(S)-Pyroglutamic acid, (S)-malic acid, and (S)-serine as useful starting materials in the synthesis of enantiopure hydroxyamidines

Article abstract of DOI:10.1002/(sici)1099-0690(200001)2000:1<115::aid-ejoc115>3.0.co;2-j

The synthesis of four enantiopure hydroxyamidines is described. One amidine was obtained from (S)-pyroglutamic acid. Its key step involved the addition of phenylmagnesium bromide to the corresponding ester, affording the tertiary alcohol without detectabl

Full text of DOI:10.1002/(sici)1099-0690(200001)2000:1<115::aid-ejoc115>3.0.co;2-j

FULL PAPER
(S)-Pyroglutamic Acid, (S)-Malic Acid, and (S)-Serine as Useful Starting
Materials in the Synthesis of Enantiopure Hydroxyamidines
Martin Ostendorf,[a] Jan Dijkink,[a] Floris P. J. T. Rutjes,[a] and Henk Hiemstra*[a]
Keywords: Amidines / Chiral base / N-Acyliminium ions / Enantioselective catalysis / Chiral pool
The synthesis of four enantiopure hydroxyamidines is
described. One amidine was obtained from (S)-pyroglutamic
acid. Its key step involved the addition of phenylmagnesium
bromide to the corresponding ester, affording the tertiary
alcohol without detectable racemization. The second
amidine was obtained by coupling of an (S)-malic acid
derived N-acyliminium ion with β-naphthol. The other
amidines were obtained from an (S)-serine-derived imide
which was reduced to two diastereomeric lactams that were
eventually transformed into the corresponding amidines.
nally, the enantioselectivity-inducing properties of the ami-
dines were briefly examined in two test reactions.
Introduction
The synthesis and properties of amidines are well-docu-
mented organic chemistry.[1] However, only a limited num-
ber of highly functionalized, enantiopure derivatives are
known. Some noteworthy examples follow. The bicyclic am-
idine 1 was synthesized by the group of Davis and was cap-
able of enantiodifferentiating recognition of chiral car-
boxylic acids.[2] Ganem synthesized various amidines start-
ing from -glucose, -mannose (viz. 2), and -galactose;
these amidines were evaluated as glycosidase inhibitors.[3]
Results and Discussion
The synthesis of hydroxyamidine 4 commenced with
methyl pyroglutamate (8), obtained from the acid by treat-
ment with thionyl chloride in methanol.[8] The ester was
treated with an excess of phenylmagnesium bromide at
Ϫ78°C, to afford the tertiary alcohol 9 in 51% yield after
recrystallization from Et2O (Equation 1). The enantiopurity
of the product was confirmed by comparison with literature
data (ref.[9] [α]D ϭ Ϫ86.4). The tertiary alcohol 9 was pro-
tected with TBDMSOTf to give the corresponding silyl
ether 10 ([α]D ϭ Ϫ67.1) in quantitative yield.
The synthesis and crystal structure of 3 were recently re-
ported by our research group.[4] This enantiopure hydroxy-
amidine was tested as a chiral base in base-catalysed enanti-
oselective reactions, such as the Michael reaction. In an at-
tempt to increase the asymmetric induction, we designed
new highly functionalized enantiopure amidines which, as
a result of more steric bulk, might result in better selectivit-
ies.[5] Whereas an oxazaborolidine-mediated desymmetriz-
ation, developed in our group, was employed as the basis
for the synthesis in the latter case, the hydroxyamidines 4Ϫ7
reported in this article were all synthesized from readily
available enantiopure starting materials. Amidine 4, a di-
phenyl-substituted analogue of 3, was synthesized from (S)-
pyroglutamic acid. Amidine 5 was synthesized with chemis-
try developed in our group, from (S)-malic acid,[6] while
amidines 6 and 7 were both prepared from (S)-serine.[7] Fi-
A pathway similar to the one developed for the synthesis
of 3 was applied to lactam 10 (Scheme 1).[4] The lactam
reacted in a Michael-type fashion with acrylonitrile;[10] 11
was furnished in quantitative yield. The nitrile group was
reduced with NaBH4 and CoCl2[11] and the resulting amine
was directly treated with tBoc2O to give the carbamate 12
in 66% yield. The lactam moiety was then activated towards
cyclization by conversion into thiolactam 13,[12] after which
the tertiary alcohol was deprotected with tetrabutylam-
monium fluoride (TBAF) to give alcohol 14 (61% yield over
two steps). Next, a three-step, one-pot procedure was ap-
plied to perform the cyclization. After treatment of the thi-
[a]
Laboratory of Organic Chemistry, Institute of Molecular
Chemistry, University of Amsterdam
Nieuwe Achtergracht 129, NL-1018 WS Amsterdam,
The Netherlands
Fax: (internat.) ϩ 31-20/525-5670
E-mail: henkh@org.chem.uva.nl
Eur. J. Org. Chem. 2000, 115Ϫ124
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0101Ϫ115 $ 17.50ϩ.50/0
115

M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes, H. Hiemstra
FULL PAPER
Scheme 1. Synthesis of hydroxyamidine 4
olactam with MeI and removal of the Boc group with tri- group (MOM) was introduced, in 76% yield, through the
fluoroacetic acid (TFA), the resulting amine was subjected reaction with NaH (1.1 equiv) and an excess of MOMCl (2
to various cyclization conditions. Both treatment with Et3N equiv.) in an 8:1 mixture of THF/DMF. The lactam hydroxy
in CH2Cl2[5] or subjection to ion-exchange chromatography group was removed by saponification of the acetate (cat.
(Amberlite IRA 400)[4] did not result in clean product for- NaOMe), followed by the Barton deoxygenation
mation. Eventually, treatment of the amine with aqueous method,[15] which involves reduction of the corresponding
NaOH at 0°C, followed by acid/base extraction afforded thiocarbonate with Bu3SnH and AIBN in refluxing benzene
1
amidine 4 in good yield (86%) as a white solid which was (80% overall yield). Room-temperature H- and 13C-NMR
recrystallized from benzene.
spectra showed that the β-naphthol-substituted compounds
In an earlier paper, we described the synthesis of enanti- mentioned in Scheme 2 consisted of a mixture of two rota-
opure acetoxylactam 15 from (S)-malic acid in five steps in mers, due to restricted rotation around the sp2Ϫsp3 CϪC
73% yield (5:1 cis/trans mixture, Scheme 2).[4] Our group bond between the aromatic and the lactam moiety. Product
investigated aromatic substitution reactions on this and 21 was obtained as a solid (m.p. 107Ϫ109°C) with satisfac-
other N-acyliminium ion precursors.[13] Treatment of 15 tory elemental analysis and 1H- and 13C-NMR spectra,
1
with β-naphthol (16) in the presence of BF3·OEt2 provided thus confirming the assigned structure. H-NMR analysis
adduct 17 in 76% yield. This product results from attack of of the Mosher ester of the deprotected alcohol showed that
the most nucleophilic α-position of β-naphthol onto the le- product 21 was obtained in > 98% enantiomeric excess.[16]
ast hindered side of the N-acyliminium ion. According to This compound was subjected to an identical series of ev-
NMR spectroscopy, the trans diastereomer was exclusively ents as that described previously (the arylϪOH was also
formed in this reaction. Next, protection of the phenolic liberated in the TFA step) to afford the hydroxyamidine 5.
alcohol of 17 was investigated. A tert-hexyldimethylsilyl
Finally, the syntheses of amidines 6 and 7 were studied.
group was efficiently introduced (tHexMe2SiCl, imidazole, First, (S)-serine had to be converted into an appropriately
DMF, 96% yield), but appeared to be unstable under the functionalized amine. For this purpose, the commercially
basic nitrile reduction conditions.[14] The methoxymethyl available HCl salt of the methyl ester of (S)-serine (24) was
Scheme 2. Synthesis of hydroxyamidine 5
116
Eur. J. Org. Chem. 2000, 115Ϫ124

(S)-Pyroglutamic Acid, (S)-Malic Acid, and (S)-Serine as Useful Starting Materials
FULL PAPER
successively treated with tBoc2O and TBDPSCl to give the
N- and O-protected product 26 in quantitative yield
(Scheme 3).[17] The introduction of the nitrile function was
performed in a three-step sequence. After reduction of the
ester with LiBH4, the resulting primary alcohol 27 was con-
verted into the mesylate by treatment with MsCl. Then, the
cyanide group was introduced through KCN and 18-crown-
6 in refluxing acetonitrile,[18] to afford the cyanide 29 in
good yield. Finally, the tBoc group was removed under
standard conditions.
Figure 1. Crystal structure of 6
eoisomers, resulting from re and si face attack of each of
the carbonyl groups. However, when the reduction was per-
formed with an excess of NaBH4, at Ϫ15°C, in EtOH, and
in the presence of a catalytic amount of acid,[20] only the
kinetic cis products 32a and 32b were formed. Unfortu-
nately, the isomers could not be separated by column chro-
matography. Therefore, the mixture of hydroxylactams was
treated with TFA and Et3SiH; in situ reduction of the inter-
mediate N-acyliminium ions took place, to generate lactams
33a and 33b. At this stage, the diastereomers could be sepa-
rated by column chromatography, to afford a 45:55 ratio of
33a and 33b in good overall yield. It was not possible to
Scheme 3. Synthesis of aminonitrile 30
After the formation of the appropriate serine derivative assign the structures of the two diastereomeric products so-
30 was established, the syntheses of the hydroxyamidines lely on the basis of 1H-NMR spectra. Eventually, the X-ray
could be completed (Scheme 4). The first step was the con- crystal structure of amidine 6 (derived from lactam 33a, see
densation of amine 30 with cyclohexane-1,2-dicarboxylic Figure 1) clearly showed the relative stereochemistry shown
anhydride at 200°C in the absence of a solvent.[19] This led in Scheme 4. The lactams were separately subjected to the
to the chiral imide 31 in 30% yield after flash chromatogra- series of reactions described for amidine 4, to afford the
phy. Next, the removal of one of the imide carbonyls was diastereomeric amidines 6 and 7. These compounds were
investigated. Reduction of imide 31 gives four possible ster- purified by recrystallization from benzene. In our hands,
Scheme 4. Synthesis of hydroxyamidines 6 and 7
Eur. J. Org. Chem. 2000, 115Ϫ124
117

M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes, H. Hiemstra
FULL PAPER
only amidine 6 afforded crystals that could be used for an
X-ray crystal structure determination. The crystal structure
(Figure 1) shows the absolute stereochemistry, i.e.,
(1R,4bS,8bR); this means that both the hydroxymethyl
group (at the 1-position) and the cis-fused six-membered
ring are on the same (front) face of the amidine ring.
Results on the catalytic activities of the hydroxyamidines
4Ϫ7 are summarized in Tables 1 and 2. The Michael-type
addition of thiophenol to cyclohexenone is a well-studied
asymmetric reaction[21] and was chosen as a model system
to identify the enantioselective catalytic properties of the
four amidines. It was shown that the addition reaction pro-
ceeded well in the presence of 2Ϫ5% of amidine, to give the
thioether 37 in 44Ϫ100% yield (Table 1). However, optically
active product was only obtained when amidine 4 was used
(14% ee, entry 1).
Conclusion
In summary, the hydroxyamidines 4Ϫ7 were synthesized
from the readily available starting materials (S)-pyroglut-
amic acid, (S)-malic acid, and (S)-serine. The structure of
amidine 6 was confirmed by an X-ray crystal structure de-
termination. These compounds represent a new class of chi-
ral functionalized amidines. Preliminary results on the cata-
lytic activities of these hydroxyamidines show that they pos-
sess unsatisfactory enantioselectivity-inducing properties.
