -5.4, 18.2, 25.8,
38.2, 61.1, 64.3, 127.1, 128.6, 129.3, 133.1, 136.5; HRFABMS
m/z 308.1489 (M + H+, C16H26NOSSi requires m/z 308.1504).
A Typ ica l P r oced u r e for P r ep a r a tion of Th iou r ea s 64b
(step 4 in Ta ble 1): N-[(S)-1-Ben zyl-2-(ter t-bu tyld im eth -
ylsilyloxy)et h yl]-N′-[(1S,2S)-1,2-d ip h en yl-2-(et h oxyca r -
bon yla m in o)eth yl]th iou r ea (6a ). A mixture of 4a (9.11 g,
29.7 mmol) and 1,2-diphenyl-N-ethoxycarbonylethylenedi-
amine (5) (8.43 g, 29.7 mmol) in CH2Cl2 (178 mL) was refluxed
for 20 h and evaporated. Purification of the residue by column
chromatography (SiO2, CHCl3) gave 6a (17.2 g, 98%) as
amorphous mass; IR (neat) νmax 1685, 1525, 1255, 1115, 1045
cm-1; UV λmax 207.2 (ꢀ 33900) nm; [R]20D -26.9 (c 1.00, CHCl3);
1H NMR δ 0.03 (s, 6H), 0.91 (s, 9H), 1.22 (t, J ) 7.1 Hz, 3H),
2.66 (br s, 1H), 2.87 (br s, 1H), 3.48-3.58 (m, 2H), 4.10 (q, J
) 7.1 Hz, 2H), 4.50 (br s, 1H), 4.95 (t, J ) 8.8 Hz, 1H), 5.54
(br s, 1H), 5.81 (br s, 1H), 6.13 (br s, 1H), 7.03-7.26 (m, 15H);
13C NMR δ -5.6, 14.4, 18.2, 25.8, 36.4, 61.0, 61.4, 62.1, 63.1,
126.3, 127.4, 127.5, 127.8, 128.3, 128.4, 129.3, 137.8, 138.4,
157.2, 181.5. Anal. Calcd for C33H45N3O3SSi: C, 66.97; H, 7.66;
N, 7.10. Found: C, 66.97; H, 7.69; N, 7.02.
1710, 1645 cm-1; UV λmax 206.4 (ꢀ 24100) nm; [R]21 -11.9 (c
D
1
1.00, CHCl3); H NMR δ 0.94 (t, J ) 6.4 Hz, 3H), 3.07 (dd, J
) 13.6, 7.7 Hz, 1H), 3.13 (dd, J ) 13.6, 6.8 Hz, 1H), 3.63 (dd,
J ) 11.2, 3.2 Hz, 1H), 3.95-4.00 (m, 3H), 4.49-4.63 (m, 1H),
4.76 (d, J ) 4.2 Hz, 1H), 4.78 (d, J ) 4.2 Hz, 1H), 7.11-7.37
(m, 15H); 13C NMR δ 13.8, 37.9, 46.5, 53.9, 62.2, 70.1, 74.0,
125.8, 126.1, 126.7, 127.4, 127.7, 128.6, 128.7, 128.8, 129.5,
137.3, 142.4, 144.1, 152.7; HRFABMS m/z 462.1964 (M + H+,
C
C
27H29ClN3O2 requires m/z 462.1948), 464.1931 (M + 2 + H+,
27H29ClN3O2 requires m/z 464.1932). (ii) (3S,7S,8S)-3-Ben -
zyl-7,8-d ip h en yl-6-et h oxyca r b on yl-1,4,6-t r ia za b icyclo-
[3.3.0]oct-4-en e (10a ). Obtained as a more polar colorless oil
(1.32 g, 48%); IR (neat) νmax 1745, 1715, 1660 cm-1; UV λmax
1
207.2 (ꢀ 25200) nm; [R]22 +45.1 (c 1.00, CHCl3); H NMR δ
D
1.11 (t, J ) 7.0 Hz, 3H), 2.87-3.01 (m, 3H), 3.19 (dd, J ) 13.5,
4.4 Hz, 1H), 4.01 (d, J ) 5.7 Hz, 1H), 4.09-4.25 (m, 2H), 4.71-
4.76 (m, 1H), 5.04 (d, J ) 5.7 Hz, 1H), 6.94-6.97 (m, 2H),
7.19-7.36 (m, 13H); 13C NMR δ 13.9, 41.3, 50.3, 62.4, 67.6,
71.8, 73.5, 125.98, 126.01, 126.5, 127.99, 128.02, 128.3, 128.5,
128.7, 129.3, 137.1, 138.4, 139.2, 151.0, 160.8; HRFABMS m/z
426.2156 (M + H+, C27H28N3O2 requires m/z 426.2182).
