Regioselective electrophilic substitution of 2,3-aziridino-γ-lactones: preliminary studies aimed at the synthesis of α,α-disubstituted α- or β-amino acids

Article abstract of DOI:10.1016/j.tet.2007.10.082

2,3-Aziridino-γ-lactones are versatile synthons for the preparation of polysubstituted α- or β-amino acids. With the intention of preparing α,α-disubstituted α- or β-amino acids, regioselective electrophilic substitution of aziridino-γ-lactones at C2 was

Full text of DOI:10.1016/j.tet.2007.10.082

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Tetrahedron 64 (2008) 419e432
www.elsevier.com/locate/tet
Regioselective electrophilic substitution of 2,3-aziridino-g-lactones:
preliminary studies aimed at the synthesis of a,a-disubstituted
a- or b-amino acids
*
Marcelo Siqueira Valle, Aurelie Tarrade-Matha, Philippe Dauban , Robert H. Dodd
*
´
Institut de Chimie des Substances Naturelles, CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
Received 5 September 2007; received in revised form 17 October 2007; accepted 19 October 2007
Available online 25 October 2007
Abstract
2,3-Aziridino-g-lactones are versatile synthons for the preparation of polysubstituted a- or b-amino acids. With the intention of preparing
a,a-disubstituted a- or b-amino acids, regioselective electrophilic substitution of aziridino-g-lactones at C2 was realized using two different
methods. In the first, the anion was generated at C2 with LDA in the presence of the electrophilic agent. In the second method, the anion
was trapped with TMS. Subsequent treatment of the C2 silylated product with a fluoride ion source regenerated the anion, which then reacted
in situ with various electrophiles. Intramolecular aziridine opening of the C2 benzyl derivative prepared by the first method allowed access to
a novel furan derivative, a direct precursor of an a,a-disubstituted b-amino acid.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of the ester functionality into an oxazoline (2a) or thiazoline
(2b) also allowed Florio and co-workers5 to generate the C2
lithiated species using n-butyllithium at ꢀ78 ꢁC, which could
be reacted with a variety of electrophiles. Using a tert-butyl es-
ter to minimize self-condensation and a 2-methoxy-1-phenyl-
ethyl group on the aziridine nitrogen to stabilize the anion (3),
Husson and co-workers6 were able to prepare the C2 lithiated
derivative with LDA in THF at ꢀ78 ꢁC. They obtained C2
substituted aziridines in reasonable yields and with generally
excellent retention of configuration in contrast to results
with the thiol esters. More recently, Wulff and co-workers7 de-
scribed the successful lithiation/electrophilic substitution at
C2 of C3-substituted N-benzhydryl protected aziridine
Chiral non-racemic aziridine carboxylic esters are easily
prepared compounds which, by virtue of their propensity to
nucleophilic attack at C3 by all types of nucleophiles, allow
a convenient access to a wide variety of a-amino acids.1 In or-
der to allow preparation of more complex a-amino acids, and
particularly their a-substituted versions,2 several groups have
studied the possibility of generating stabilized anion species
from such aziridine esters or their equivalents and reacting
these with electrophiles.3 The first reported attempts in this di-
rection were those of Seebach and co-workers.4 While treat-
ment of aziridine esters with LDA in THF at ꢀ78 ꢁC led
only to degradation or self-condensation, replacement of the
carboxylate function by a thiol ester (1) allowed formation
of the C2 anion under the same conditions and subsequent in-
corporation of substituents at this position (Fig. 1). Conversion
Ph
Ph
R
Ph
Ph
N
Ph
Me
OMe
N
N
N
N
CO2t-Bu
CO2Et
COSPh
X
* Corresponding authors. Tel.: þ33 (0)1 69 82 45 94; fax: þ33 (0)1 69 07
72 47.
1
2a X = O
2b X = S
3
4
E-mail addresses: philippe.dauban@icsn.cnrs-gif.fr (P. Dauban), robert.
dodd@icsn.cnrs-gif.fr (R.H. Dodd).
Figure 1.
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.082

420
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
2-carboxylates (4) also using LDA. Interestingly, the self-
condensation product was observed only when no substituent
was present at C3 (R¼H). Both retention and inversion of con-
figuration at C2 were observed depending on the electrophile.
In our laboratory, 2,3-aziridino-g-lactones (5) have been
used as synthetic tools for the preparation of polysubstituted
a- or b-amino acids as demonstrated by the synthesis of (e)-
polyoxamic acid (6),8 (2S,3S,4S )-3,4-dihydroxyglutamic acid
(7),9 and APTO (8), the b-amino acid fragment of microsclero-
dermins C and D (Fig. 2).10 In contrast to aziridine carboxylic
esters, this possibility of preparing either type of amino acid is
due to a particular feature of 2,3-aziridino-g-lactones whereby
they are attacked regioselectively at C2 or C3 by soft or hard
nucleophiles, respectively.11
g-lactones as a first step toward the synthesis of a,a-disubsti-
tuted amino acids. Preliminary results concerning intra- and
intermolecular nucleophilic ring opening of these substrates
are also presented.
2. Results and discussion
2.1. Preparation of 2,3-aziridino-g-lactones
We have previously shown that 2,3-aziridino-g-lactones of
type 5 can be conveniently prepared in three steps starting
from D-ribonolactone.8,12 For the purposes of this study, the
primary hydroxyl group of the latter was first selectively pro-
tected with a trityl13 or a TBDPS14 group (Scheme 1, 12a and
12b, respectively). These were treated with triflic anhydride/
pyridine at ꢀ78 ꢁC to generate the corresponding enol triflates
13a (81%) and 13b (78%). The aziridines 14a and 14b were
then formed in good yields (64%) by way of a Michael-type
1,4-addition of 3,4-dimethoxybenzylamine (DMBNH2) in
DMF with concomitant cyclization. As previously demon-
strated,8 the DMB group can be easily replaced by an elec-
tron-withdrawing substituent in order to activate aziridine
ring opening (vide infra).