Further studies on hydroxyamidines and other chiral bases
will be approached in a combinatorial way, which makes a
more rapid discovery of promising structures for catalysis
possible
Experimental Section
For general information see ref.[5]
Table 1. Thiophenol addition to cyclohexenone
(5S)-(Hydroxydiphenylmethyl)pyrrolidin-2-one (9): Phenylmag-
nesium bromide (90 mL, 270 mmol, 3.0  solution in Et2O) was
slowly added to a solution of methyl pyroglutamate (8)[8] (11.2 g,
78.5 mmol) in THF (100 mL) at Ϫ78°C over 30 min. After being
stirred for 15 min at Ϫ40°C and 30 min at 0°C, the reaction mix-
ture was quenched with a 5% aqueous HCl solution. After extrac-
tion of the water layer (CH2Cl2, 5 ϫ), the combined organic layers
were dried (Na2SO4) and concentrated in vacuo. The solid residue
was recrystallized from Et2O to give white crystals (11.0 g,
39.7 mmol, 51%), m.p. 191Ϫ192°C. Ϫ IR (CHCl3): ν˜ ϭ 3415 cmϪ1
1692. Ϫ H NMR (400 MHz): δ ϭ 7.48Ϫ7.18 (m, 10 H, 2 ϫ Ph),
4.79 (br. s, 1 H, NH), 4.71Ϫ4.67 (dd, 1 H, J ϭ 8.2, 4.8 Hz, NHCH),
3.95 (br. s, 1 H, OH), 2.37Ϫ2.29 [m, 1 H, C(O)CHH], 2.26Ϫ2.17
,
1
[a]
Determined from the known specific rotation.[21]
[m,
1 H, C(O)CHH], 2.13Ϫ2.04 [m, 1 H, C(O)CH2CHH],
1.96Ϫ1.87 [m, 1 H, C(O)CH2CHH]. Ϫ 13C NMR (100 MHz): δ ϭ
178.0 [s, C(O)], 145.2, 143.2 (s, Ph), 128.7, 128.2, 127.3, 126.9,
125.7, 125.5 (d, Ph), 78.6 [s, C(Ph)2OH], 60.5 (d, NHCH), 30.1 [t,
C(O)CH2], 21.5 [t, C(O)CH2CH2]. Ϫ [α]D ϭ Ϫ80.8 (c ϭ 1.3;
CHCl3).
Table 2. Michael addition to methyl vinyl ketone
(5S)-[(tert-Butyldimethylsilyloxy)diphenylmethyl]pyrrolidin-2-one
(10): tert-Butyldimethylsilyl triflate (103 µL, 0.45 mmol) and 2,6-
lutidine (70 µL, 0.60 mmol) were slowly added to a solution of
alcohol 9 (41 mg, 0.15 mmol) in CH2Cl2 (2.0 mL) at 0°C . After
being stirred for 17 h at room temp., another portion of TBSOTf
(75 µL, 0.30 mmol) and 2,6-lutidine (35 µL, 0.30 mmol) were ad-
ded. After 5 h at room temp., the reaction mixture was quenched
with 5% aqueous HCl. After extraction of the water layer (CH2Cl2,
5 ϫ), the combined organic layers were dried (Na2SO4) and con-
centrated in vacuo. After flash chromatography (EtOAc/PE, 1:1),
10 was obtained as a white solid (57 mg, 0.15 mmol, 100%). An
analytic sample was recrystallized from EtOAc, m.p. 160.5Ϫ161°C.
Ϫ IR (CHCl3): ν˜ ϭ 3500 cmϪ1, 1692. Ϫ 1H NMR (400 MHz): δ ϭ
7.35Ϫ7.26 (m, 10 H, 2 ϫ Ph), 6.04 (br. s, 1 H, NH), 4.64Ϫ4.61
(dd, 1 H, J ϭ 8.4, 3.1 Hz, NHCH), 2.19Ϫ2.05 [m, 2 H, C(O)CH2],
[a]
Determined by chiral HPLC (Chiralpak AS).
A variety of asymmetric amidine-catalysed reactions with
carbon nucleophiles such as nitromethane, malonates, and
diketones were explored. However, some asymmetric induc-
tion was observed only with β-oxo ester 38 (Table 2). In the
presence of 3Ϫ10% of catalyst, the Michael addition of 38
to methyl vinyl ketone proceeded in excellent yields to give
the product 39. The highest ee was obtained when hydroxy-
amidine 5 was used (entry 2, 27% ee).
1.87Ϫ1.79 [m,
1 H, C(O)CH2CHH], 1.02Ϫ0.90 [m, 1 H,
C(O)CH2CHH], 0.93 [s, 9 H, SiC(CH3)3], Ϫ0.36 and Ϫ0.39 [2 ϫ s,
6 H, Si(CH3)2]. Ϫ 13C NMR (100 MHz): δ ϭ 178.5 [s, C(O)], 142.8,
142.2 (s, Ph), 128.7, 128.5, 128.0, 127.6, 127.5, (d, Ph), 82.3 [s,
C(Ph2)OSi], 59.7 (d, NCH), 28.7 [t, C(O)CH2], 26.0 [q, SiC(CH3)3],
22.2 [t, C(O)CH2CH2], 18.7 [s, SiC(CH3)3], Ϫ3.34 and Ϫ3.36 [q,
Si(CH3)2]. Ϫ C23H31NO2Si (381.6): calcd. C 72.39, H 8.19, N 3.67;
found C 72.46, H 8.19, N, 3.30. Ϫ [α]D ϭ Ϫ67.1 (c ϭ 1.0; CHCl3).
118
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(S)-Pyroglutamic Acid, (S)-Malic Acid, and (S)-Serine as Useful Starting Materials
FULL PAPER
3-{(2S)-[(tert-Butyldimethylsilyloxy)diphenylmethyl]-5-oxopyrrol-
idin-1-yl}propionitrile (11): To a solution of lactam 10 (10.1 g,
25.8 mmol) in THF (70 mL) was added, at room temp, acrylonitrile
(2.50 mL, 38.7 mmol) and a catalytic amount of powdered NaOH.
After being stirred for 3.5 h at room temp, the reaction mixture was
quenched with water. After extraction of the water layer (CH2Cl2, 5
0.19 mmol) in toluene (2 mL) was heated at 90°C for 40 min. After
concentration of the reaction mixture in vacuo, the residue was
chromatographed (EtOAc/PE, 1:3); 13 was obtained as a green
foam (170 mg, 0.30 mmol, 86%). Ϫ IR (film): ν˜ ϭ 3500 cmϪ1, 1709,
1692. Ϫ H NMR (400 MHz): δ ϭ 7.46Ϫ7.26 (m, 10 H, 2 ϫ Ph),
5.13 (br. s, 1 H, NHBoc), 5.05Ϫ5.03 (d, 1 H, J ϭ 9.1 Hz, NCH),
1
ϫ), the combined organic layers were dried (Na2SO4) and concen- 4.48Ϫ4.41 (dt, J ϭ 14.1, 7.4 Hz, 1 H, NCHHCH2), 3.25Ϫ3.21 (br.
trated in vacuo. After flash chromatography (EtOAc/PE, 1:1.5), 11
was obtained as a yellow foam (11.4 g, 25.8 mmol, 100%). Ϫ IR
(film): ν˜ ϭ 2361 cmϪ1, 1678. Ϫ 1H NMR (400 MHz): δ ϭ
m, 2 H, NCHHCH2CHHNH), 2.86Ϫ2.82 (m, 1 H, CHHNHBoc),
2.42Ϫ2.35 [dd, 1 H, J ϭ 18.3, 9.6 Hz, C(S)CHH], 2.24Ϫ2.06 [m, 2
H, C(S)CHHCHH], 1.80Ϫ1.77 (m, 2 H, NCH2CH2), 1.42 [s, 9 H,
7.46Ϫ7.26 (m, 10 H, 2 ϫ Ph), 4.95Ϫ4.92 (m, 1 H, NCH), CO2C(CH3)3], 1.33Ϫ1.23 [m, 1 H, C(S)CH2CHH], 0.90 [s, 9 H,
3.75Ϫ3.69 (m, 1 H, NCHHCH2), 3.43Ϫ3.38 (m, 1 H, NCHHCH2), SiC(CH3)3], Ϫ0.45 and Ϫ0.46 [2 ϫ s, 6 H, Si(CH3)2]. Ϫ 13C NMR
2.73Ϫ2.65 (m, 1 H, NCH2CHH) 2.37Ϫ2.30 (m, 1 H, NCH2CHH),
(100 MHz): δ ϭ 205.4 [s, NC(S)], 155.5 [s, NHC(O)], 141.0, 139.4
2.19Ϫ2.12 [m, 2 H, C(O)CH2], 1.74Ϫ1.67 [m, 1 H, C(O)CH2CHH], (s, Ph), 128.9, 128.7, 128.6, 128.1, 128.0, 127.7 (d, Ph), 83.0 [s,
0.88 [s, 9 H, SiC(CH3)3], 0.88Ϫ0.77 [m, 1 H, C(O)CH2CHH], C(Ph2)OSi], 78.9 [s, CO2C(CH3)3], 71.5 (d, NCH), 44.0 and 42.6 (t,
Ϫ0.46 and Ϫ0.47 [2 ϫ s, 6 H, Si(CH3)2]. Ϫ 13C NMR (100 MHz):
δ ϭ 176.9 [s, C(O)], 141.2, 140.0 (s, Ph), 129.1, 128.9, 128.5, 128.0,
NCH2CH2CH2NH), 37.2 [t, C(S)CH2], 28.3 [q, CO2C(CH3)3], 26.4
(t, NCH2CH2), 26.1 [q, SiC(CH3)3], 23.4 [t, C(S)CH2CH2], 18.8 [s,
128.0, 127.7 (d, Ph), 118.1 (s, CN), 82.3 [s, C(Ph2)OSi], 64.9 (d, SiC(CH3)3], Ϫ3.0 and Ϫ3.3 [q, Si(CH3)2]. Ϫ HRMS (FABϩ):
NCH), 38.1 (t, NCH2CH2) 28.3 [t, C(O)CH2], 26.1 [q, SiC(CH3)3], calcd. for C31H47N2O3SSi (M ϩ H) 555.3077, found 555.3050. Ϫ
21.8 [t, C(O)CH2CH2], 18.7 [s, SiC(CH3)3], 15.9 (t, CH2CN), Ϫ3.34
and Ϫ3.36 (q, Si(CH3)2). HRMS (FABϩ): calcd. for
C26H35N2O2Si (M ϩ H) 435.2468, found 435.2455. Ϫ [α]D ϭ Ϫ34.0
(c ϭ 0.98; CHCl3).
[α]D ϭ Ϫ91.2 (c ϭ 1.0; CHCl3).
Ϫ
tert-Butyl (3-[(2S)-(Hydroxydiphenylmethyl)-5-thioxopyrrolidin-1-
yl]propyl)carbamate (14): To a solution of 13 (5.32 g, 9.4 mmol) in
THF (40 mL) was added TBAF (10 mL, 10 mmol, 1.0  solution
in THF) at room temp. After 1 h, another portion of TBAF (5 mL,
tert-Butyl (3-{(2S)-[(tert-Butyldimethylsilyloxy)diphenylmethyl]-5-
oxopyrrolidin-1-yl}propyl)carbamate (12): To a vigorously stirred, 5 mmol, 1.0  solution in THF) was added. After being stirred
purple solution of CoCl2·H2O (12.1 g, 50.9 mmol) in MeOH for 50 min, the reaction mixture was quenched with H2O. After
(50 mL) was added, at 0°C, NaBH4 (480 mg, 12.7 mmol). The extraction of the water layer (CH2Cl2, 5 ϫ), the combined organic
deep-black solution was stirred for 15 min at room temp and co-
layers were dried (Na2SO4) and concentrated in vacuo. After flash
oled again. Then a solution of cyanide 11 (11.3 g, 25.5 mmol) in
chromatography (EtOAc/PE, 1:1), 14 was obtained as a white foam
2% NH3 in MeOH (100 mL) was added dropwise. NaBH4 pellets (3.01 g, 6.7 mmol, 71%). Ϫ IR (film): ν˜ ϭ 3450 cmϪ1, 1703, 1693.