A Typ ica l P r oced u r e for P r ep a r a tion of 3,7,8-Tr isu b-
st it u t ed Bicyclic Gu a n id in es 11 (st ep 8 in Ta b le 1):
(3S,7S,8S)-3-Ben zyl-7,8-diph en yl-1,4,6-tr iazabicyclo[3.3.0]-
A Typ ica l P r oced u r e for P r ep a r a tion of N,O-Dip r o-
tected 2-Im in oim id a zolid in es 74b (step 5 in Ta ble 1):
(15) During our research works, an effective asymmetric Strecker
reaction catalyzed by C2-symmetrical bicyclic guanidines was reported
by Corey et al.3b

7784 J . Org. Chem., Vol. 65, No. 23, 2000
Isobe et al.
oct-4-en e (11a ). A mixture of 10a (1.59 g, 3.74 mmol) and
28% MeONa in MeOH (5.70 g, 29.5 mmol) in MeOH (35 mL)
was stirred at room temperature, poured into water, and
extracted with CH2Cl2. The residue obtained from the organic
extract was purified by column chromatography (NH-SiO2,
CHCl3) followed by recrystallization from MeCN gave 11a (1.18
g, 89%) as colorless prisms, mp 156-157 °C; IR (neat) νmax
Th e DMC-In d u ced Cycliza tion of th e Hyd r oxyeth -
ylgu a n id in e 18. An unprotected hydroxyethylguanidine was
converted into the hydrochloride salt by treatment of its
benzene solution with an equimolar amount of 4 N HCl
solution in EtOAc followed by evaporation and washing the
residue with isopropyl ether. To a stirred mixture of the
hydrochloride (0.99 g, 2.35 mmol) and DMC(0.80 g, 4.7 mmol)
in CH2Cl2 (10 mL) was added Et3N (0.95 g, 9.4 mmol) at room
temperature, and then the whole was stirred at room temper-
ature for 1 h. After evaporation the residue was dissolved in
MeOH (30 mL), and then KOH (2.24 g, 0.4 mol) was added.
The whole was stirred at room temperature for 18 h, poured
into water, and extracted with CH2Cl2. The residue obtained
from the organic extract was purified by column chromatog-
raphy (NH-SiO2, CH2Cl2) to give two products. (i) (4S,5S)-
2-[(S)-2-Ben zyla zir id in -1-yl]-4,5-d ip h en yl-1-m eth yl-2-im -
id a zolin e (21). Obtained as less polar colorless needles (0.16
1670 cm-1; UV λmax 206.4 (ꢀ 40200) nm; [R]23 +10.4 (c 1.00,
D
CHCl3); 1H NMR δ 2.82-2.93 (m, 2H), 2.95 (d, J ) 8.1 Hz,
1H), 3.04 (dd, J ) 8.2, 2.2 Hz, 1H), 3.94 (d, J ) 9.0 Hz, 2H),
4.22-4.29 (m, 1H), 4.85 (d, J ) 9.0 Hz, 1H), 5.16 (br s, 1H),
7.11-7.33 (m, 15H); 13C NMR δ 42.0, 50.4, 64.0, 79.3, 126.3,
127.0, 127.1, 127.4, 127.7, 128.2, 128.4, 128.5, 129.3, 138.4,
139.0, 141.6, 168.1; FABMS m/z 354 (M + H+). Anal. Calcd
for C24H23N3: C, 81.55; H, 6.56; N, 11.89. Found: C, 81.27; H,
6.50; N,11.83.