O
O
RO
N
R1
2,3-Aziridino-γ-lactones (5)
OH
OH
CO2H
OH NH2
(-)-Polyoxamic acid (6)
HO
HO2C
CO2H
HO
OH NH2
(2S,3S,4S)-3,4-Dihydroxyglutamic
acid (7)
TrCl, py,
60-65 °C,
O
NH2
Ph
CO2H
overnight
O
O
O
O
O
O
Tf2O, py,
or
OH
HO
APTO (8)
RO
HO
RO
TBDPSCl,
DMF,
imidazole,
0 °C rt, 1h
CH2Cl2,
HO
OH
-78 °C -25 °C
HO
OH
OTf
D-Ribonolactone
Figure 2.
12a, R = Tr, 91%
12b, R = TBDPS, 70%
13a, R = Tr, 81%
13b, R = TBDPS, 78%
By analogy with the formation of lithiated aziridine carbox-
ylic esters and their derivatives, we decided to investigate the
possibility of preparing C2 lithiated aziridino-g-lactones and
their subsequent reaction with electrophiles. The resulting
new a-substituted aziridine-g-lactones formed (9) can be en-
visaged as synthons for the preparation of a,a-disubstituted
a- or b-amino acids such as 10 and 11, respectively (Fig. 3).
In comparison with aziridine tert-butyl esters 3 or the C2
oxa- and thiazolines 2, the lactone function of our synthons
was anticipated to be particularly sensitive to strong lithiating
bases. On the other hand, the rigid nature of these substrates
was expected to guarantee the configurational stability of the
anion generated.
DMBNH2, DMF,
-60 °C, 30'
DMB =
O
O
O
O
RO
RO
OCH3
OCH3
DMBHN
OTf
N
DMB
14a, R = Tr, 64% (47% overall yield)
14b, R = TBDPS, 64% (35% overall yield)
Scheme 1.
2.2. Electrophilic substitution of 2,3-aziridino-g-lactones
We first investigated formation of aziridine-g-lactone an-
ions using Husson’s6 reaction conditions for the lithiation of
tert-butyl aziridine-2-carboxylates (3). Thus, treatment of
14b with 2 equiv of freshly prepared LDA in THF at
ꢀ78 ꢁC for 1 h followed by addition of methyl iodide and
DMPU led exclusively to formation of the self-condensation
product 15 (25%) accompanied by degradation products
(Scheme 2). Use of a 5:1 mixture of DME and Et2O as sol-
vent6 led, in the absence of DMPU, essentially to the same re-
sult. Hodgson and co-workers15 have shown that aziridine
anions can be effectively generated using very short exposure
to LTMP as base followed by addition of the electrophile. In
our hands, treatment of 14b with 3 equiv of LTMP in THF
for 90 s at ꢀ78 ꢁC followed by addition of methyl iodide led
once more to formation of dimer 15 in 35% yield as the only
We present herein two complementary methodologies for
the regioselective electrophilic substitution of 2,3-aziridino-
Nu
CO2H
HO
E
NH2
OH
Lithiation/
Electrophile
trapping
α,α-Disubstituted
O
2
O
Nucleophilic
O
O
α-amino acid (10)
or
RO
RO
opening
E
N
NH2
N
R1
5
R1
9
CO2H
HO
E
Nu
OH
α,α-Disubstituted
β-amino acid (11)
Figure 3.

M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
421
Table 1
Electrophilic substitution of 14a and 14b by electrophiles mediated by LDA
isolable product. These results indicate that the C2 anion is in-
deed formed under these reaction conditions but reacts rapidly
with the lactone function before it can be trapped by the
electrophile.
O
O
O
O
RO
RO
LDA (2.0 eq),
+ E
R1
N
N
THF, -78 °C→rt, 2h
DMB
N
DMB
DMB
O
1) Base (2-3 eq),
(additive),
O
O
O
TBDPSO
TBDPSO
14a: R = Tr
14b: R = TBDPS
17a-29a: R = Tr
17b, 18b, 24b, 26b, 28b: R = TBDPS
solvent
OTBDPS
N
DMB
N
DMB
2) MeI (5 eq)
O
HO
Entry
E
Product (R1)
Yielda (%)
14b
15
R¼Tr
17a:0
R¼TBDPS
17b:10
18b:25
Scheme 2.
1
2
MeI
BnBr
Me
Bn
18a:25
A similar observation was made by Kobayashi and co-
workers16 during the course of their study of the anion derived
from an a,b-epoxy-g-butyrolactone. A solution to this problem
was found by generating the anion in the presence of an excess of
the electrophilic agent, in their case, TMSCl, thereby trapping
the anion before it can react to form the dimer. We were thus
pleased to observe that addition of a solution of aziridine 14a
and of excess TMSCl in THF to a solution of LDA in THF at
ꢀ78 ꢁC led, after 0.5 h at room temperature, to formation of
the desired C2-trimethylsilyl aziridine-g-lactone derivative
16a, obtained in 89% yield after flash chromatography. Under
the same reaction conditions, the 5-O-TBDPS aziridine-g-lac-
tone 14b furnished the analogous TMS derivative 16b in 85%
yield (Scheme 3).
Ph
3
4
5
PhCHO
19a:51b
20a:66
21a:30b
OTBS
tert-BuCHO
i-PrCHO
n-PrCHO
OH
OTBS
6
7
8
22a:15b
23a:28
24a:44
OTBS
OH
Ph
CHO
Ph
OH
Cyclopentanone
Cyclohexanone
24b:33
O
O
O
O
RO
RO
LDA (2 eq),
TMSCl
(3 eq)
+
OH
TMS
THF, -78 °Cꢀrt, 0.5h
N
N
9
25a:56
26a:45
DMB
14a, R = Tr
14b, R = TBDPS
DMB
16a, R = Tr, 89%
16b, R = TBDPS, 85%
OH
Scheme 3.