(19.2 g, 509 mmol) were added in portions over 5 h, during which
hydrogen gas evolved. After being stirred another 1 h at 0°C, the
reaction mixture was quenched with H2O and filtered through Ce-
lite. The Celite was washed (MeOH/H2O, 9:1, 3 ϫ). The solution
was concentrated in vacuo and the residue was taken up in 5%
aqueous NH3. After extraction of the water layer (EtOAc, 5 ϫ),
drying of the combined organic layers (Na2SO4) and concentration
in vacuo, the crude product was obtained as a purple oil (9.85 g,
22.2 mmol, 89%). To a solution of this amine (9.5 g, 21.2 mmol) in
CH2Cl2 (40 mL) was added Boc2O (9.3 g, 42.4 mmol) and a cata-
lytic amount of DMAP. After being stirred for 1 h at room temp.,
the reaction mixture was concentrated in vacuo and purified by
flash chromatography (EtOAc/PE, 1:2); the product was obtained
as a white foam (9.21 g, 16.8 mmol, 66% from 11). Ϫ IR (film):
ν˜ ϭ 3500 cmϪ1, 1687, 1673. Ϫ 1H NMR (400 MHz): δ ϭ 7.48Ϫ7.26
(m, 10 H, 2 ϫ Ph), 5.20 (br. s, 1 H, NHBoc), 4.71Ϫ4.68 (d, 1 H,
J ϭ 9.0 Hz, NCH), 3.76Ϫ3.65 (m, 1 H, NCHHCH2), 3.28Ϫ3.25
(m, 1 H, CHHNHBoc), 2.77Ϫ2.69 (m, 2 H, NCHHCH2CHHNH),
2.22Ϫ2.12 [m, 2 H, C(O)CH2], 2.08Ϫ1.97 [m, 1 H, C(O)CH2CHH],
1.78Ϫ1.60 (m, 2 H, NCH2CH2), 1.39 [s, 9 H, CO2C(CH3)3], 0.90
[s, 9 H, SiC(CH3)3], 0.86Ϫ0.80 [m, 1 H, C(O)CH2CHH], Ϫ0.45 and
Ϫ0.49 [2 ϫ s, 6 H, Si(CH3)2]. Ϫ 13C NMR (100 MHz): δ ϭ 177.5
[s, NC(O)], 155.9 [s, NHC(O)], 141.9, 139.8 (s, Ph), 129.1, 129.0,
128.7, 127.9, 127.7, 127.4 (d, Ph), 82.4 [s, C(Ph2)OSi], 78.7 [s,
CO2C(CH3)3], 63.1 (d, NCH), 38.3 and 36.9 (t,
NCH2CH2CH2NHBoc), 28.5 [t, C(O)CH2], 28.3 [q, CO2C(CH3)3],
27.0 (t, NCH2CH2), 26.1 [q, SiC(CH3)3], 21.5 [t, C(O)CH2CH2],
18.8 [s, SiC(CH3)3], Ϫ3.1 and Ϫ3.4 [q, Si(CH3)2]. Ϫ HRMS
(FABϩ): calcd. for C31H47N2O4Si (M ϩ H) 539.3305, found
539.3283. Ϫ [α]D ϭ Ϫ76.0 (c ϭ 1.1; CHCl3).
Ϫ
1H NMR (400 MHz): δ ϭ 7.46Ϫ7.24 (m, 10 H, 2 ϫ Ph),
5.08Ϫ5.06 (d, 1 H, J ϭ 8.6 Hz, NCH), 4.84 (br. s, 1 H, NHBoc),
4.29Ϫ4.22 (dt, 1 H, J ϭ 14.3, 7.4 Hz, NCHHCH2), 3.12Ϫ3.09 (m,
1 H, CHHNHBoc), 2.96 (br. s, 1 H, ϪOH), 2.83Ϫ2.68 (m, 2 H,
NCHHCH2CHHNH), 2.50Ϫ2.48 [m, 1 H, C(S)CHH], 2.22Ϫ2.16
[m, 1 H, C(S)CHH], 2.07Ϫ2.01 [m, 1 H, C(S)CH2CHH], 1.74Ϫ1.60
(m,
2 H, NCH2CH2), 1.42 [m, 10 H, CO2C(CH3)3 and
C(S)CH2CHH]. Ϫ 13C NMR (100 MHz): δ ϭ 207.4 [s, NC(S)],
155.9 [s, NHC(O)], 144.0, 143.7 (s, Ph), 128.6, 128.4, 127.7, 127.6,
126.2, 125.9 (d, Ph), 80.6 [s, C(Ph2)OH], 79.1 [s, CO2C(CH3)3], 72.0
(d, NCH), 44.8 and 43.6 (t, NCH2CH2CH2NHBoc), 37.3 [t,
C(S)CH2], 28.3 [q, CO2C(CH3)3], 26.0 (t, NCH2CH2), 24.6 [t,
C(S)CH2CH2]. Ϫ HRMS (FABϩ): calcd. for C25H33N2O3S (M ϩ
H) 441.2212, found 441.2207. Ϫ [α]D ϭ ϩ6.8 (c ϭ 1.0; CHCl3).
[(6S)-2,3,4,6,7,8-Hexahydropyrrolo[1,2-a]pyrimidin-6-
yl]diphenylmethanol (4): A solution of 14 (2.9 g, 6.5 mmol) in MeI
(15 mL) was stirred for 17 h at room temp in the dark. After con-
centration in vacuo, a pale yellow powder was obtained (3.8 g,
6.5 mmol, 100%). This iodine salt (1.32 g, 2.27 mmol) was dis-
solved in 50% TFA in CH2Cl2 (12 mL) at 0°C. After being stirred
for 4.5 h at this temperature, the product was extracted (H2O, 3 ϫ).
The combined aqueous extracts were made basic with solid NaOH
and the product was extracted (CH2Cl2, 3 ϫ). The combined or-
ganic extracts were dried (Na2SO4) and concentrated in vacuo. The
product (600 mg, 1.96 mmol, 86%, white powder) was recrystallized
from benzene as white crystals, m.p. 235Ϫ240°C (decomposition).
Ϫ IR (CHCl3): ν˜ ϭ 3300 cmϪ1, 1650. Ϫ 1H NMR (400 MHz): δ ϭ
7.58Ϫ7.57 (d, 2 H, J ϭ 1.3 Hz, Ph), 7.56Ϫ7.51 (m, 2 H, Ph),
7.49Ϫ7.19 (m, 6 H, Ph), 4.59Ϫ4.56 (dd, 1 H, J ϭ 8.6, 3.6 Hz,
NCH), 3.36Ϫ3.32 (b dt, 1 H, J ϭ 14.6 Hz, CϭNCHH), 3.10Ϫ3.05
(b t, 1 H, J ϭ 9.9 Hz, CϭNCHH), 2.75Ϫ2.70 (m, 1 H, CϪNCHH),
tert-Butyl (3-{(2S)-[(tert-Butyldimethylsilyloxy)diphenylmethyl]-5-
thioxopyrrolidin-1-yl}propyl)carbamate (13): A solution of lactam 2.43Ϫ2.18 (m, 3 H, CϪNCHH, NϭCCH2), 2.17Ϫ1.95 (m, 2 H,
12 (190 mg, 0.35 mmol) and LawessonЈs reagent (77 mg, NϭCCH2CHH and ϪOH), 1.90Ϫ1.82 (m, 1 H, NϭCCH2CHH),
Eur. J. Org. Chem. 2000, 115Ϫ124
119

M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes, H. Hiemstra
FULL PAPER
1.64Ϫ1.56 (m, 1 H, CϭNCH2CHH), 1.49Ϫ1.39 (m, 1 H, Cϭ
3.81 (m, 1 H, NCHH), 3.65 (ddd, 1 H, J ϭ 13.2, 6.1, 5.4 Hz,
NCH2CHH). Ϫ 13C NMR (100 MHz): δ ϭ 162.5 (s, CϭN), 145.9, NCHH), 3.54 (s, 3 H, OCH3), 3.45 (s, 3 H, OCH3), 3.14Ϫ2.26 (m,
144.9 (s, Ph), 128.1, 128.0, 126.8, 126.7, 125.8, 125.7 (d, Ph), 79.0
[s, C(Ph)2OH], 71.0 (d, NCH), 45.5, 43.4 (t, CH2NϭCϪNCH2),
6 H). Ϫ 13C NMR (50 MHz, mixture of rotamers): δ ϭ 174.5, 172.9
[s, C(O)], 154.8, 153.5, 132.9, 131.6, 130.3, 129.2, 117.7, 117.2 (s,
30.3 (t), 23.4 (t), 20.8 (t). Ϫ C20H22N2O (306.4): calcd. C 78.40, H Naph), 131.3, 130.8, 129.3, 128.8, 127.6, 127.3, 124.4, 124.0, 121.9,
7.24, N 9.14; found C 78.60, H 7.18, N 9.08. Ϫ [α]D ϭ Ϫ14.6 (c ϭ
0.5; CHCl3).
121.4, 116.5, 114.9 (d, Naph), 116.8 (s, CN), 96.0, 94.2 (t, OCH2O),
70.7, 70.3 (d, NCH), 65.9, 62.6 (d, CHOH), 56.5, 56.2 (q, OCH3),
41.2, 39.9 (t, NCH2), 36.6, 36.4 [t, C(O)CH2], 16.0, 15.3 [t,
CH2CN). Ϫ C19H20N2O4 (296.3): cacld. C 67.03, H 5.93, N 8.23;
found C 67.14, H 5.93, N 8.21. Ϫ [α]D ϭ ϩ113 (c ϭ 1.1; MeOH].
(2S,3S)-1-(2-Cyanoethyl)-2-(2-hydroxynaphthalen-1-yl)-5-oxo-
pyrrolid-3-yl Acetate (17): To a solution of lactam 16 (2.54 g,
10 mmol) in CH2Cl2 (150 mL) were added at 0°C β-naphthol
(2.88 g, 20 mmol) and BF3·OEt2 (7.5 mL, 60 mmol). After being O-{(2S,3S)-[1-(2-Cyanoethyl)-2-(2-methoxymethylnaphthalen-1-yl)-
stirred at room temp for 48 h, the reaction mixture was quenched
with aqueous saturated NaHCO3. After extraction of the water
5-oxopyrrolidin-3-yl] O-Phenyl Thiocarbonate (20): To a solution of
alcohol 19 (3.42 g, 10.0 mmol) and DMAP (2.44 g, 20 mmol) in
layer (CH2Cl2, 2 ϫ), the combined organic layers were dried CH2Cl2 (60 mL) was added, at 0°C, a solution of phenyl chloro-
(Na2SO4) and concentrated in vacuo. The product (2.57 g,
7.60 mmol, 76%) was obtained as a white solid after flash chroma-
thionoformate (1.73 mL, 12.5 mmol) in CH2Cl2 (10 mL). After be-
ing stirred for 2 h at this temperature, the reaction mixture was
tography (EtOAc). An analytical sample was recrystallized from concentrated in vacuo. The product (4.61 g, 9.7 mmol, 97%) was
EtOAc, m.p. 214Ϫ219°C. Ϫ IR (KBr): ν˜ ϭ 2950 cmϪ1, 2140, 1750, purified by column chromatography (EtOAc); it formed a pink
1
1645. Ϫ 1H NMR (400 MHz, major rotamer): δ ϭ 7.64 (s, 1 H,
foam. Ϫ H NMR (200 MHz, major rotamer): δ ϭ 8.24Ϫ6.97 (m,
ϪOH), 8.04Ϫ7.16 (m, 6 H, Naph), 5.72 (s, 1 H, NCH), 5.47 (br. d, 11 H, Naph), 5.95 (s, 1 H, NCH), 5.91 [dd, 1 H, J ϭ 8.2, 2.2 Hz
1 H, J ϭ 8.2 Hz, CHOAc), 3.61 (dt, 1 H, J ϭ 13.9, 6.6 Hz, NCHH), CHOC(S)], 5.30 (s, 2 H, OCH2O), 3.59 (m, 1 H, NCHH), 3.49 (s,
2.96 (dt, 1 H, J ϭ 13.9, 7.5 Hz, NCHH), 3.33 [dd, 1 H, J ϭ 18.1,
3 H, OCH3), 3.38 [dd, 1 H, J ϭ 18.4, 8.2 Hz, C(O)CHH], 2.93 (m,
8.2 Hz, C(O)CHH], 2.62 [dd, 1 H, J ϭ 18.1, 2.1 Hz, C(O)CHH], 1 H, NCHH), 2.62 (dt, 1 H, J ϭ 16.8, 7.5 Hz, CHHCN), 2.85
2.65 (m, 1 H, CHHCN), 2.29 (dt, 1 H, J ϭ 16.9, 5.6 Hz, CHHCN), [dd, 1 H, J ϭ 18.4, 2.5 Hz, C(O)CHH], 2.30 (dt, 1 H, J ϭ 16.8,
2.13 [s, 3 H, C(O)CH3]. Ϫ 13C NMR (50 MHz, [D6]DMSO): δ ϭ
172.4, 170.1 [s, 2 ϫ C(O)], 154.2, 133.4, 128.1, 113.7 (s, Naph),
130.6, 128.8, 127.2, 122.7, 121.3, 118.5 (d, Naph), 118.9 (s, CN),
72.9 (d, CHOAc), 61.4 (d, NCH), 38.4 (t, NCH2), 36.2 t,
[C(O)CH2], 20.0 [q, C(O)CH3], 15.8 (t, CH2CN). Ϫ C19H18N2O4
(338.4): calcd. C 67.43, H 5.37, N 8.28; found C 67.52, H 5.40, N
8.25. Ϫ [α]D ϭ ϩ42.4 (c ϭ 0.65; MeOH).