(4S,5S)-2-[(S)-1-Ben zyl-2-(ter t-bu tyld im eth ylsilyloxy)-
eth ylim in o]-1-ter t-bu toxyca r bon yl-4,5-d ip h en yl-3-m eth -
ylim id a zolid in e (15). A 1.66 M solution of n-BuLi in THF
(4.54 mL, 7.53 mmol) was dropped to a solution of 14 (3.67 g,
6.27 mmol) in THF (30 mL). After 10 min, methyl iodide (1.07
g, 7.53 mmol) was added, and the whole was stirred at room
temperature for 3 h. The reaction mixture was quenched with
water and extracted with CH2Cl2. The residue obtained from
the organic extract was purified by column chromatography
(SiO2, hexanes-EtOAc ) 1:1) followed by recrystallization
from hexane gave 15 (3.58 g, 95%) as colorless prisms, mp 91-
g, 18%), mp 118-119 °C; IR (neat) νmax 1605 cm-1; UV λmax
1
207.2 (ꢀ 38800) nm; [R]23 +53.7 (c 1.00, CHCl3); H NMR δ
D
2.20 (d, J ) 3.5 Hz, 1H), 2.58 (d, J ) 5.3 Hz, 1H), 2.66 (s, 3H),
2.75-2.83 (m, 2H), 3.16-3.24 (m, 1H), 4.17 (d, J ) 9.4 Hz,
1H), 4.63 (d, J ) 9.4 Hz, 1H), 7.14-7.37 (m, 15H); 13C NMR δ
32.0, 33.6, 38.6, 40.4, 75.2, 78.4, 126.7, 126.9, 127.0, 127.1,
127.8, 128.3, 128.6, 128.7, 128.9, 137.9, 140.1, 143.6, 167.7;
HRFABMS m/z 368.2124 (M + H+, C25H26N3 requires m/z
368.2127). (ii) (3S,7S,8S)-3-Ben zyl-7,8-d ip h en yl-6-m eth yl-
1,4,6-tr ia za bicyclo[3.3.0]oct-4-en e (20). Obtained as more
polar colorless needles (0.58 g, 67%), which were recrystallized
from MeCN, mp 136-138 °C; IR (neat) νmax 1660 cm-1; UV
92 °C; IR (neat) νmax 1740, 1725, 1670, 1150 cm-1; UV λmax
1
208.8 (ꢀ 37000) nm; [R]22 -33.7 (c 1.00, CHCl3); H NMR δ
D
λ
max 207.2 (ꢀ 37200) nm; [R]23D +43.1 (c 1.00, CHCl3); 1H NMR
-0.04 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H), 1.31 (s, 9H), 2.70 (s,
3H), 2.82 (dd, J ) 12.8, 9.3 Hz, 1H), 3.27 (dd, J ) 12.8, 3.3
Hz, 1H), 3.45-3.55 (m, 2H), 3.83-3.93 (m, 1H), 3.96 (d, J )
δ 2.75 (s, 3H), 2.87 (t, J ) 8.2 Hz, 1H), 2.92 (dd, J ) 13.4, 8.4
Hz, 1H), 3.06 (dd, J ) 13.4, 4.4 Hz, 1H), 3.10 (dd, J ) 8.2, 1.8
Hz, 1H), 3.85 (d, J ) 8.4 Hz, 1H), 4.27 (d, J ) 8.4 Hz, 1H),
4.45-4.52 (m, 1H), 6.90-6.94 (m, 2H), 7.12-7.15 (m, 2H),
7.21-7.33 (m, 11H); 13C NMR δ 30.9, 41.9, 51.3, 70.4, 70.8,
78.3, 126.0, 126.9, 127.8, 128.1, 128.2, 128.45, 128.51, 128.7,
129.5, 136.8, 137.6, 139.5, 168.3. Anal. Calcd for C25H25N3: C,
81.71; H, 6.86; N, 11.44. Found: C, 81.58; H, 6.83; N,11.41.