10
Et2C]O
26b:40
28b:48
Using this methodology (Table 1), a variety of electrophiles
could now be introduced at C2 of aziridines 14a in generally rea-
sonable to good yields and starting material was recovered in
almost all cases. Thus, while use of methyl iodide still gave no
C2-alkylated product starting from 14a, the use of another alkyl
halide, benzyl bromide, gave a low but reproducible yield of the
expected C2 benzyl derivative 18a (25%, entry 2). In contrast,
benzaldehyde gave a satisfactory yield of the addition product
from 14a, isolated as the more stable tert-butyldimethylsilyl de-
rivative 19a by treatment of the crude product with TBSOTf/
Et3N (51%, entry 3). Use of pivaldehyde as electrophile also
gave a good yield of addition product 20a (66%, entry 4) while
enolizable aldehydes such as isobutyraldehyde and butyralde-
hyde were less satisfactory (21a, 30%, and 22a, 15%, entries 5
and 6) as was trans-cinnamaldehyde (23a, 28%, entry 7). In con-
trast tothe analogous results of Kobayashi using epoxy-g-butyro-
lactone substrates,16 no appreciable diastereoselectivity was
observed with respect to the newly created chiral center in these
products. Reaction of ketones with the aziridine anion of 14a
gave more consistent results. Thus, the use of cyclopentanone,
cyclohexanone, and 3-pentanone afforded the expected prod-
ucts 24a, 25a, and 26a, respectively, in 44, 56, and 45% yields
(entries 8e10). Other electrophiles such as benzenesulfonyl
11
12
13
a
PhSO2F
Bu3SnCl
I2
SO2Ph
SnBu3
I
27a:62
28a:55
29a:41
The yields were calculated based on the recovery of starting material.
Isolated as the silylated derivative (TBSOTf, Et3N, CH2Cl2).
b
fluoride and tri-n-butylstannyl chloride also provided the corres-
ponding C2 substituted aziridine lactones 27a and 28a in
good yields (62 and 55%, entries 11 and 12) while iodine gave
the 2-iodo product 29a in 41% yield (entry 13). Use of the
5-O-TBDPS aziridine-g-lactone 14b as starting material in
these reactions gave essentially similar results for the electro-
philes tested (entries 2, 8, 10, and 12) except in the case of
methyl iodide whereby the C2 methylated aziridino-g-lactone
17b could finally be isolated, albeit in low yield (10%, entry
1). The poor results with methyl iodide are probably due to its
incompatibility with a strong lithiated base such as LDA.17
As demonstrated by Kobayashi and co-workers16 using ep-
oxy-g-butyrolactones and Aggarwal and co-workers18 using
simple aziridines, treatment of their C2 TMS derivatives
with a fluoride ion source at room temperature or at 40 ꢁC, re-
spectively, generates the corresponding anion, which reacts

422
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
cleanly with diverse electrophiles. Application of this tech-
nique to the TMS aziridine-g-lactones 16a and 16b, obtained
in very high yields from 14a and 14b, respectively would thus
present an alternative route to the C2 substituted derivatives
described in Table 1.
shown in Table 1. Except in the case of benzaldehyde (entry
3) the yields of C2 substituted aziridines were consistently lower
using the other aldehydes (isobutyraldehyde, butyraldehyde,
entries 4 and 5) and ketones (cyclopentanone, cyclohexanone,
3-pentanone, entries 6e8) as electrophiles. Similarly, benzene-
sulfonyl fluoride and iodine gave lower yields of C2 substituted
products 27a and 29a, respectively (32 and 16%, entries 9 and
11, compared to 62 and 41% via the one-step procedure). In con-
trast to the one-step procedure, however, neither methyl iodide,
benzyl bromide nor tri-n-butylstannyl chloride gave the ex-
pected products starting from silylated aziridine 16a (entries
1, 2, and 10, respectively). This procedure thus appears to be
generally less satisfactory than the direct lithiation/electrophilic
substitution method.
In initial experiments, a solution of the silylated aziridine 16a
and excess aldehyde (benzaldehyde, propionaldehyde) in THF
treated at ꢀ40 ꢁC or at ꢀ30 ꢁC with 1 equiv of TBAT (tetrabuty-
lammonium triphenyldifluorosilicate)19 resulted only in recov-
ery of starting material. On the other hand, when the reaction
was conducted at room temperature, the product of desilylation
14a was obtained suggesting that the anion is indeed formed un-
der these conditions but is insufficiently reactive with respect to
the aldehyde. Finally, addition of a mixture of silylated aziridine
16a and benzaldehyde to a solution of TBAT in THF held at
40 ꢁC gave, after 30 min and after in situ silylation of the second-
ary hydroxyl group, product 19a in 51% yield (entry 3, Table 2)
identical to that obtained by the previous method (entry 3,
Table 1). Again, no diastereoselectivity was observed in this
reaction in contrast to the results observed by Aggarwal and
co-workers.18
2.3. Intra/intermolecular opening of the C2 substituted
aziridino-g-lactones: preliminary results
To examine the reactivity and the regioselectivity of nucleo-
philic ring opening of C2 substituted aziridino-g-lactones,
the DMB group was first replaced by a more activating Cbz
group (Scheme 4).8,20 Thus, treatment of the C2 silyl and
benzyl aziridino-g-lactones 16b and 18b with DDQ in wet
CH2Cl2 at room temperature for 8 h followed by reaction of
the crude products with CbzCl in pyridine provided the corres-
ponding N-Cbz aziridine derivatives 30 and 31, respectively.
Treatment of compound 30 with excess thiophenol (solvent)
in the presence of BF3$Et2O, conditions shown previously
by us to provide high yields of aziridine ring opened products
when the C2 position is unsubstituted (i.e., of type 5),11 gave
in this case only the product of Cbz cleavage, compound 32.
Alternatively, treatment of compound 31 with methanol and
BF3$Et2O at reflux for 18 h led to degradation products with
no observable formation of the desired C3 ring-opened prod-
uct 33. This unexpected lack of reactivity of these C2
substituted aziridino-g-lactones may be attributed to the high
steric hindrance provided by the combination of the C2 sub-
stituent and the OTBDPS group at C5.