6.2 Hz, CHHCN).
3-[(2S)-(2-Methoxymethylnaphthalen-1-yl)-5-oxopyrrolidin-1-
yl]propionitrile (21): A solution of 20 (4.61 g, 9.7 mmol), Bu3SnH
(5.38 mL, 19.4 mmol) and AIBN (cat) in benzene (50 mL) was re-
fluxed for 1.5 h. The reaction mixture was concentrated in vacuo.
The residue was purified by column chromatography (EtOAc) and
recrystallization (Et2O/PE), to give the product (2.99 g, 9.22 mmol,
95%) as white crystals, m.p. 107Ϫ109°C. Ϫ IR (CHCl3): ν˜ ϭ 2250
cmϪ1, 1675. Ϫ 1H NMR (400 MHz, mixture of rotamers): δ ϭ
(2S,3S)-1-(2-Cyanoethyl)-2-(2-methoxymethylnaphthalen-1-yl)-5-
oxopyrrolid-3-yl Acetate (18): A solution of alcohol 17 (3.38 g,
10 mmol) in DMF (25 mL) was added at 0°C to a solution of NaH 8.15Ϫ7.34 (m, 12 H, Naph), 6.04 (t, 1 H, J ϭ 8.6 Hz, NCH), 5.90
(0.42 g, 11 mmol) in THF (200 mL). After the reaction mixture was (dd, 1 H, J ϭ 9.2, 4.3 Hz, NCH), 5.31 (AB d, 1 H, J ϭ 6.9 Hz,
stirred at this temperature for 30 min, MOMCl (1.45 mL, 20 mmol) OCHHO), 5.29 (AB d, 1 H, J ϭ 6.9 Hz, OCHHO), 5.244 (AB d,
was added. After being stirred at room temp for 18 h, the reaction 1 H, J ϭ 7.1 Hz, OCHHO), 5.240 (AB d, 1 H, J ϭ 7.1 Hz,
mixture was diluted with EtOAc (200 mL) and concentrated in va-
cuo. The product (2.78 g, 7.60 mmol, 76%) was obtained as a light
purple foam after flash chromatography (CH2Cl2/acetone, 4:1). Ϫ
1H NMR (250 MHz, major rotamer, selected signals): δ ϭ 5.74 (d,
OCHHO), 3.75 (dt, 1 H, J ϭ 13.9, 6.9 Hz, NCHH), 3.64 (dt, 1 H,
J ϭ 13.9, 6.6 Hz, NCHH), 3.53 (s, 3 H, OCH3), 3.45 (s, 3 H,
OCH3), 2.82Ϫ2.70 (m, 14 H). Ϫ 13C NMR (63 MHz, mixture of
rotamers): δ ϭ 176.1, 175.3 [s, C(O)], 154.2, 154.0, 132.9, 131.6,
1 H, J ϭ 1.9 Hz, NCH), 5.43 (dt, 1 H, J ϭ 8.2, 2.4 Hz, CHOAc), 130.5, 129.4, 119.9, 118.6 (s, Naph), 131.1, 130.6, 129.5, 129.0,
5.28 (AB d, 1 H, J ϭ 7.1 Hz, OCHHO), 5.22 (AB d, 1 H, J ϭ 127.6, 127.2, 124.2, 124.0, 122.4, 121.2, 116.1 (d, Naph), 118.1,
7.1 Hz, OCHHO), 3.60 (dt, 1 H, J ϭ 12.8, 5.4 Hz, NCHH), 3.45 117.6 (s, CN), 95.8, 94.5 (t, OCH2O), 56.5, 56.4 (d, NCH), 55.2,
(s, 3 H, OCH3), 3.22 [dd, 1 H, J ϭ 18.1, 8.4 Hz, C(O)CHH], 2.60 54.3 (q, OCH3), 37.1, 37.0 (t, NCH2), 30.8, 30.7 [t, C(O)CH2], 24.7,
[dd, 1 H, J ϭ 18.1, 2.5 Hz, C(O)CHH], 2.09 [s, 3 H, C(O)CH3].
24.5 [t, C(O)CH2CH2], 16.3, 15.5 (t, CH2CN). Ϫ C19H20N2O3
(324.4): calcd. C 70.34, H 6.22, N 8.64; found C 70.52, H 6.23, N
8.65. Ϫ [α]D ϭ ϩ86.9 (c ϭ 1.4; MeOH). Ϫ [α]365 ϩ338.
3-[(2S,3S)-3-Hydroxy-2-(2-methoxymethylnaphthalen-1-yl)-5-oxo-
pyrrolidin-1-yl]propionitrile (19): To a solution of acetate 18 (10.3 g,
28.1 mmol) in MeOH (100 mL) was added, at 0°C, NaOMe tert-Butyl {3-[(2S)-(2-Methoxymethylnaphthalen-1-yl)-5-oxopyrroli-
(1.4 mL, 1.4 mmol, 1.0  in MeOH). After the reaction mixture din-1-yl]propyl}carbamate (22): According to the procedure de-
was stirred for 45 min at this temperature, another portion of Na- scribed for 12, 1.73 g of 21 (5.32 mmol) was transformed into 1.55 g
OMe (1.4 mL, 1.4 mmol, 1.0  in MeOH) was added. After being (3.62 mmol, 68%, white foam) of 22. Ϫ IR (CHCl3): ν˜ ϭ 3452
stirred for 1 h at 0°C, the reaction mixture was quenched with cmϪ1, 1703, 1666. Ϫ 1H NMR (400 MHz, mixture of rotamers):
aqueous saturated NH4Cl. The product (8.37 g, 24.4 mmol, 87%)
was isolated by filtration and purified by recrystallization from
δ ϭ 8.10Ϫ7.33 (m, 12 H, Naph), 5.89 (t, 1 H, J ϭ 8.6 Hz, NCH),
5.71 (dd, 1 H, J ϭ 9.1, 4.8 Hz, NCH), 5.25 (m, 2 H, NHBoc), 5.293
EtOAc; white crystals were obtained, m.p. 164Ϫ166°C. Ϫ IR (AB d, 1 H, J ϭ 6.9 Hz, OCHHO), 5.290 (AB d, 1 H, J ϭ 6.9 Hz,
(CHCl3): ν˜ ϭ 3407 cmϪ1, 2250, 1681. Ϫ 1H NMR (400 MHz, mix-
OCHHO), 5.25 (AB d, 1 H, J ϭ 7.0 Hz, OCHHO), 5.22 (AB d, 1
ture of rotamers): δ ϭ 8.2Ϫ7.4 (m, 12 H, Naph), 5.84 (d, 1 H, J ϭ H, J ϭ 7.0 Hz, OCHHO), 3.68Ϫ3.55 (m, 2 H, NCHH), 3.51 (s, 3
6.0 Hz, NCH), 5.64 (d, 1 H, J ϭ 2.2 Hz, NCH), 5.35 (AB d, 1 H, H, OCH3), 3.46 (s, 3 H, OCH3), 2.88Ϫ2.19 (m, 10 H), 1.40 (m, 4
J ϭ 6.7 Hz, OCHHO), 5.32 (AB d, 1 H, J ϭ 6.7 Hz, OCHHO), H, NCH2CH2), 1.38, 1.37 [2 ϫ s, 18 H, CO2C(CH3)3]. Ϫ 13C NMR
5.22 (AB d, 1 H, J ϭ 7.0 Hz, OCHHO), 5.20 (AB d, 1 H, J ϭ
(63 MHz, mixture of rotamers): δ ϭ 175.9, 175.4 [s, NC(O)], 155.9
6.7 Hz, OCHHO), 4.91 (m, 1 H, CHOH), 4.66 (m, 1 H, CHOH), [s, NHC(O)], 154.0, 153.8, 132.9, 131.9, 130.4, 129.4, 120.4, 119.1
120
Eur. J. Org. Chem. 2000, 115Ϫ124

(S)-Pyroglutamic Acid, (S)-Malic Acid, and (S)-Serine as Useful Starting Materials
FULL PAPER
(s, Naph), 130.7, 130.3, 129.3, 129.0, 127.3, 126.9, 124.1, 123.8,
122.6, 121.1, 115.9, 115.5 (d, Naph), 95.6, 94.5 (t, OCH2O), 78.8 [s,
CO2C(CH3)3], 56.4, 56.3 (d, NCH), 54.4, 53.8 (q, OCH3), 37.7 (t,
CH2NHBoc), 37.5, 37.3 (t, NCH2), 30.9, 31.2 [t, C(O)CH2], 28.4
[q, CO2C(CH3)3], 27.4, 26.8 (t, NCH2CH2), 24.6, 24.4 [t,
C(O)CH2CH2]. Ϫ HRMS (FABϩ): calcd. for C24H33N2O5 (M ϩ
H) 429.2389, found 429.2284. Ϫ [α]D ϭ ϩ41.6 (c ϭ 1.3; MeOH).
67.10, H 8.21, N 3.26; found C 67.24, H 8.17, N 3.24. Ϫ [α]D
ϩ4.7 (c ϭ 1.2; CHCl3).
ϭ
(2S)-2-(tert-Butoxycarbonylamino)-3-(tert-butyldiphenylsilyl-
oxy)propyl Methanesulfonate (28): To a solution of alcohol 27
(4.69 g, 11.0 mmol) in CH2Cl2 (50 mL) were added Et3N (1.55 mL,
11.5 mmol) and mesyl chloride (0.90 mL, 11.5 mmol) at 0°C. After
being stirred at 0°C for 0.5 h, the reaction mixture was washed
(H2O, 2 ϫ), dried (MgSO4), and concentrated in vacuo. The crude
tert-Butyl {3-[(2S)-(2-Methoxymethylnaphthalen-1-yl)-5-thioxopyr-
rolidin-1-yl]propyl}carbamate (23): According to the procedure de-
scribed for 13, 8.82 g of 22 (20.6 mmol) was transformed into 7.63 g
(17.1 mmol, 83%, colourless foam) of 23. Ϫ IR (CHCl3): ν˜ ϭ 3450
cmϪ1, 1695, 1490. Ϫ 1H NMR (250 MHz, mixture of rotamers):
δ ϭ 8.07Ϫ7.34 (m, 12 H, Naph), 6.18 (t, 1 H, J ϭ 9.2 Hz, NCH),
5.99 (dd, 1 H, J ϭ 9.2, 5.7 Hz, NCH), 5.3 (m, 2 H, NHBoc), 5.32
(s, 2 H, OCHHO), 5.27 (AB d, 1 H, J ϭ 7.1 Hz, OCHHO), 5.20
(AB d, 1 H, J ϭ 7.1 Hz, OCHHO), 4.5Ϫ4.1 (m, 2 H, NCHH), 3.52
(s, 3 H, OCH3), 3.47 (s, 3 H, OCH3), 3.5Ϫ1.5 (m, 14 H), 1.39, 1.38
[2 ϫ s, 18 H, CO2C(CH3)3]. Ϫ 13C NMR (100 MHz, mixture of
rotamers): δ ϭ 201.5, 201.1 [s, NC(S)], 155.7, 155.6 [s, NHC(O)],
153.9, 153.6, 132.4, 131.4 130.1, 129.2, 118.6, 117.4 (s, Naph),
131.2, 130.8, 129.3, 128.9, 127.5, 127.4, 124.1, 123.8, 122.0, 120.8,
115.5, 115.2 (d, Naph), 95.3, 94.4 (t, OCH2O), 78.8 [s,
CO2C(CH3)3], 62.3, 61.3 (d, NCH), 56.4, 56.3 (q, OCH3), 45.0, 44.2
(t, NCH2), 42.8, 42.6 (t, CH2NHBoc), 28.2 [q, CO2C(CH3)3], 26.8
[t, C(S)CH2], 26.6, 26.1 (t, NCH2CH2), 25.9, 25.7 [t, C(S)CH2CH2].