4.6 Hz, 1H), 4.72 (d, J ) 4.6 Hz, 1H), 7.13-7.42 (m, 15H); 13
C
NMR δ -5.1, 18.7, 26.1, 28.0, 32.5, 39.4, 62.1, 67.1, 68.3, 70.4,
81.6, 125.4, 126.0, 126.6, 127.6, 127.7, 128.2, 128.6, 129.0,
130.2, 140.3, 140.6, 141.8, 146.8, 152.9; HRFABMS m/z
600.3616 (M + H+, C36H50N3O3Si requires m/z 600.3621).
(4S,5S)-2-[(S)-1-Ben zyl-2-h yd r oxyet h ylim in o]-1-ter t-
bu toxycar bon yl-4,5-diph en yl-3-m eth ylim idazolidin e (16).
According to the procedure for O-deprotection mentioned above
(step 6 in Table 1), a solution of 15 (7.89 g, 13.2 mmol) in THF
(34 mL) was treated with a 1 M solution of TBAF in THF (17.1
mL, 17.1 mmol) at room temperature for 24 h. After workup
purification of the crude prodcut by column chromatography
(SiO2, CHCl3) gave 16 (4.85 g, 76%) as a colorless viscous oil;
A Typ ica l P r oced u r e for P r ep a r a tion of Lin ea r -typ e
Gu a n id in es 24-29 (step 1 in Ta ble 3): N-[(S)-1-Ben zyl-
2-h ydr oxyeth yl]-N′,N′′-di[(S)-1-ph en yleth yl]gu an idin e (24).
A mixture of a carbodiimide 22 (2.00 g, 8.00 mmol) and (S)-
phenylalaninol 1a (1.21 g, 8.00 mmol) in toluene (50 mL) was
heated at 60 °C for 9 h. After evaporation, purification of the
residue by column chromatography (CHCl3 to CHCl3-MeOH
) 20:1) gave 24 (2.86 g, 89%) as colorless oil; IR (neat) νmax
IR (neat) νmax 3310, 1700, 1630, 1160 cm-1; UV λmax 207.2 (ꢀ
1
26700) nm; [R]25 +144.6 (c 1.00, CHCl3); H NMR δ 1.45 (s,
3430, 1620 cm-1; UV λmax 207.2 (ꢀ 24100) nm; [R]26 +49.9 (c
D
D
1
9H), 2.70 (s, 3H), 2.71 (dd, J ) 13.6, 8.1 Hz, 1H), 3.13 (dd, J
) 13.6, 5.3 Hz, 1H), 4.08 (dd, J ) 7.3, 5.9 Hz, 1H), 4.27-4.41
(m, 2H), 5.44 (d, J ) 11.0 Hz, 1H), 5.61 (d, J ) 11.0 Hz, 1H),
7.08-7.34 (m, 15H); 13C NMR δ 28.5, 30.1, 43.2, 54.9, 64.1,
65.7, 73.1, 79.4, 126.3, 127.2, 127.7, 128.2, 128.4, 128.5, 129.1,
129.4, 135.7, 138.8, 140.4, 155.4, 163.5.
1.00, CHCl3); H NMR δ 1.24 (d, J ) 6.4 Hz, 6H), 2.36 (dd, J
) 13.9, 9.7 Hz, 1H), 2.74 (dd, J ) 13.9, 5.0 Hz, 1H), 3.37 (dd,
J ) 10.6, 8.2 Hz, 1H), 3.65 (dd, J ) 10.6, 1.1 Hz, 1H), 3.81-
3.88 (m, 1H), 4.08 (q, J ) 6.4 Hz, 2H), 6.88-7.58 (m, 15H);
13C NMR δ 25.4, 37.8, 53.2, 56.6, 68.8, 125.4, 126.3, 126.8,
128.4, 128.5, 128.8, 138.1, 145.1, 152.4; HRFABMS m/z
402.2549 (M + H+, C26H32N3O requires m/z 402.2545).