This methodology was applied to other electrophiles in order
to compare its efficiency with that of the one-step procedure
Table 2
Electrophilic substitution of 16a by electrophiles mediated by TBAT
O
O
O
O
TrO
TrO
TBAT,
+ E
R
TMS
N
DMB
N
DMB
THF, 40 °C, 0.5 h
16a
Entry
E
Product (R)
Yielda (%)
1
2
MeI
BnBr
Me
Bn
17a:0
18a:0
Ph
3
PhCHO
19a:51b
OTBS
OTBS
4
5
6
7
i-PrCHO
n-PrCHO
21a:19b
22a:10b
24a:21
25a:43
We thus proceeded to remove the latter by treating com-
pound 31 with TBAF in THF, affording compound 34 in
68% yield (Scheme 5). Interestingly, treatment of alcohol 34
OTBS
O
O
O
O
1. DDQ, CH2Cl2/H2O
10:1, rt, 8h
OH
TBDPSO
TBDPSO
Cyclopentanone
Cyclohexanone
R
R
N
DMB
16b, R = TMS
18b, R = Bn
N
Cbz
2. CbzCl, DMAP,
py, 24h
OH
30, R = TMS (21%)
31, R = Bn (85%)
PhSH,
BF3.OEt2,
rt, 4 days
O
O
TBDPSO
OH
30
TMS
N
H
35%
8
Et2C]O
26a:30
32
MeOH
BF3.OEt2,
reflux, 18h
O
O
9
PhSO2F
Bu3SnCl
I2
SO2Ph
SnBu3
I
27a:32
28a:0
29a:16
TBDPSO
10
11
a
NHCbz
31
MeO
Bn
33
The yields were calculated based on the recovery of starting material.
Isolated as the silylated derivative (TBSOTf, Et3N, CH2Cl2).
b
Scheme 4.

M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
423
BF3.OEt2,
CH3CN
TBAF,
THF,
H
O
HO
(0.01M),
-20 °C,
2h, rt, 1h
O
O
7
NHCbz
CO2H
Bn
O
HO
0 °C→rt, 4h
31
Bn
68%
56%
O
Bn
N
Cbz
CbzN
H
O
H
34
35
36
Scheme 5.
with BF3$OEt2 in CH3CN at room temperature provided bicy-
clic lactone 35 in 56% yield, the product of regioselective in-
tramolecular aziridine ring opening at the more substituted
carbon (C2) with concomitant inversion of configuration.
The regioselectivity of attack was confirmed by a COSY ex-
periment, which indicated a coupling between the hydrogen
atom of the amine and H7. The formation of compound 35
opens the way to the preparation of potentially valuable,
highly substituted, optically pure tetrahydrofuran derivatives
(36) after hydrolysis of the lactone.
reference to tetramethylsilane (TMS) as internal standard.
NMR experiments were carried out in deuterochloroform
(CDCl3) or in deuterobenzene (C6D6). The following abbrevi-
ations are used for the multiplicities: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet for proton spectra. Coupling
constants (J ) are reported in hertz (Hz). Mass spectra were ob-
tained either with an AEI MS-9 instrument using electron
spray (ESI-MS) or with a MALDI-TOF instrument for high
resolution mass spectra (HREIMS). Thin-layer chromatogra-
phy was performed on silica gel 60 plates with a fluorescent
indicator and visualized under a UVP Mineralight UVGL-58
lamp (254 nm) and with a 7% solution of phosphomolybdic
acid in ethanol. Flash chromatography was performed using
silica gel 60 (40e63 mm, 230e400 mesh ASTM) at medium
pressure (200 mbar). All solvents were distilled and stored
3. Conclusion
In conclusion, we have demonstrated that regioselective
substitution at C2 of 2,3-aziridino-g-lactones by a variety
of electrophiles is possible using two different but comple-
mentary methodologies. The more direct method, involving
LDA treatment of the aziridine substrate in the presence of
the electrophile, generally presented better results than that
in which the anion is first trapped by a TMS group and is
afterward regenerated by fluoride ion. Attempts at intermo-
lecular aziridine opening have so far failed, most likely for
reasons of steric hindrance around both electrophilic sites.
However, intramolecular aziridine opening at C2 by the 5-hy-
droxy group of the 2-benzyl aziridine-g-lactone 34 was suc-
cessful, providing a precursor of a tetrahydrofuran derivative
having three contiguous stereogenic centers. The latter (36),
particularly rich in synthetic possibilities, may also be seen
as an a,a-disubstituted b-amino acid. The possibility of im-
proving the yields of lithiation/electrophilic trapping of azir-
idino-g-lactones by incorporating an N-substituent able to
chelate the C2 anion is currently being investigated as is
the use of less sterically encumbered substrates, which can
facilitate intermolecular aziridine opening of the C2
substituted derivatives.
˚
over 4 A molecular sieves before use. Benzaldehyde, isobutyr-
aldehyde, butyraldehyde, cyclopentanone, and cyclohexanone
˚
were dried over CaSO4, distilled and stored over 4 A molecu-
lar sieves before use. Et3N and pyridine were dried over so-
˚
dium metal, distilled and stored over 4 A molecular sieves.
All reagents were obtained from commercial suppliers unless
otherwise stated. Organic extracts were, in general, dried over
magnesium sulfate (MgSO4) or sodium sulfate (Na2SO4).
Elemental analyses were performed at the ICSN, CNRS,
Gif-sur-Yvette, France.
4.2. (3R,4S,5R)-3,4-Dihydroxy-5-(trityloxymethyl)-
dihydrofuran-2(3H )-one (12a)
To a solution of D-ribonolactone (2.00 g, 13.50 mmol) in pyr-
idine (100 mL) was added chlorotriphenylmethane (4.54 g,
16.30 mmol) under argon. The reaction mixture was stirred at
60e65 ꢁC overnight. The cooled mixture was then diluted
with methanol (10 mL), concentrated under vacuum to 1/3 of
volume, diluted again with CH2Cl2 (110 mL), and washed suc-
cessively with water (50 mL), saturated aqueous NaHCO3
(50 mL), and water (50 mL). The organic layer was dried over
anhydrous Na2SO4, filtered, and the solvent was removed in va-
cuo. Hot EtOAc (35 mL) was added to the residue and the insol-
uble solids formed were removed by filtration. The filtrate was
concentrated and the oil obtained was dissolved in warm hep-
tane (30 mL) and chloroform (5 mL). The solution was stored
at 0 ꢁC overnight affording compound 12a as a white solid
(4.79 g, 12.28 mmol) in 91% yield. Rf 0.23 (EtOAc/heptane
1:1); [a]2D0 þ43.0 (c 1.08, CH2Cl2) (lit.13 [a]2D0 þ50.0 (c 3.80,
CH2Cl2)); mp 172e174 ꢁC (lit.13 172e173 ꢁC); IR (film,
cmꢀ1): 3428 (OH), 3059, 2922, 1781 (C]O), 1449, 1092; 1H
NMR (300 MHz, CDCl3): d 3.19 (dd, J¼2.3, 11.1 Hz, 1H,
H6), 3.67 (dd, J¼3.0, 11.1 Hz, 1H, H60), 4.25 (d, J¼5.1 Hz,
4. Experimental
4.1. General
Melting points, measured in capillary tubes and recorded
using a Buchi B-540 melting point apparatus, are uncorrected.