Ϫ HRMS (FABϩ): calcd. for C24H33N2O5 (M ϩ H) 429.2389,
product (5.33 g, 10.5 mmol, 96%) was obtained as a yellow oil
1
˜ ϭ 3384
which was pure according to H NMR. Ϫ IR (film): ν
1
cmϪ1, 1713. Ϫ H NMR (400 MHz): δ ϭ 7.65Ϫ7.63 (m, 4 H, Ph),
7.46Ϫ7.36 (m, 6 H, Ph), 4.87Ϫ4.85 (br. d, 1 H, J ϭ 7.9 Hz,
NHBoc), 4.39Ϫ4.29 (m, 2 H, CH2OMs), 4.0 (br. m, 1 H, CHNH),
3.80Ϫ3.77 (ABX dd, 1 H, J ϭ 10.3, 4.0 Hz, CHHOSi), 3.71Ϫ3.67
(ABX dd, 1 H, J ϭ 10.3, 5.7 Hz, CHHOSi), 2.96 (s, 3 H, SO2CH3),
1.43 [s, 9 H, CO2C(CH3)3], 1.07 [s, 9 H, SiC(CH3)3]. Ϫ 13C NMR
(100 MHz): δ ϭ 155.0 [CO2C(CH3)3], 135.4 (d, Ph), 135.3 (s, Ph),
132.5 (s, Ph), 129.9 (d, Ph), 127.8 (d, Ph), 79.9 [s, CO2C(CH3)3],
67.7 (t, CH2OMs), 61.9 (t, CH2OSi), 50.6 (d, CHNH), 37.1 (q,
SO2CH3), 28.1 [q, CO2C(CH3)3], 26.7 [q, SiC(CH3)3], 19.1 [s,
SiC(CH3)3]. Ϫ [α]D ϭ Ϫ3.1 (c ϭ 1.2; CHCl3).
tert-Butyl [(R)-2-Cyano-1-(tert-butyldiphenylsilyloxy)ethyl]carba-
mate (29): To a solution of mesylate 28 (4.62 g, 9.10 mmol) in
CH3CN (30 mL) were added KCN (1.18 g, 18.2 mmol) and 18-
crown-6 (2.40 g, 9.10 mmol) at room temp. After being refluxed for
2 h, the reaction mixture was concentrated in vacuo. The product
(2.89 g, 6.59 mmol, 72%) was obtained as a yellow oil after column
found 429.2284. Ϫ [α]D ϭ ϩ70.1 (c ϭ 0.60; MeOH). Ϫ [α]365
ϩ106.7.
ϭ
chromatography (EtOAc/PE, 1:5). Ϫ IR (film): ν˜ ϭ 3500 cmϪ1
,
1
2250, 1716. Ϫ H NMR (400 MHz): δ ϭ 7.75Ϫ7.72 (m, 1 H, Ph),
7.67Ϫ7.64 (m, 3 H, Ph), 7.49Ϫ7.35 (m, 6 H, Ph), 4.87Ϫ4.85 (br. d,
1 H, J ϭ 7.9 Hz, NHBoc), 4.00 (br. m, 1 H, CHNH), 3.81Ϫ3.77
(ABX bdd, 1 H, J ϭ 10.5, 4.0 Hz, CHHOSi), 3.72Ϫ3.68 (ABX dd,
1 H, J ϭ 10.4, 5.4 Hz, CHHOSi), 2.73Ϫ2.71 (d, 2 H, J ϭ 5.4 Hz,
CH2CN), 1.45 [s, 9 H, CO2C(CH3)3], 1.10 [s, 9 H, SiC(CH3)3]. Ϫ
13C NMR (100 MHz): δ ϭ 154.8 [s, CO2C(CH3)3], 135.4 (d, Ph),
134.7 (s, Ph), 132.3 (s, Ph), 129.5 (d, Ph), 127.9 (d, Ph), 127.6 (d,
Ph), 117.1 (s, CN), 80.2 [s, CO2C(CH3)3], 63.9 (t, CH2OSi), 48.5
(d, CHNH), 28.2 [q, CO2C(CH3)3], 26.7 [q, SiC(CH3)3], 19.2, 18.9
1-[(6S)-2,3,4,6,7,8-Hexahydropyrrolo[1,2-a]pyrimidin-6-yl]naph-
thalen-2-ol (5): Accoding to the procedure described for the syn-
thesis of 4, 23 (1.30 g, 4.89 mmol, 60%) was obtained as colourless
crystals after recrystallization from a MeOH/iPrOH mixture, m.p.
220Ϫ220°C (decomposition). Ϫ IR (CHCl3): ν˜ ϭ 3100 cmϪ1, 1665.
Ϫ
1H NMR (400 MHz, CD3OD, mixture of rotamers): δ ϭ
8.01Ϫ7.04 (m, 12 H, Naph), 6.23 (t, 1 H, J ϭ 8.8 Hz, CϪNCH),
5.95 (dd, 1 H, J ϭ 9.2, 5.6 Hz, CϪNCH), 3.42Ϫ2.80 (m, 12 H),
2.61 (m, 2 H, CϪNCHCH2), 2.48 (m, 2 H, CϪNCHCH2), 1.95 (m,
2 H, CϪNCH2CH2), 1.86 (m, 2 H, CϪNCH2CH2). Ϫ 13C NMR
(100 MHz): δ ϭ 165.3 (s, CϭN), 152.8 (s, Naph), 132.8 (s, Naph),
131.6 (d, Naph), 129.3 (d, Naph), 129.1 (s, Naph), 127.8 (d, Naph),
123.7 (d, Naph), 120.3 (d, Naph), 118.2 (d, Naph), 113.1 (s, Naph),
62.4 (d, NCH), 40.6, 38.4, (d, CϭNCH2 and CϪNCH2), 30.8 (t,
NϭCCH2), 25.2 (t, NϭCCH2CH2), 18.4 (t, CϪNCH2CH2). Ϫ
[α]D ϭ ϩ24.8 (c ϭ 0.91; MeOH).
[t, CH2CN, s, SiC(CH3)3].
Ϫ HRMS (EIϩ): calcd. for
C25H34N2O3Si 438.2339, found 438.2335. Ϫ [α]D ϭ Ϫ7.4 (c ϭ
1.0; CHCl3).
(3R)-Amino-4-(tert-butyldiphenylsilyloxy)butyronitrile (30): Cyan-
ide 29 (2.89 g, 6.59 mmol) was dissolved in freshly distilled tri-
fluoroacetic acid (15 mL) at 0°C. After being stirred for 1 h at 0°C,
the reaction mixture was concentrated in vacuo. The residue was
dissolved in aqueous saturated NaHCO3. The water layer was ex-
tracted (CH2Cl2, 5 ϫ) and the combined organic layers were dried
(MgSO4) and concentrated in vacuo. The product (2.23 g,
6.59 mmol, 100%) was obtained as a yellow oil. Ϫ IR (film): ν˜ ϭ
3500 cmϪ1, 2240. Ϫ 1H NMR (400 MHz): δ ϭ 7.74Ϫ7.71 (m, 1 H,
Ph), 7.68Ϫ7.63 (m, 3 H, Ph), 7.59Ϫ7.32 (m, 6 H, Ph), 3.66Ϫ3.57
(m, 2 H, CH2OSi), 3.21Ϫ3.15 (quint, 1 H, J ϭ 5.4 Hz, CHNH2),
2.58Ϫ2.53 (ABX dd, 1 H, J ϭ 16.6, 5.4 Hz, CHHCN), 2.49Ϫ2.43
(ABX dd, 1 H, J ϭ 16.6, 6.9 Hz, CHHCN), 2.03 (br. s, 2 H, NH2),
1.08 [s, 9 H, SiC(CH3)3]. Ϫ 13C NMR (100 MHz): δ ϭ 135.4 (d,
Ph), 134.7 (s, Ph), 132.7 (s, Ph), 129.9 (d, Ph), 127.8 (d, Ph), 127.6
(d, Ph), 117.9 (s, CN), 66.9 (t, CH2OSi), 49.9 (d, CHNH2), 26.7 [q,
SiC(CH3)3], 19.1, 18.9 [t, CH2CN, s, SiC(CH3)3]. Ϫ HRMS
(FABϩ): calcd. for C20H26N2OSiNa (M ϩ Na) 361.1712, found
361.1682. Ϫ [α]D ϭ ϩ3.6 (c ϭ 0.73; CHCl3).
tert-Butyl [(1R)-2-(tert-Butyldiphenylsilyloxy)-1-(hydroxymethyl)-
ethyl]carbamate (27): LiBH4 (2.0 g, 93.8 mmol) was added, at 0°C,
to a solution of ester 26 (30.7 g, 67.0 mmol) in Et2O (300 mL).
After being stirred for 20 min at 0°C and 40 min at room temp, the
reaction mixture was carefully poured into 2% aqueous HCl. The
water layer was extracted (CH2Cl2, 2 ϫ). The combined organic
layers were dried (MgSO4) and concentrated in vacuo. The product
(19.7 g, 45.8 mmol, 68%) was obtained after flash chromatography
as a white solid. An analytical sample of colourless needles was
recrystallized from PE. M.p. 73Ϫ74°C. Ϫ IR (CHCl3): ν˜ ϭ 3444
1
cmϪ1, 1704. Ϫ H NMR (400 MHz): δ ϭ 7.67Ϫ7.64 (m, 4 H, Ph),
7.47Ϫ7.37 (m, 6 H, Ph), 5.09 (br. s, 1 H, NHBoc), 3.84Ϫ3.67 (m,
5 H, SiOCH2CHCH2), 2.41 (br. s, 1 H, ϪOH), 1.45 [s, 9 H,
CO2C(CH3)3], 1.08 [s, 6 H, SiC(CH3)3]. Ϫ 13C NMR (100 MHz):
not observed [CO2C(CH3)3], δ ϭ 135.4 (d, Ph), 132.8 (s, Ph), 132.7
(s, Ph), 129.8 (d, Ph), 127.8 (d, Ph), 79.5 [s, CO2C(CH3)3], 64.0
(t, CH2OSi), 53.0 (d, CHNHBoc), 28.7 [q, CO2C(CH3)3], 26.8 [q, (3R)-4-(tert-Butyldiphenylsilyloxy)-3-(1,3-dioxooctahydroisoindol-2-
SiC(CH3)3], 19.1 [s, SiC(CH3)3]. Ϫ C24H35NO4Si (429.6): cacld. C yl)butyronitrile (31): A mixture of amine 30 (2.23 g, 6.59 mmol) and
Eur. J. Org. Chem. 2000, 115Ϫ124
121

M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes, H. Hiemstra
powdered cis-1,2-cyclohexanedicarboxylic anhydride (1.0 g, SiC(CH3)3], 27.6, 23.4, 23.2, 22.7 [t, Ϫ(CH2)4Ϫ], 19.0, 17.6, [t,
FULL PAPER
6.59 mmol) was heated at 200°C for 10 min. The product was puri-
CH2CN, s, SiC(CH3)3].
Ϫ
HRMS (FABϩ): calcd. for
fied by column chromatography (EtOAc/PE, 1:4); a yellow oil
C28H37N2O2Si (M ϩ H) 461.2624, found 461.2638. Ϫ [α]D ϭ ϩ6.2
(951 mg, 2.0 mmol, 30%) was obtained. Ϫ IR (film): ν˜ ϭ 2260 (c ϭ 0.41; CHCl3).