P r ep a r a tion of (4S,5S)-2-[(S)-1-Ben zyl-2-h yd r oxyeth -
ylim in o]-4,5-d ip h en yl-1-m et h ylim id a zolid in e (18): (a )
F r om th e Mon op r otected Im id a zolid in e 16. A mixture of
16 (1.23 g, 2.54 mmol), TFA (6.0 g), and CH2Cl2 (14.0 g) was
stirred at room temperature for 17 h, poured into 5% NaOH
aqueous solution, and extracted with CH2Cl2. The residue
obtained from the organic extract was purified by column
chromatography (SiO2, CHCl3-MeOH ) 50:1) gave 18 (0.98
g, quant) as colorless needles, mp 181-182 °C; IR (neat) νmax
An Exa m p le of th e P r ep a r a tion of 1,4-Disu bstitu ted
2-Im in oim id a zolid in es 30-35 (step 2 in Ta ble 3): (S)-4-
Ben zyl-1-[(S)-1-p h en yleth yl]-2-[(S)-1-p h en yleth ylim in o]-
im id a zolid in e (30). According to the above DMC-induced
cyclization of deprotected hydroxyethylguanidine the hydro-
chloride of 24 (2.79 g, 6.38 mmol) was treated with DMC (3.24
g, 19.2 mmol) and Et3N (1.94 g, 1.92 mmol) in MeCN (50 mL)
at room temperature for 3 h and then with KOH (2.63 g) in
MeOH (100 mL) at room temperature for 1 h. Workup followed
by purification by column chromatography (NH-SiO2, CHCl3)
3270, 1605, 1100 cm-1; UV λmax 207.2 (ꢀ 32900) nm; [R]24
D
1
-23.3 (c 1.00, CHCl3); H NMR δ 2.39 (s, 3H), 2.81 (dd, J )
gave 30 (2.01 g, 82%) as colorless oil; IR (neat) νmax 1645 cm-1
;
13.2, 9.0 Hz, 1H), 2.90 (dd, J ) 13.2, 4.2 Hz, 1H), 3.61-3.78
(m, 3H), 3.90 (d, J ) 9.2 Hz, 1H), 4.26 (br s, 1H), 7.03-7.30
(m, 15H); 13C NMR δ 31.5, 38.5, 53.6, 67.2, 71.1, 126.6, 126.6,
127.3, 127.4, 128.0, 128.3, 128.6, 128.7, 129.3, 139.0, 139.2,
141.9, 160.3. Anal. Calcd for C25H27N3O3: C, 77.89; H, 7.06;
N, 10.90. Found: C, 78.10; H, 7.17; N, 10.62.
(b) F r om th e Dip r otected Im id a zolid in e 15. A mixture
of 15 (2.00 g, 3.34 mmol), TFA (19.7 g), and CH2Cl2 (46.0 g)
was similarly treated at room temperature for 24 h and
workup gave 18 (1.19 g, 93%).
1
UV λmax 208.0 (ꢀ 30600) nm; [R]23 -20.9 (c 1.00, CHCl3); H
D
NMR δ 1.45 (d, J ) 6.4 Hz, 3H), 1.70 (d, J ) 6.4 Hz, 3H), 2.50
(dd, J ) 13.6, 6.4 Hz, 1H), 2.63 (dd, J ) 13.6, 3.3 Hz, 1H),
2.83 (dd, J ) 9.4, 5.5 Hz, 1H), 3.37 (t, J ) 9.4 Hz, 1H), 4.16
(m, 1H), 5.22-5.27 (m, 1H), 6.03 (q, J ) 6.4 Hz, 1H), 6.57 (d,
J ) 7.1 Hz, 2H), 6.86 (d, J ) 7.0 Hz, 2H), 6.96 (t, J ) 7.3 Hz,
2H), 7.07-7.28 (m, 7H), 7.61 (dd, J ) 6.3, 2.4 Hz, 2H), 8.99
(d, J ) 7.0 Hz, 1H), 9.07 (s, 1H); 13C NMR δ 16.7, 23.2, 39.8,
46.2, 52.2, 53.5, 54.4, 126.6, 126.7, 126.8, 127.5, 127.7, 128.5,

Modified Guanidines as Potential Chiral Superbases. 3.