¨
Infrared spectra were recorded on a PerkineElmer Spectrum
BX FT-IR spectrometer. Optical rotations were determined
with a JASCO P-1010 polarimeter. Proton (1H) and carbon
(13C) NMR spectra were recorded on Bruker spectrometers:
AC 250 (250 MHz), Aspect 3000 (300 MHz), Avance 300
NMR or 500 NMR (300 and 500 MHz, respectively). Chemi-
cal shifts (d) are reported in parts per million (ppm) with

424
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
1H, H4), 4.52 (m, 1H, H5), 4.88 (d, J¼5.5 Hz, 1H, H3), 7.20e
7.41 (m, 15H, H arom); ESI-MS m/z 391 [MþH]þ.
trifluoromethanesulfonic anhydride (4.20 mL, 24.60 mmol) in
CH2Cl2 (30 mL). After 15 min of stirring at ꢀ78 ꢁC, the reac-
tion mixture was slowly warmed to ꢀ25 ꢁC over a period of
3 h. The reaction solution was then poured into cold diethyl
ether (110 mL). The precipitate was removed by filtration and
the filtratewas evaporated invacuo at 0 ꢁC. The resulting residue
was purified by flash chromatography on silica gel (EtOAc/hep-
tane 1:2) to afford triflate 13b (3.55 g, 7.1 mmol, 78%) as a yel-
low oil. Rf 0.80 (EtOAc/heptane 1:1); IR (film, cmꢀ1): 3073,
4.3. (3R,4S,5R)-5-((tert-Butyldiphenylsilyloxy)methyl)-
3,4-dihydroxydihydrofuran-2(3H )-one (12b)
To a solution of D-ribonolactone (4.00 g, 27.0 mmol) in N,N-
dimethylformamide (27 mL) held at 0 ꢁC under argon, were
successively added imidazole (4.04 g, 59.0 mmol) and tert-
butyldiphenylsilyl chloride (7.6 mL, 30.0 mmol). After
30 min of stirring at 0 ꢁC, the mixture was warmed to room
temperature and stirred for an additional 30 min. The reaction
solution was diluted with EtOAc (35 mL) and water (35 mL).
The layers were separated, and the aqueous layer was extracted
with EtOAc (2ꢂ30 mL). The organic extracts were combined,
washed with water (2ꢂ30 mL), dried over MgSO4, and evapo-
rated to dryness. The resulting residue was purified by flash
chromatography on silica gel (heptane/EtOAc 2:1) to afford
the diol 12b (7.30 g, 19.03 mmol) in 70% yield as a white solid.
Rf 0.30 (EtOAc/heptane 7:3); [a]2D1 þ43 (c 1.35, CHCl3) (lit.14
[a]D21 þ46.3 (c 0.84, CHCl3)); mp 69.5e71 ꢁC (lit.14 65e
70 ꢁC); IR (film, cmꢀ1): 3362, 1782, 1427, 1178, 1113, 700;
1H NMR (CDCl3, 300 MHz): d 0.99 (s, 9H, C(CH3)3), 3.82
(dd, J¼2.1, 11.9 Hz, 1H, H6), 3.91 (dd, J¼2.8, 11.9 Hz, 1H,
H60), 4.52 (t, J¼2.3 Hz, 1H, H5), 4.55 (d, J¼5.5 Hz, 1H, H4),
4.88 (d, J¼5.7 Hz, 1H, H3), 7.2e7.6 (m, 10H, H arom); 13C
NMR (75 MHz, CDCl3): d 19.2, 26.5, 63.4, 69.4, 70.3, 85.6,
128.1, 130.2, 131.8, 132.2, 135.5, 135.6, 176.8 (C]O).
1
2934, 2861, 1792, 1656, 1433, 1221, 1137, 1104, 703; H
NMR (250 MHz, CDCl3): d 0.98 (s, 9H, C(CH3)3), 3.84 (ddd,
J¼3.8, 4.5, 11.5 Hz, 2H, H6, H60), 4.98 (dt, J¼4.1, 1.8 Hz,
1H, H5), 7.03 (d, J¼1.9 Hz, 1H, H4), 7.2e7.6 (m, 10H, H
arom); 13C NMR (CDCl3, 75 MHz): d 22.7, 26.6, 62.7, 88.1,
121.0, 128.0, 128.3, 130.2, 132.0, 132.2, 135.5, 135.7, 138.0,
163.6 (C]O); HREIMS m/z calcd for C22H23F3O6SSiNaþ
[MþNa]þ: 523.0834, found 523.0823.
4.6. (1R,4S,5S )-6-(3,4-Dimethoxybenzyl)-4-
(trityloxymethyl)-3-oxa-6-azabicyclo[3.1.0]-
hexan-2-one (14a)
To a solution of triflate 13a (3.55 g, 7.1 mmol) in N,N-
dimethylformamide (35 mL) held at ꢀ60 ꢁC under argon
was added dropwise 3,4-dimethoxybenzylamine (1.6 mL,
10.7 mmol). The reaction mixture was stirred for 30 min at
ꢀ60 ꢁC, diluted with EtOAc (40 mL) and water (40 mL).