1
cmϪ1, 1713. Ϫ H NMR (400 MHz): δ ϭ 7.66Ϫ7.59 (m, 4 H, Ph),
(3aS,7aR) Isomer 33b: IR (film): ν˜ ϭ 2260 cmϪ1, 1694. Ϫ 1H NMR
7.46Ϫ7.33 (m, 6 H, Ph), 4.60Ϫ4.54 (m, 1 H, CHN), 3.97Ϫ3.92 (dd,
1 H, J ϭ 10.2, 7.8 Hz, CHHOSi), 3.84Ϫ3.79 (dd, 1 H, J ϭ 10.1,
6.8 Hz, CHHOSi), 3.18Ϫ3.11 (dd, 1 H, J ϭ 16.9, 10.9 Hz,
CHHCN), 2.85Ϫ2.78 [m, 2 H, C(O)CHCH], 2.76Ϫ2.71 (dd, 1 H,
J ϭ 16.8, 5.2 Hz, CHHCN), 1.85Ϫ1.81 (m, 4 H), 1.44Ϫ1.42 (m, 4
H), 1.03 [s, 9 H, SiC(CH3)3]. Ϫ 13C NMR (100 MHz): δ ϭ 179.1
[s, C(O)], 135.4 (d, Ph), 135.3 (s, Ph), 132.4 (s, Ph), 132.3 (d, Ph),
130.0 (d, Ph), 129.9 (d, Ph), 127.8 (d, Ph), 127.7, (d, Ph), 116.6 (s,
CN), 61.9 (t, CH2OSi), 49.2 (d, CHN), 39.6, 39.5 [d, C(O)CHCH],
26.6 [q, SiC(CH3)3], 23.9, 23.7, 21.6 [t, Ϫ(CH2)4Ϫ], 18.9 and 17.0
(250 MHz): δ ϭ 7.65Ϫ7.62 (m, 4 H, Ph), 7.48Ϫ7.38 (m, 6 H, Ph),
4.33Ϫ4.30 (m, 1 H, CHN), 3.88Ϫ3.84 (ABX dd, 1 H, J ϭ 10.6,
6.0 Hz, CHHOSi), 3.81Ϫ3.77 (ABX dd, 1 H, J ϭ 10.6, 5.7 Hz,
CHHOSi), 3.50Ϫ3.46 (ABX dd, 1 H, J ϭ 9.1, 5.9 Hz, NCHH),
3.11Ϫ3.08 (ABX dd, 1 H, J ϭ 9.2, 2.6 Hz, NCHH), 2.84Ϫ2.78
(ABX dd, 1 H, J ϭ 16.9, 8.1 Hz, CHHCN), 2.69Ϫ2.64 (ABX dd,
1 H, J ϭ 16.9, 5.6 Hz, CHHCN), 2.48Ϫ2.45 [m, 1 H, C(O)CH],
2.35Ϫ2.32 [m, 1 H, C(O)CHCHH], 2.00Ϫ1.96 (m, 1 H, NCH2CH),
1.67Ϫ1.65 (m, 1 H), 1.56Ϫ1.45 (m, 3 H), 1.28Ϫ1.18 (m, 3 H), 1.07
[s, 9 H, SiC(CH3)3], 0.85 (m, 1 H). Ϫ 13C NMR (50 MHz): δ ϭ
176.4 [s, C(O)], 135.4 (d, Ph), 135.3 (s, Ph), 132.3 (s, Ph), 130.0 (d,
Ph), 127.8 (d, Ph), 117.4 (s, CN), 63.1 (t, CH2OSi), 50.3 (d, CHN),
49.5 (t, NCH2), 41.8 [d, C(O)CH], 32.6 [d, C(O)CHCH], 26.7 [q,
SiC(CH3)3], 27.6, 23.3, 23.2, 22.7 [t, Ϫ(CH2)4Ϫ], 19.0, 17.7, [t,
[t, CH2CN, s, SiC(CH3)3].
C28H34N2O3SiNa (M ϩ Na) 497.2236, found 497.2236. Ϫ [α]D
Ϫ2.0 (c ϭ 0.86; CHCl3).
Ϫ HRMS (FABϩ): calcd. for
ϭ
(3R)-4- (t er t- Bu tyldiphe nyls ilyloxy) -3-( 1- hydrox y-3-
oxooctahydroisoindol-2-yl)butyronitrile (32): NaBH4 (325 mg,
CH2CN, s, SiC(CH3)3].
Ϫ
HRMS (FABϩ): calcd. for
8.60 mmol) was added at Ϫ15°C to a solution of imide 31 (812 mg, C28H37N2O2Si (M ϩ H) 461.2624, found 461.2604. Ϫ [α]D ϭ ϩ1.5
1.72 mmol) in EtOH (10 mL). Three drops of a 0.5  solution of
H2SO4 in EtOH were added every 15 min. After being stirred for
1.5 h at Ϫ15°C, the reaction mixture was poured into aqueous
saturated NaHCO3. The water layer was extracted (CH2Cl2, 5 ϫ)
and the combined organic layers were dried (Na2SO4) and concen-
trated in vacuo. The products (773 mg, 1.64 mmol, 95%) were ob-
tained as a white foam. An analytical sample was purified by col-
umn chromatography (EtOAc/PE, 1:3). The products could not be
separated. Ϫ IR (CHCl3): ν˜ ϭ 3365 cmϪ1, 2270, 1668. Ϫ 1H NMR
(400 MHz, mixture of diastereomers): δ ϭ 7.68Ϫ7.31 (m, 28 H,
Ph), 5.28Ϫ5.26 (br. d, 1 H, J ϭ 3.7 Hz, CHOH), 5.18 (br. s, 1 H,
CHOH), 4.17Ϫ4.11, 4.01Ϫ3.97 and 3.93Ϫ3.80 (3 ϫ m, 7 H, CHN,
CH2OSi and ϪOH), 3.13Ϫ3.03 (m, 2 H, CHHCN), 2.68Ϫ2.56 (m,
2 H, CHHCN), 2.48Ϫ2.45 (m, 2 H), 2.41 (m, 3 H), 1.97Ϫ1.89 (m,
2 H), 1.74Ϫ1.57 (m, 7 H), 1.49Ϫ1.21 (m, 12), 1.08 [s, 18 H,
SiC(CH3)3]. Ϫ HRMS (FABϩ): calcd. for C28H36N2O3SiNa (M ϩ
Na) 499.2393, found 499.2372.
(c ϭ 1.1; CHCl3).
tert-Butyl
{(3R)-4-(tert-Butyldiphenylsilyloxy)-3-[(3aR,7aS)-1-
oxooctahydrohydroisoindol-2-yl]butyl}carbamate (34a): According
to the procedure described for 12, 1.96 g (4.26 mmol) of 33a was
transformed into 34a (1.12 g, 1.98 mmol, 46%). Ϫ IR (film): ν˜ ϭ
3400 cmϪ1, 1685. Ϫ 1H NMR (400 MHz): δ ϭ 7.70Ϫ7.62 (m, 4 H,
Ph), 7.48Ϫ7.37 (m, 6 H, Ph), 5.44 (br. s, 1 H, NHBoc), 4.27Ϫ4.20
(m, 1 H, NCH), 3.64Ϫ3.63 (d, 2 H, J ϭ 6.3 Hz, CH2OSi),
3.37Ϫ3.33 (ABX dd and m, 2 H, J ϭ 9.4, 5.8 Hz, NCHH,
CHHNHBoc), 2.82Ϫ2.74 (ABX d and m, 2 H, J ϭ 9.1 Hz, NCHH,
CHHNHBoc), 2.51Ϫ2.44 [m, 1 H, C(O)CH], 2.33Ϫ2.26 [m, 1 H,
C(O)CHCHH], 2.09Ϫ2.04 (m, 1 H, NCH2CH), 1.73Ϫ1.70 (m, 1
H), 1.58Ϫ1.47 (m, 4 H), 1.43 [s, 9 H, CO2C(CH3)3], 1.39Ϫ1.11 (m,
4 H), 1.02 [s, 9 H, SiC(CH3)3]. Ϫ 13C NMR (100 MHz): δ ϭ 176.7
[s, NC(O)], 155.9 [s, CO2C(CH3)3], 135.5 (d, Ph), 135.4 (d, Ph),
133.0 (s, Ph), 132.9 (s, Ph), 129.7 (d, Ph), 129.6 (d, Ph), 127.6 (d,
Ph), 78.7 [s, CO2C(CH3)3], 64.3 (t, CH2OSi), 50.2 (d, NCH), 47.4
(t, NCH2), 41.9 [d, C(O)CH], 36.8 (t, CH2NHBoc), 32.3 (d,
NCH2CH), 28.3 [q, CO2C(CH3)3], 28.0 (t, CH2CH2NHBoc), 26.7
[q, SiC(CH3)3], 28.5, 23.6, 23.4, 22.9 [t, Ϫ(CH2)4Ϫ], 19.0 [q,
(3R)-4-(tert-Butyldiphenylsilyloxy)-3-(1-oxooctahydroisoindol-2-
yl)butyronitrile (33): A mixture of trifluoroacetic acid (10 mL) and
triethylsilane (10 mL) in CH2Cl2 (10 mL) was added at Ϫ15°C to
a solution of hydroxylactams 32 (2.50 g, 5.25 mmol) in CH2Cl2 SiC(CH3)3]. Ϫ HRMS (FABϩ): calcd. for C33H49N2O4Si (M ϩ H)
(25 mL). After being stirred for 2 h at Ϫ15°C, the reaction mixture
was poured into aqueous saturated NaHCO3. The water layer was
extracted (CH2Cl2, 5 ϫ) and the combined organic layers were
dried (Na2SO4) and concentrated in vacuo. The products 33a
(1.0 g, 2.17 mmol, 41%) and 33b (1.2 g, 2.61 mmol, 50%) were ob-
tained separately, as colourless oils, after purification by column
chromatography (EtOAc/PE, 1:3).
565.3462, found 565.3434. Ϫ [α]D ϭ ϩ22.6 (c ϭ 0.87; CHCl3).
tert-Butyl {(3R)-4-(tert-Butyldiphenylsilyloxy)-3-[(3aS,7aR)-1-
oxooctahydrohydroisoindol-2-yl]butyl}carbamate (34b): According
to the procedure described for 12, 2.25 g (4.88 mmol) of 33b was
transformed into 34b (1.32 g, 2.41 mmol, 49%). Ϫ IR (film): ν˜ ϭ
3400 cmϪ1, 1711, 1677. Ϫ 1H NMR (400 MHz): δ ϭ 7.67Ϫ7.59
(m, 4 H, Ph), 7.48Ϫ7.37 (m, 6 H, Ph), 5.29 (br. s, 1 H, NHBoc),
4.29Ϫ4.26 (m, 1 H, NCH), 3.74Ϫ3.69 (ABX dd, 1 H, J ϭ 10.9,
(3aR,7aS) Isomer 33a: IR (film): ν˜ ϭ 2260 cmϪ1, 1699. Ϫ 1H NMR
(250 MHz): δ ϭ 7.64Ϫ7.61 (m, 4 H, Ph), 7.47Ϫ7.38 (m, 6 H, Ph), 7.5 Hz, CHHOSi), 3.65Ϫ3.62 (ABX dd, 1 H, J ϭ 10.9, 4.4 Hz,
4.40Ϫ4.35 (m, 1 H, CHN), 3.80Ϫ3.78 (dd, 2 H, J ϭ 5.9, 1.1 Hz, CHHOSi), 3.36Ϫ3.34 (m, 1 H, CHHNHBoc), 3.26Ϫ3.22 [ABX dd,
CH2OSi), 3.42Ϫ3.38 (ABX dd, 1 H, J ϭ 9.2, 5.8 Hz, NCHH), 1 H, J ϭ 9.3, 5.9 Hz, C(O)NCHH], 3.09Ϫ3.06 [ABX dd, 1 H, J ϭ
3.05Ϫ3.02 (ABX dd, 1 H, J ϭ 9.3, 2.2 Hz, NCHH), 2.80Ϫ2.74 9.4, 2.6 Hz, C(O)NCHH], 2.63Ϫ2.61 (m, 1 H, CHHNHBoc),
(ABX dd, 1 H, J ϭ 16.9, 8.1 Hz, CHHCN), 2.69Ϫ2.63 (ABX dd, 2.50Ϫ2.46 [m, 1 H, C(O)CH], 2.35Ϫ2.28 [m, 1 H, C(O)CHCHH],
1 H, J ϭ 16.9, 5.5 Hz, CHHCN), 2.46Ϫ2.42 [m, 1 H, C(O)CH], 2.03Ϫ1.99 [m, 1 H, C(O)NCH2CH], 1.80Ϫ1.45 (m, 5 H), 1.42 [s, 9
2.32Ϫ2.29 [m, 1 H, C(O)CHCHH], 2.06Ϫ2.02 (m, 1 H, NCH2CH), H, CO2C(CH3)3], 1.29Ϫ1.20 (m, 3 H), 1.04 [s, 9 H, SiC(CH3)3],
1.72Ϫ1.69 (m, 1 H), 1.58Ϫ1.47 (m, 3 H), 1.30Ϫ1.15 (m, 3 H), 1.06 0.89Ϫ0.83 (m, 1 H). Ϫ 13C NMR (100 MHz): δ ϭ 177.1 [s, NC(O)],
[s, 9 H, SiC(CH3)3], 0.91Ϫ0.82 (m, 1 H). Ϫ 13C NMR (50 MHz): not observed [CO2C(CH3)3], 135.6 (d, Ph), 135.5 (d, Ph), 133.0 (s,
δ ϭ 176.3 [s, C(O)], 135.4 (d, Ph), 132.3 (s, Ph), 130.0 (d, Ph), 127.8
Ph), 132.9 (s, Ph), 129.8 (d, Ph), 129.7 (d, Ph), 127.7 (d, Ph), 78.7
(d, Ph), 117.3 (s, CN), 63.1 (t, CH2OSi), 50.0 (d, CHN), 49.1 (t, [s, CO2C(CH3)3], 64.5 (t, CH2OSi), 50.2 (d, NCH), 47.2 (t, NCH2),
NCH2), 41.8 [d, C(O)CH], 32.6 [d, C(O)CHCH], 26.7 [q, 42.1 [d, C(O)CH], 36.8 (t, CH2NHBoc), 32.4 (d, NCH2CH), 28.4
122
Eur. J. Org. Chem. 2000, 115Ϫ124

(S)-Pyroglutamic Acid, (S)-Malic Acid, and (S)-Serine as Useful Starting Materials
FULL PAPER
[q, CO2C(CH3)3], 27.6 (t, CH2CH2NHBoc), 26.8 [q, SiC(CH3)3], dd, 1 H, J ϭ 10.7, 5.9 Hz, CHHOH), 3.39Ϫ3.38 (m, 1 H,
28.5, 23.5, 23.4, 22.8 [t, Ϫ(CH2)4Ϫ], 19.0 [s, SiC(CH3)3]. Ϫ HRMS CHHNHBoc), 3.23Ϫ3.20 [ABX dd, 1 H, J ϭ 10.8, 2.4 Hz,
(FABϩ): calcd. for C33H49N2O4Si (M ϩ H) 565.3462, found C(S)NCHH], 2.89Ϫ2.81 [m, 2 H, C(S)CH and CHHNHBoc],
565.3453. Ϫ [α]D ϭ ϩ27.0 (c ϭ 0.67; CHCl3).