J . Org. Chem., Vol. 65, No. 23, 2000 7785
128.65, 128.73, 129.6, 135.0, 138.6, 143.0, 155.8; HRFABMS
m/z 384.2410 (M + H+, C26H30N3 requires m/z 384.2440).
(3S,8S)-3,8-Diben zyl-6-[(S)-1-p h en yleth yl]-1,4,6-tr ia za -
bicyclo[3.3.0]oct-4-en e (41). According to the above DMC-
induced cyclization of deprotected hydroxyethylguanidine 37
(23.4 g, 42.9 mmol) and Et3N (13.0 g, 129 mmol) in CH2Cl2
(200 mL) containing MSA (4.12 g, 42.9 mmol) was treated with
DMC (10.9 g, 64.4 mmol) at room temperature for 3.5 h and
then with KOH (39.5 g) in MeOH (150 mL) at room temper-
ature for 40 min. Workup followed by purification by column
chromatography (NH-SiO2, CHCl3) gave an inseparable mix-
ture (17.9 g, 79%) of 38 and 39 and a cyclized product 41 (2.47
g, 15%) as a less polar and a more polar compopnents,
respectively, the former of which was further subjected to the
DMC-induced cyclization as mentioned above.
(neat) νmax 3250, 1625 cm-1; UV λmax 206.4 (ꢀ 18000) nm; [R]22
D
1
-139.8 (c 1.00, CHCl3); H NMR δ 0.67 (t, J ) 7.3 Hz, 3H),
1.10-1.22 (m, 2H), 2.38-2.51 (m, 1H), 2.53 (dd, J ) 11.3, 9.0
Hz, 2H), 2.65-2.73 (m, 1H), 2.80 (dd, J ) 11.3, 3.3 Hz, 2H),
3.47-3.57 (m, 4H), 3.72 (d, J ) 7.9 Hz, 2H), 7.05 (d, J ) 6.4
Hz, 4H), 7.21-7.40 (m, 6H); 13C NMR δ 10.7, 22.2, 37.0, 43.4,
57.2, 66.8, 126.4, 128.3, 128.7, 137.6, 156.3; HRFABMS m/z
370.2497 (M + H+, C22H32N3O2 requires m/z 370.2495).