The layers were separated and the aqueous layer was extracted
with EtOAc (2ꢂ30 mL). The combined organic extracts were
dried over MgSO4 and evaporated to dryness. The resulting
oily residue was purified by flash chromatography on silica
gel (EtOAc/heptane 1:2) to afford the aziridine-g-lactone
14a (2.35 g, 4.5 mmol) in 64% yield as a viscous oil, which
crystallized on standing. Rf 0.20 (EtOAc/heptane 2:3); [a]D20
þ19.0 (c 1.00, CHCl3); mp 62e63 ꢁC; IR (film, cmꢀ1):
3058, 2933, 1777, 1516, 1449, 1265, 1157, 1027, 763, 706;
1H NMR (250 MHz, CDCl3): d 2.78 (d, J¼4.4 Hz, 1H, H5),
2.80 (d, J¼4.4 Hz, 1H, H1), 3.09 (dd, J¼3.1, 10.5 Hz, 1H,
H7), 3.38 (d, J¼13.2 Hz, 1H, NeCHH), 3.39 (dd, J¼4.1,
10.5 Hz, 1H, H7), 3.62 (d, 1H, J¼13.2 Hz, 1H, NeCHH ),
3.79 (2ꢂs, 6H, 2ꢂOCH3), 4.40 (t, J¼3.5 Hz, 1H, H4),
6.62e7.39 (m, 18H, H arom); 13C NMR (75 MHz, CDCl3):
d 38.9 (C1), 43.4 (C5), 54.9 (2ꢂOCH3), 59.8 (CH2, Ne
CH2), 62.3 (C7), 78.4 (C4), 86.0 (CPh3), 110.2 (C20, C50),
119.0 (C60), 126.3, 127.0, 127.5 (CH arom), 128.7 (C10),
142.2 (Cq, CPh3), 147.5 (C30), 148.1 (C40), 171.1 (C]O);
ESI-MS m/z 544 [MþNa]. Anal. Calcd for C33H31NO5: C,
75.99; H, 5.99; N, 2.69; O, 15.34. Found: C, 75.79; H, 6.27;
N, 2.62; O, 15.49.
4.4. (S )-2-Oxo-5-(trityloxymethyl)-2,5-dihydrofuran-3-yl
trifluoromethanesulfonate (13a)
To a solution of diol 12a (1.20 g, 3.10 mmol) in CH2Cl2
were added pyridine (1.2 mL, 15.00 mmol) and trifluorome-
thanesulfonic anhydride (1.4 mL, 8.00 mmol) at ꢀ78 ꢁC under
argon. The reaction mixture was stirred for 15 min at ꢀ78 ꢁC
and then at ꢀ25 ꢁC for 3 h. The solution was added to cold
ether (100 mL), the salt precipitate was removed by filtration
and the filtrate was concentrated in vacuo at 0 ꢁC. The orange
solid obtained was purified by column chromatography on sil-
ica gel (EtOAc/heptane 1:2) to give the product 13a as a yellow
solid (1.27 g, 2.50 mmol) in 81% yield. Rf 0.73 (EtOAc/hep-
tane 1:1); IR (film, cmꢀ1): 3033, 3020, 2995, 1788 (C]O),
1653 (C]C), 1436, 1138 (SO2); 1H NMR (300 MHz,
CDCl3): d 3.46 (dd, J¼4.4, 10.5 Hz, 1H, H6), 3.57 (dd,
J¼4.6, 10.5 Hz, 1H, H60), 5.10 (dt, J¼1.9, 4.5, 4.5 Hz, 1H,
H5), 7.30 (m, 16H, H arom and H4); 13C NMR (75 MHz,
CDCl3): d 62.9 (C6), 77.8 (C5), 87.5 (CPh3), 128.0, 127.6,
128.2, 128.6 (CH arom), 136.3 (C4), 137.9 (C3), 143.1 (Cq,
CPh3), 164.0 (C]O); ESI-MS m/z 527 [MþNa]þ.
4.7. (1R,4S,5S )-4-((tert-Butyldiphenylsilyloxy)methyl)-6-
(3,4-dimethoxybenzyl)-3-oxa-6-azabicyclo[3.1.0]hexan-
2-one (14b)
4.5. (S )-5-((tert-Butyldiphenylsilyloxy)methyl)-2-oxo-
2,5-dihydrofuran-3-yl trifluoromethanesulfonate (13b)
To a solution of diol 12b (3.50 g, 9.10 mmol) in CH2Cl2
(85 mL) held at ꢀ78 ꢁC under argon were successively
added pyridine (3.5 mL, 45.51 mmol) and a solution of
To a solution of triflate 13b (3.55 g, 7.12 mmol) in N,N-dime-
thylformamide (35 mL) held at ꢀ60 ꢁC under argon was added
dropwise 3,4-dimethoxybenzylamine (1.6 mL, 10.65 mmol).

M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
425
The reaction mixture was stirred for 30 min at ꢀ60 ꢁC, diluted
with EtOAc (40 mL) and water (40 mL). The layers were sepa-
rated and the aqueous layer was extracted with EtOAc
(2ꢂ30 mL). The combined organic extracts were dried over
MgSO4 and evaporated to dryness. The resulting oily residue
was purified by flash chromatography on silica gel (heptane/
EtOAc 2:1) to afford aziridine-g-lactone 14b (2.35 g,
4.53 mmol) in 64% yield as a viscous oil that crystallized on
standing. Rf 0.50 (EtOAc/heptane 1:1); [a]2D0 þ15.0 (c 1.08,
CH2Cl2); mp 46e47 ꢁC; IR (film, cmꢀ1): 3071, 2933, 1781,
(C]O lactone); HREIMS m/z calcd for C60H70N2O10Si2Naþ
[MþNa]þ: 1057.4467, found 1057.4512.
4.9. General procedures for the preparation of the
substituted aziridino-g-lactones
4.9.1. General method A
In a flame-dried round-bottom flask equipped with a mag-
netic stirring bar and a septum, a solution of diisopropylamine
(59 mL, 0.42 mmol) was treated with n-BuLi (250 mL of
a 1.6 M solution in hexanes, 0.40 mmol) in THF (1 mL) at
ꢀ78 ꢁC under argon. After 30 min of stirring, a solution of
the aziridine 14a (100 mg, 0.19 mmol) and of the electrophile
(0.57 mmol) in THF (3 mL) was added to the LDA solution
via cannula. The final concentration of the aziridine was
0.032 M. The color of the reaction turned to transparent
brown. The reaction mixture was then gradually allowed to
reach room temperature under constant stirring. After 2 h,
the reaction was quenched with saturated aqueous NH4Cl
and washed successively with saturated aqueous NaHCO3
(2ꢂ2 mL) and then with saturated aqueous NaCl (2ꢂ2 mL).