2.50Ϫ2.42 [m, 1 H, C(S)CHCHH], 2.34Ϫ2.30 (m, 1 H, NCH2CH),
2.04 (br. s, 1 H, ϪOH), 1.87Ϫ1.63 (m, 4 H), 1.62Ϫ1.47 (m, 2 H),
1.43 [s, 9 H, CO2C(CH3)3], 1.30Ϫ1.21 (m, 2 H), 1.11Ϫ1.03 (m, 1
H). Ϫ 13C NMR (100 MHz): δ ϭ 206.4 [s, NC(S)], 156.0 [s,
CO2C(CH3)3], 79.1 [s, CO2C(CH3)3], 62.9 (t, CH2OH), 55.9 (d,
NCH), 53.6 [t, C(S)NCH2], 52.8 [d, C(S)CH], 36.7 (t, CH2NHBoc),
33.9 (d, NCH2CH), 28.4 (t, CH2CH2NHBoc), 28.3 [q,
CO2C(CH3)3], 27.4, 26.1, 23.4, 22.2 [t, Ϫ(CH2)4Ϫ]. Ϫ HRMS
(FABϩ): calcd. for C17H31N2O3SSi (M ϩ H) 343.2055, found
343.2032. Ϫ [α]D ϭ Ϫ24.3 (c ϭ 0.93; CHCl3).
tert-Butyl
{(3R)-4-(tert-Butyldiphenylsilyloxy)-3-[(3aR,7aS)-1-
thioxooctahydrohydroisoindol-2-yl]butyl}carbamate (35a): Accord-
ing to the procedure described for 13, 1.12 g (1.98 mmol) of 34a
was transformed into 35a (931 mg, 1.60 mmol, 81%). Ϫ IR (film):
1
ν˜ ϭ 3400 cmϪ1, 1700. Ϫ H NMR (400 MHz): δ ϭ 7.65Ϫ7.61 (m,
4 H, Ph), 7.47Ϫ7.37 (m, 6 H, Ph), 5.60 (br. s, 1 H, NHBoc),
5.25Ϫ5.18 (quint, 1 H, J ϭ 6.9 Hz, NCH), 3.73Ϫ3.68 (m, 2 H,
CH2OSi), 3.60Ϫ3.56 [ABX dd, 1 H, J ϭ 10.7, 5.9 Hz, C(S)NCHH],
3.37Ϫ3.36 (m, 1 H, CHHNHBoc), 3.17Ϫ3.14 [ABX dd, 1 H, J ϭ
10.8, 2.3 Hz, C(S)NCHH], 2.81Ϫ2.69 [m, 2 H, C(S)CH and
CHHNHBoc], 2.38Ϫ2.22 [m, 2 H, C(S)CHCHH and NCH2CH],
1.74Ϫ1.47 (m, 4 H), 1.43 [s, 9 H, CO2C(CH3)3], 1.38Ϫ1.11 (m, 4
H), 1.02 [s, 9 H, SiC(CH3)3], 0.89Ϫ0.82 (m, 1 H). Ϫ 13C NMR
(100 MHz): δ ϭ 206.0 [s, NC(S)], not observed [CO2C(CH3)3],
135.6 (d, Ph), 135.4 (s, Ph), 132.9 (s, Ph), 132.6 (d, Ph), 129.8 (d,
Ph), 129.7 (d, Ph), 127.7 (d, Ph), 78.9 [s, CO2C(CH3)3], 64.1 (t,
CH2OSi), 55.6 (d, NCH), 53.7 [t, C(S)NCH2], 52.7 [d, C(S)CH],
36.6 (t, CH2NHBoc), 34.1 (t, NCH2CH), 28.3 [q, CO2C(CH3)3],
28.1 (t, CH2CH2NHBoc), 26.7 [q, SiC(CH3)3], 27.5, 26.2, 23.5, 22.2
[t, -(CH2)4-], 19.0 [s, SiC(CH3)3]. Ϫ HRMS (FABϩ): calcd. for
C33H49N2O3SSi (M ϩ H) 581.3233, found 581.3219. Ϫ [α]D ϭ Ϫ4.0
(c ϭ 0.87; CHCl3). Ϫ [α]365 ϭ Ϫ538.
tert-Butyl {(3R)-4-Hydroxy-3-[(3aS,7aR)-1-thioxooctahydrohydro-
isoindol-2-yl]butyl}carbamate (36b): According to the procedure de-
scribed for 36a, 33.7 mg (0.058 mmol) of 35b was transformed into
36b (20 mg, 0.058 mmol, 100%, yellow solid), which was recrys-
tallized as pale yellow crystals from an EtOAc/PE mixture. M.p.
99Ϫ100°C. Ϫ IR (CHCl3): ν˜ ϭ 3400 cmϪ1, 1703. Ϫ 1H NMR
(400 MHz): δ ϭ 5.28Ϫ5.21 (m, 2 H, NHBoc and NCH), 3.84Ϫ3.80
(ABX dd, 1 H, J ϭ 11.6, 4.4 Hz, CHHOH), 3.75Ϫ3.71 (m, 1 H,
CHHOH), 3.54Ϫ3.50 [ABX dd,
1 H, J ϭ 10.7, 6.2 Hz,
C(S)NCHH], 3.38Ϫ3.34 [ABX dd, 1 H, J ϭ 10.8, 3.7 Hz,
C(S)NCHH], 3.33Ϫ3.30 (m, 1 H, CHHNHBoc), 2.83Ϫ2.79 [m, 2
H, C(S)CH and CHHNHBoc], 2.47Ϫ2.41 [m, 1 H, C(S)CHCHH],
2.23Ϫ2.18 (m, 1 H, NCH2CH), 1.97 (br. s, 1 H, ϪOH), 1.79Ϫ1.70
(m, 3 H), 1.65Ϫ1.58 (m, 1 H), 1.53Ϫ1.49 (m, 1 H), 1.42 [s, 9 H,
CO2C(CH3)3], 1.38Ϫ1.33 (m, 4 H). Ϫ 13C NMR (100 MHz): δ ϭ
206.8 [s, NC(S)], 155.9 [s, CO2C(CH3)3], 79.2 [s, CO2C(CH3)3], 63.0
(t, CH2OH), 55.7 (d, NCH), 53.1 [d, C(S)CH], 53.0 [t, C(S)NCH2],
36.9 (t, CH2NHBoc), 34.1 (d, NCH2CH), not observed
(CH2CH2NHBoc), 28.3 [q, CO2C(CH3)3], 26.5, 26.1, 23.1, 22.3 [t, -
(CH2)4-]. Ϫ C17H30N2O3S (342.4): calcd. C 59.62, H 8.83, N 8.18;
found C 59.60, H 8.69, N 8.14. Ϫ [α]D ϭ ϩ45.9 (c ϭ 0.93; CHCl3).
tert-Butyl
{(3R)-4-(tert-Butyldiphenylsilyloxy)-3-[(3aS,7aR)-1-
thioxooctahydrohydroisoindol-2-yl]butyl}carbamate (35b): Accord-
ing to the procedure described for 13, 1.32 g (2.41 mmol) of 34b
was transformed into 35b (876 mg, 1.51 mmol, 63%). Ϫ IR (film):
ν˜ ϭ 3400 cmϪ1, 1712, 1699. Ϫ 1H NMR (400 MHz): δ ϭ 7.69Ϫ7.60
(m, 4 H, Ph), 7.46Ϫ7.38 (m, 6 H, Ph), 5.33 (br. s, 1 H, NHBoc),
5.25Ϫ5.21 (m, 1 H, NCH), 3.81Ϫ3.76 (ABX dd, 1 H, J ϭ 11.1,
7.4 Hz, CHHOSi), 3.74Ϫ3.70 (ABX dd, 1 H, J ϭ 11.1, 4.0 Hz,
CHHOSi), 3.53Ϫ3.45 [m, 2 H, C(S)NCH2], 3.29 (m, 1 H,
CHHNHBoc), 2.81Ϫ2.77 [m, 1 H, C(S)CH], 2.70Ϫ2.69 (m, 1 H,
CHHNHBoc), 2.44Ϫ2.43 [m, 1 H, C(S)CHCHH], 2.23Ϫ2.21 (m,
1 H, NCH2CH), 1.78Ϫ1.69 (m, 2 H), 1.65Ϫ1.51 (m, 2 H), 1.42 [s,
9 H, CO2C(CH3)3], 1.37Ϫ1.20 (m, 4 H), 1.04 [s, 9 H, SiC(CH3)3],
0.90Ϫ0.83 (m, 1 H). Ϫ 13C NMR (100 MHz): δ ϭ 206.2 [s, NC(S)],
155.8 [s, CO2C(CH3)3], 135.6 (d, Ph), 135.4 (d, Ph), 132.8 (s, Ph),
132.6 (s, Ph), 129.8 (d, Ph), 129.7 (d, Ph), 127.7 (d, Ph), 78.9 [s,
CO2C(CH3)3], 64.3 (t, CH2OSi), 55.4 (d, NCH), 53.3 [t,
C(S)NCH2], 53.0 [d, C(S)CH], 36.7 (t, CH2NHBoc), 34.0 (d,
NCH2CH), 28.3 [q, CO2C(CH3)3], 28.2 (t, CH2CH2NHBoc), 26.7
[q, SiC(CH3)3], 26.6, 26.1, 23.2, 22.2 [t, -(CH2)4-], 19.0 [s,
SiC(CH3)3]. Ϫ HRMS (FABϩ): calcd. for C33H49N2O3SSi (M ϩ
H) 581.3233, found 581.3223. Ϫ [α]D ϭ ϩ33.2 (c ϭ 0.98; CHCl3).