(3S,8S)-3,8-Diben zyl-6-p r op yl-1,4,6-tr ia za bicyclo[3.3.0]-
oct-4-en e (44). According to the above DMC-induced cycliza-
tion of deprotected hydroxyethylguanidine the hydrochloride
of 43 (2.27 g, 6.15 mmol) was treated with DMC (6.22 g, 68.8
mmol) and Et3N (3.72 g, 36.8 mmol) in CH2Cl2 (40 mL) at room
temperature for 17 h and then with KOH (8.24 g) in MeOH at
room temperature for 24 h. Workup followed by purification
column chromatography (NH-SiO2, hexane-CHCl3)1:1) gave
The mixture (16.9 g, 32.1 mmol) was deprotected with a 1
M solution of TBAF in THF (50.3 mL, 50.3 mmol) in THF (98
mL) at room temperature for 24 h to give the guanidine (11.7
g, 88%) after purification by column chromatography (NH-
SiO2, CHCl3). A part (7.16 g, 17.3 mmol) of it was treated with
DMC (8.79 g, 52.0 mmol) and Et3N (10.5 g, 104 mmol) in
MeCN (207 mL) at room temperature for 6 h and then with
KOH (20.7 g) in MeOH (311 mL) at room temperature for 1 h
to afford 41 (5.62 g, 72%) as a colorless oil after purification
by column chromatography (NH-SiO2, CH2Cl2); IR (neat) νmax
44 (1.38 g, 67%) as a colorless oil; IR (neat) νmax 1655 cm-1
;
1
UV λmax 207.2 (ꢀ 23000) nm; [R]25 -17.9 (c 1.00, CHCl3); H
D
NMR δ 0.91 (t, J ) 7.5 Hz, 3H), 1.49-1.61 (m, 2H), 2.55 (dd,
J ) 8.3, 8.0 Hz, 1H), 2.69 (dd, J ) 13.3, 9.9 Hz, 1H), 2.74 (dd,
J ) 13.5, 6.2 Hz, 1H), 2.84 (dd, J ) 13.5, 5.9 Hz, 1H), 2.85
(dd, J ) 8.3, 2.4 Hz, 1H), 2.99 (dd, J ) 13.3, 4.4 Hz, 1H), 3.15
(t, J ) 7.0 Hz, 2H), 3.27-3.38 (m, 2H), 3.43-3.51 (m, 1H),
4.22-4.28 (m, 1H), 7.15-7.32 (m, 10H); 13C NMR δ 11.2, 21.0,
39.4, 41.9, 47.2, 52.2, 56.5, 59.5, 71.4, 125.9, 126.7, 128.2, 128.6,
129.1, 129.4, 137.8, 139.9, 168.6; HRFABMS m/z 334.2293 (M
+ H+, C22H28N3 requires m/z 334.2283).
1655 cm-1; UV λmax 208.0 (ꢀ 29900) nm; [R]27 -65.6 (c 1.00,
D
CHCl3); 1H NMR δ 1.52 (d, J ) 7.0 Hz, 3H), 2.54-2.63 (m,
2H), 2.68-2.77 (m, 2H), 2.84 (dd, J ) 8.2, 2.9 Hz, 1H), 2.94-
3.03 (m, 2H), 3.26-3.35 (m, 1H), 3.45 (dd, J ) 8.6, 7.1 Hz,
1H), 4.27-4.35 (m, 1H), 5.11 (q, J ) 7.0 Hz, 1H), 7.02 (d, J )
7.7 Hz, 2H), 7.18-7.38 (m, 13H); 13C NMR δ 17.0, 38.8, 41.9,
51.3, 52.0, 52.1, 59.3, 71.1, 125.9, 126.6, 127.0, 127.3, 128.1,
128.4, 128.5, 129.1, 129.4, 137.6, 139.7, 140.8, 167.7; HR-
FABMS m/z 396.2420 (M + H+, C27H30N3 requires m/z
396.2440).
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of compounds (2, 4, 6-8, 10, 11)b, (2, 4, 6-8, 10, 11)c,
14 and its synthetic intermediates, 25-29, 31-35, (5S)-3-[(S)-
1-phenylethyl]-2-[(S)-1-phenylethylimino]-1,3-diazabicyclo[3.3.0]-
octane and its synthetic intermediates, 37 and its synthetic
intermediates, and 42 and its synthetic intermediates; 1H and
13C NMR charts of compounds 2a , 4a , (7-10)a , 15, 16, 21,
24, 30, 41, 43, and 44; 2D NMR charts of compound 12. This
material is available free of charge via the Internet at
http://pubs.acs.org.
N,N′-Bis[(S)-1-ben zyl-2-h yd r oxyeth yl]-N′′-p r op ylgu a n i-
d in e (43). According to the above deprotection method 42 (4.45
g, 7.45 mmol) in THF (19 mL) was treated with a 1 M solution
of TBAF in THF (19.4 mL, 19.4 mmol) at room temperature
for 21 h to give 43 (2.27 g, 83%) after purification by column
chromatography (NH-SiO2, CHCl3); An amorphous mass; IR
J O000746F