The organic layer was dried over anhydrous MgSO4, filtered,
and the solvent was removed in vacuo. The resulting crude
product was purified by column chromatography on silica
gel using a gradient of EtOAc/heptane. This method was
also used for aziridine 14b utilizing reagents of same molarity.
1
1516, 1113, 704; H NMR (250 MHz, CDCl3): d 0.97 (s, 9H,
C(CH3)3), 2.71 (d, J¼4.3 Hz, 2H, H1, H5), 3.43 (d,
J¼13.4 Hz, 2H, NeCH2), 3.78 (dd, J¼2.9, 11.4 Hz, 1H, H7),
3.93 (s, 6H, 2ꢂOCH3), 3.93 (dd, J¼3.9, 11.4 Hz, 1H, H70),
4.37 (m, 1H, H4), 6.76e7.64 (m, 13H, H arom); 13C NMR
(75 MHz, CDCl3): d 19.1, 26.7, 39.9, 44.2, 55.9, 60.9, 63.5,
80.2, 111.1, 120.1, 127.9, 129.7, 130.8, 132.8, 135.5, 149.1,
172.0 (C]O); ESI-MS m/z 517 [MþHꢀTBDPS]þ. Anal. Calcd
for C30H35NO5Si: C, 69.60; H, 6.81; N, 2.71. Found: C, 69.12;
H, 6.87; N, 2.51.
4.8. Selected procedure for the preparation of dimer 15
In a flame-dried round-bottom flask equipped with a mag-
netic stirring bar and a septum, diisopropylamine (100 mL,
0.71 mmol) was treated with n-BuLi (1.6 M in hexanes,
0.4 mL, 0.65 mmol) in THF (0.5 mL) at ꢀ10 ꢁC under argon.
After 1 h of stirring, a solution of the aziridine 14b (168 mg,
0.33 mmol) in THF (3.2 mL) was added to the LDA solution
via cannula. The yellow solution was stirred at ꢀ78 ꢁC for
1 h, and a solution of methyl iodide (61 mL, 0.97 mmol) and
DMPU (118 mL, 0.97 mmol) in THF (0.5 mL) was added.
The reaction mixture was then gradually allowed to reach
room temperature under constant stirring. After 8 h, the reac-
tion was quenched with saturated aqueous NH4Cl and washed
successively with saturated aqueous NaHCO3 (2ꢂ5 mL) and
saturated aqueous NaCl (2ꢂ5 mL). The organic layer was
dried over MgSO4, filtered, and the solvent was removed in va-
cuo. The oil obtained was purified by flash chromatography
(EtOAc/heptane 1:5) to furnish 15 (84 mg, 0.08 mmol, 25%
yield) as a pasty solid. Rf 0.4 (EtOAc/heptane 3:4); IR (film,
cmꢀ1): 3495 (OH), 3071, 2999, 2933, 2858, 1757 (C]O lac-
tone), 1516, 1464, 1264, 1112, 1030, 703; 1H NMR
(250 MHz, CDCl3): d 1.02 (s, 9H, SiC(CH3)3), 1.10 (s, 9H,
SiC(CH3)3), 2.52 (d, 1H, J10,9¼3.8 Hz, H10), 2.55 (d, 1H,
J9,10¼3.8 Hz, H9), 3.31 (4H, J¼13.0 Hz, 2ꢂNCH2Ar), 3.47
(s, 1H, H5), 3.59e3.89 (m, 10H, 2ꢂOCH3, H7, H70, H12,
H120), 4.17 (m, 2H, H4, H11), 6.63e6.93 (m, 6H, H arom
DMB), 7.34e7.75 (m, 20H, H arom); 13C NMR (75 MHz,
CDCl3): d 19.2 (2ꢂSiC(CH3)3), 26.6, 26.9 (2ꢂSiC(CH3)3),
43.0 (C10), 46.5 (C5), 48.2 (C9), 49.8 (C1), 55.9
(4ꢂOCH3), 60.8 (2ꢂNCH2Ar), 63.9, 64.8 (C7, C12), 74.4,
80.6 (C4, C11), 102.0 (C8), 110.9, 111.1, 111.4, 111.8,
120.0, 120.8 (CH arom DMB), 127.8, 127.9, 130.0, 130.4,
130.8 132.6, 132.8, 133.0, 133.1, 135.5, 135.6 (CH arom,
2ꢂCq, DMB), 148.2, 148.7, 148.8 (4ꢂCq, OCH3), 172.8
4.9.2. General method B
To a solution of TBAT (92 mg, 0.17 mmol) in THF (1 mL)
at 40 ꢁC was added a solution of aziridine 14a (100 mg,
0.17 mmol) and of the electrophile (0.51 mmol) in THF
(3 mL) via cannula. After 30 min of stirring, the reaction
was quenched with saturated aqueous NH4Cl and washed suc-
cessively with saturated aqueous NaHCO3 (2ꢂ2 mL) and then
saturated aqueous NaCl (2ꢂ2 mL). The organic layer was
dried over anhydrous MgSO4, filtered, and the solvent was re-
moved in vacuo. The resulting crude product was purified by
column chromatography on silica gel using a gradient of
EtOAc/heptane.