(1R,4bS,8aR)-(1,2,3,4b,5,6,7,8,8a,9-Decahydro-4,9a-diazafluoren-1-
yl)methanol (6): Accoding to the procedure for 4, 6 (49.7 mg,
0.24 mmol, 46%) was obtained as white crystals after recrystalliza-
tion from benzene, m.p. 166Ϫ170°C. Ϫ IR (CHCl3): ν˜ ϭ 3300
1
cmϪ1, 1647. Ϫ H NMR (400 MHz, C6D6): δ ϭ 3.63Ϫ3.57 (dt, 1
H, J ϭ 14.1, 4.2 Hz, CϭNCHH), 3.42Ϫ3.35 (m, 2 H, CϭNCHH,
CHHOH), 3.28Ϫ3.26 (m, 1 H, CHHOH), 3.05Ϫ2.96 (m, 1 H,
CϪNCH), 2.88Ϫ2.86 (AB d, 1 H, J ϭ 8.6 Hz, CϪNCHH),
2.75Ϫ2.71 (ABX dd, 1 H, J ϭ 8.6, 5.7 Hz, CϪNCHH), 2.50Ϫ2.44
(m, 2 H), 1.82Ϫ1.77 (m, 1 H), 1.66Ϫ1.63 (m, 1 H), 1.58Ϫ1.50 (m,
1 H), 1.44Ϫ1.38 (m, 5 H), 1.18Ϫ1.06 (m, 1 H). Ϫ 13C NMR
(100 MHz, C6D6): not observed (CϭN), δ ϭ 64.1 (t, CH2OH), 53.7
(d, CϪNCH), 53.7, 41.5 (t, CϭNCH2, CϪNCH2), 41.7 (d, Nϭ
CCH), 33.7 (d, CϪNCH2CH), 27.7, 24.5, 24.0, 22.5, 22.4 [t,
Ϫ(CH2)4Ϫ, CϭNCH2CH2]. Ϫ C12H20N2O (208.3): cacld. C 69.19,
H 9.68, N 13.45; found C 69.34, H 9.54, N 13.47. Ϫ [α]D ϭ Ϫ12.7
(c ϭ 0.15; CHCl3).
tert-Butyl {(3R)-4-Hydroxy-3-[(3aR,7aS)-1-thioxooctahydrohydro-
isoindol-2-yl]butyl}carbamate (36a): TBAF (1.4 mL, 1.4 mmol, 1.0
 solution in THF) was added at room temp to a solution of 35a
(751 mg, 1.29 mmol) in THF (10 mL). After 20 min, another por-
tion of TBAF (1.5 mL, 1.5 mmol, 1.0  solution in THF) was ad-
ded. After being stirred for 25 min at 40°C (rotavapor bath), the
reaction mixture was quenched with H2O. After extraction of the
water layer (CH2Cl2, 5 ϫ), the combined organic layers were dried
(Na2SO4) and concentrated in vacuo. After flash chromatography
Crystallographic Data for 6: Orthorhombic, P212121, a ϭ 8.469 (1)
3
˚
˚
b ϭ 10.399 (5), c ϭ 12.454 (1) A, V ϭ 1096.8 (5) A , S ϭ 1.03,
λ ϭ 0.71073 A, µ ϭ 0.8 cmϪ1, F(000) ϭ 456. Final R ϭ 0.048. The
˚
hydrogen bond is between O and N5 of different molecules.[22]
(EtOAc/PE, 4:1), 36a was obtained as a yellow oil (448 mg, (1R,4bR,8aS)-(1,2,3,4b,5,6,7,8,8a,9-Decahydro-4,9a-diazafluoren-1-
1.29 mmol, 100%). Ϫ IR (CHCl3): ν˜ ϭ 3370 cmϪ1, 1703. Ϫ 1H
yl)methanol (7): According to the procedure for 4, 7 (70.5 mg,
NMR (400 MHz): δ ϭ 5.46 (br. s, 1 H, NHBoc), 5.24Ϫ5.17 (m, 1 0.34 mmol, 69%) was obtained as white crystals after recrystalliza-
H, NCH), 3.82Ϫ3.78 (ABX dd, 1 H, J ϭ 11.8, 4.4 Hz, CHHOH), tion from benzene, m.p. 142Ϫ142.5°C. Ϫ IR (CHCl3): ν˜ ϭ 3300
1
3.73Ϫ3.71 [AB d, 1 H, J ϭ 9.0 Hz, C(S)NCHH], 3.68Ϫ3.64 (ABX
Eur. J. Org. Chem. 2000, 115Ϫ124
cmϪ1, 1653. Ϫ H NMR (400 MHz, C6D6): δ ϭ 3.76Ϫ3.72 (ABX
123

M. Ostendorf, J. Dijkink, F. P. J. T. Rutjes, H. Hiemstra
FULL PAPER
[1]
[2]
The Chemistry of Amidines and Imidates (Eds.: S. Patai, Z. Rap-
poport), Wiley, New York, 1991, vol. 1 and 2.
dd, 1 H, J ϭ 10.7, 5.5 Hz, CHHOH), 3.65Ϫ3.60 (ABX dd, 1 H,
J ϭ 10.7, 6.8 Hz, CHHOH), 3.57Ϫ3.51 (ABX dt, 1 H, J ϭ 10.6,
4.0 Hz, CϭNCHH), 3.47Ϫ3.40 (m, 2 H, CϭNCHH, CϪNCHH),
3.31Ϫ3.29 (m, 1 H, CϪNCH), 2.61Ϫ2.57 (ABX dd, 1 H, J ϭ 9.4,
4.4 Hz, CϪNCHH), 2.55Ϫ2.50 (q, 1 H, J ϭ 5.9 Hz, NϭCCH),
2.11Ϫ2.07 (m, 1 H, NϭCCHCHH), 2.01Ϫ1.91 (m, 2 H, Cϭ
NCH2CHH, CϪNCH2CH), 1.72Ϫ1.65 (m, 1 H, CϭNCHCHH),
1.55 (m, 2 H), 1.35 (m, 3 H), 1.15 (m, 2 H). Ϫ 13C NMR (100 MHz,
C6D6): δ ϭ 162.0 (s, CϭN), 63.2 (t, CH2OH), 54.9 (d, CϪNCH),
53.9, 40.9 (t, CϭNCH2, CϪNCH2), 41.6 (d, NϭCCH), 33.9 (t,
CϪNCH2CH), 26.8, 24.5, 23.4, 22.8, 22.0 [t, Ϫ(CH2)4Ϫ, Cϭ
NCH2CH2]. Ϫ C12H20N2O (208.3): calcd. C 69.19, H 9.68, N
13.45; found C 69.19, H 9.54, N 13.42. Ϫ [α]D ϭ Ϫ41.1 (c ϭ
0.19; CHCl3).
[2a] M. A. Convery, A. P. Davis, C. J. Dunne, J. W. MacKinnon,
[2b]
J. Chem. Soc., Chem. Commun. 1994, 2557Ϫ2558. Ϫ
M. A.
Convery, A. P. Davis, C. J. Dunne, J. W. MacKinnon, Tetra-
hedron Lett. 1995, 36, 4279Ϫ4282.
[3] [3a]
G. Papandreou, M. K. Tong, B. Ganem, J. Am. Chem. Soc.
[3b]
´
Y. Bleriot, A. Genre-Grandpi-
1993, 115, 11682Ϫ11690. Ϫ
erre, C. Tellier, Tetrahedron Lett. 1994, 35, 1867Ϫ1870.
J. Dijkink, K. Goubitz, M. N. A. Van Zanden, H. Hiemstra,
Tetrahedron: Asymmetry 1996, 7, 515Ϫ524.
[4]
[5]
M. Ostendorf, S. van der Neut, F. P. J. T. Rutjes, H. Hiemstra,
Eur. J. Org. Chem. 2000, 105Ϫ113, preceding paper.
[6] [6a]
W. J. Klaver, H. Hiemstra, W. N. Speckamp, J. Am. Chem.
[6b]
Soc. 1989, 111, 2588Ϫ2595. Ϫ
S. Louwrier, M. Ostendorf,
A. Boom, H. Hiemstra, W. N. Speckamp, Tetrahedron 1996,
52, 2603Ϫ2628.
[7]
[8]
G. M. Coppola, H. F. Schuster, Asymmetric Synthesis: Con-
struction of Chiral Molecules Using Amino Acids, Wiley, New
York, 1987, chapter 4.
Thiophenol Addition (37): A mixture of thiophenol (51.0 mL,
0.29 mmol) and amidine 4 (4.6 mg, 0.015 mmol) was dissolved in
toluene (1 mL). Cyclohexenone (43.7 mL, 0.29 mmol) was added
and, after being stirred for 20 min at room temp, the reaction mix-
ture was diluted with toluene and washed (5% aqueous HCl, 2 ϫ).
The organic layer was dried (MgSO4) and concentrated in vacuo,
yielding the product (41 mg, 0.32 mmol, 44%) as a colourless oil.
The spectral data are as reported previously.[21] Ϫ [α]578 ϭ Ϫ14.1
(c ϭ 0.70; CCl4). Ϫ O.p. 14%.[21]
S. Saijo, M. Wada, J. Himizu, A. Ishida, Chem. Pharm. Bull.
1980, 28, 1449Ϫ1452.
[9]
S. Kanao, S. Inagawa, J. Pharm. Soc. Jpn. 1928, 48, 238Ϫ245.
F. G. Fang, M. Prato, G. Kim, S. J. Danishefsky, Tetrahedron
Lett. 1989, 30, 3625Ϫ3628.
[10]
[11] [11a] A. G. M. Barrett in Comprehensive Organic Synthesis (Eds.:
B. M. Trost, I. Fleming), Pergamon Press, Oxford, 1991, vol. 8,
[11b]
´
A. Echavarren, A. Galan, J. de Mendoza,
pp. 251Ϫ252. Ϫ
´
A. Salmeron, J.-M. Lehn, Helv. Chim. Acta 1988, 71, 685Ϫ693.
[11c]
Ϫ
J. O. Osby, S. W. Heinzman, B. Ganem, J. Am. Chem.
Conjugate Addition Product 39:
A mixture of 38 (272 mg,
Soc. 1986, 108, 67Ϫ72.
[12]
B. Yde, N. M. Yousif, U. Pedersen, I. Thomsen, S.-O. Lawesson,
Tetrahedron 1984, 40, 2047Ϫ2052.
1.43 mmol) and amidine 5 (11.4 mg, 0.043 mmol) was dissolved in
toluene (2 mL). Methyl vinyl ketone (130 µL, 1.57 mmol) was ad-
ded and, after being stirred for 24 h at room temp, the reaction
mixture was diluted with toluene and washed (5% aqueous HCl, 2
ϫ). The organic layer was dried (MgSO4) and concentrated in va-
cuo, yielding the product (323 mg, 1.24 mmol, 87%) as a colourless
[13] [13a]
H. E. Zaug, D. L. Arendsen, R. S. Egan, J. Heterocycl.
Chem. 1979, 16, 21Ϫ30. Ϫ [13b] J. J. J. de Boer, Reactions with ω-
Carbinollactams, Ph.D. Thesis, University of Amsterdam, 1979.
T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Syn-
thesis, Wiley, New York, 1991.
[14]
[15] [15a] D. H. R. Barton, W. B. Motherwell, Pure Appl. Chem. 1981,
1
oil. H NMR (400 MHz): δ ϭ 7.37Ϫ7.25 (m, 4 H, Ph), 3.80 [AB
[15b]
53, 15Ϫ31.
Ϫ
W. Hartwig, Tetrahedron 1983, 39,
2609Ϫ2645. Ϫ [15c] M. J. Robins, J. S. Wilson, F. Hanske, J. Am.
Chem. Soc. 1983, 105, 4059Ϫ4065.
d, 1 H, J ϭ 22.7 Hz, C(O)CHH], 3.63 (s, 3 H, OCH3), 3.58Ϫ3.52
[AB d, 1 H, J ϭ 22.8 Hz, C(O)CHH], 2.53Ϫ2.19 (m, 4 H), 2.03 [s,
3 H, C(O)CH3]. 13C NMR (100 MHz): δ ϭ 207.1, 199.1 [2 ϫ C(O)],
170.3 (CO2Me), 140.2, 136.9, 128.7, 128.0, 125.0, 124.0 (Ph), 63.7
(CCO2Me), 52.7 (OCH3), 43.2 [C(O)CH2], 38.2 [C(O)CH2CH2]
29.7 [C(O)CH3], 27.9 [C(O)CH2CH2]. Ϫ [α]D ϭ Ϫ7.1 (c ϭ 1;
CHCl3). ee: 27% [determined by chiral HPLC (Chiralpak AS)].
[16]
[17]
[18]
[19]
[20]
[21]
[22]
J. A. Dale, D. L. Dull, H. S. Mosher, J. Org. Chem. 1969, 34,
2543Ϫ2549.
K. C. Nicolaou, M. E. Bunnage, K. Koide, J. Am. Chem. Soc.
1994, 116, 8402Ϫ8403.
F. L. Cook, C. W. Bowers, C. L. Liotta, J. Org. Chem. 1974,
39, 3416Ϫ3418.
J. B. P. A. Wijnberg, H. E. Schoemaker, W. N. Speckamp, Tetra-
hedron 1978, 34, 179Ϫ187.
J. C. Hubert, J. B. P. A Wijnberg, W. N. Speckamp, Tetrahedron
1975, 31, 1437Ϫ1441.
Acknowledgments
H. Hiemstra, H. Wynberg, J. Am. Chem. Soc. 1981, 103,
417Ϫ430.
This research was financially supported by the Council for Chemi-
cal Sciences of the Netherlands Organization for Scientific Re-
search (CWϪNWO). We kindly thank H. Kooijman (Department
of Crystal and Structural Chemistry of the Bijvoet Center for Bi-
omolecular Research) for the X-ray structure determination.
Experimental details and full structural data for the structure
determination of 6 are submitted as a CIF-access paper to Acta
Crystallogr., Sect. C (Kooy¨man, Spek, 1999).
Received February 23, 1999
[O99107]
124
Eur. J. Org. Chem. 2000, 115Ϫ124