4.9.3. (1S,4S,5R)-6-(3,4-Dimethoxybenzyl)-1-
(trimethylsilyl)-4-(trityloxymethyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (16a)
Using general method
A and chlorotrimethylsilane
(0.73 mL, 5.76 mmol) as the electrophile, compound 16a
(101 mg, 0.17 mmol) was obtained from 14a in 89% yield
as a pasty white oil. Rf 0.40 (EtOAc/heptane 3:2); [a]D20
þ17.0 (c 0.80, CHCl3); IR (film, cmꢀ1): 3071, 2929, 1757,
1515, 1449, 1264, 1030, 842, 705; 1H NMR (250 MHz,
CDCl3): d ꢀ0.04, 0.16 (s, 9H, Si(CH3)3), 3.09 (s, 1H, H5),
3.34 (dd, J¼5.1, 10.3 Hz, 1H, H7), 3.43 (dd, J¼5.1,
10.3 Hz, 1H, H70), 3.64 (d, J¼13.1 Hz, 2H, NeCH2), 3.87
(2ꢂs, 6H, 2ꢂOCH3), 4.44 (t, J¼4.4 Hz, 1H, H4), 6.78e7.47
(m, 18H, H arom); 13C NMR (75 MHz, CDCl3): d ꢀ3.8, 0.0
((CH3)3), 38.8 (C1), 49.9 (C5), 51.9 (NeCH2), 56.4, 56.5
(2ꢂOCH3), 64.5 (C7), 73.8 (C4), 111.5 (C20), 112.7 (C50),
121.6 (C60), 127.9, 128.5, 129.2 (CH arom), 131.2 (C10),

426
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
143.7 (Cq, CPh3), 148.9 (C30), 149.4 (C40), 173.9 (C]O lac-
tone); ESI-MS m/z 616 [MþNa]þ. Anal. Calcd for
C36H39NO5Si: C, 72.82; H, 6.62; N, 2.36. Found: C, 72.74;
H, 6.88; N, 2.08.
1157, 1027, 882, 746, 698; 1H NMR (300 MHz, CDCl3):
d 2.78 (s, 1H, H5), 3.10 (d, J¼14.5 Hz, 1H, NeCH2), 3.19
(d, J¼14.5 Hz, 1H, NeCH2), 3.06 (dd, J¼3.4 Hz, 1H, H7),
3.44 (dd, J¼3.8, 10.2 Hz, 1H, H7), 3.59 (s, 2H, CH2Ph),
3.86, 3.88 (2ꢂOCH3), 4.34 (t, J¼3.4 Hz, 1H, H4), 6.78e
7.75 (m, 23H, H arom); 13C NMR (75 MHz, CDCl3): d 33.8
(CH2, Bn), 47.0 (C5), 48.4 (C1), 50.5 (NeCH2), 55.8, 55.9
(2ꢂOMe), 63.7 (C7), 73.2 (C4), 87.2 (CPh3), 111.0 (C20),
111.7 (C50), 120.6 (C60), 126.5, 127.3, 128.0, 128.6 129.8,
130.4 (CH arom), 136.2 (Cq, Bn), 143.2 (Cq, CPh3), 148.3
(C30), 148.9 (C40), 172.3 (C]O); HREIMS m/z calcd for
C40H37NNaOþ5 [MþNa]þ: 634.2569, found 634.2564.
4.9.4. (1S,4S,5R)-4-((tert-Butyldiphenylsilyloxy)methyl)-6-
(3,4-dimethoxybenzyl)-1-(trimethylsilyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (16b)
Using general method
A and chlorotrimethylsilane
(0.19 mL, 1.44 mmol) as the electrophile, compound 16b
was obtained from 14b (250 mg, 0.48 mmol) as a colorless
oil in 85% (241 mg, 0.40 mmol) after flash chromatography
of the crude product (EtOAc/heptane 1:5). Rf 0.5 (EtOAc/hep-
tane 1:2); [a]2D0 þ25 (c 0.9, CHCl3); IR (film, cmꢀ1): 3071,
2957, 2933, 2859, 1758 (C]O lactone), 1515, 1464, 1264,
4.9.7. (1R,4S,5S )-1-Benzyl-4-((tert-butyldiphenylsilyloxy)-
methyl)-6-(3,4-dimethoxybenzyl)-3-oxa-6-azabicyclo-
[3.1.0]hexan-2-one (18b)
1
1138, 1113, 843, 702; H NMR (300 MHz, CDCl3): d ꢀ0.07
(s, 9H, Si(CH3)3), 1.07 (s, 9H, OSiC(CH3)3), 3.17 (s, 1H,
H5), 3.53 (dd, 2H, J¼12.3 Hz, NCH2Ar), 3.68e3.87 (m, 2H,
H7, H70), 3.87 (s, 6H, 2ꢂOCH3), 4.41 (m, 1H, H4), 6.74e
7.66 (m, 13H, H arom); 13C NMR (75 MHz, CDCl3):
d ꢀ3.8 (Si(CH3)3), 19.0 (OSiC(CH3)3), 26.6 (OSiC(CH3)3),
37.9 (C1), 48.8 (C5), 51.2 (NCH2Ar), 55.6, 55.7 (2ꢂOCH3),
64.4 (C7), 74.0 (C4), 110.8, 111.9 (C20, C50), 120.8 (C60),
127.7, 129.8, 132.3, 132.4, 135.3 (Cq arom), 148.1, 148.6
(C30, C40), 172.8 (C]O lactone); HREIMS m/z calcd for
C33H43NO5Si2Naþ [MþNa]þ: 612.2578, found 612.2573.
Using general method A and benzyl bromide (69 mL,
0.10 mmol) as the electrophile, compound 18b was obtained
from 14b in 17% yield (20 mg, 0.033 mmol; 25% yield based
on recovery of starting material) as a colorless oil after flash
chromatography (EtOAc/heptane 3:7) of the crude product.
Rf 0.60 (EtOAc/heptane 1:1); [a]2D0 ꢀ5.1 (c 1.65, CHCl3); IR
(film, cmꢀ1): 2931, 2857, 1768 (C]O lactone), 1513, 1461,
1
1264, 1236, 1106, 1026, 699; H NMR (300 MHz, CDCl3):
d 1.06 (s, 9H, C(CH3)3), 3.02 (s, 1H, H1), 3.05 (d,
J¼14.1 Hz, 1H, NeCH2), 3.13 (d, J¼13.9 Hz, 1H, NeCH2),
3.57 (s, 2H, CH2, Bn), 3.70 (br d, J¼4.7 Hz, 2H, H7), 3.83,
3.86 (2ꢂs, 6H, 2ꢂOCH3), 4.31 (t, J¼4.0 Hz, 1H, H4),
6.78e7.00 (m, 18H, H arom); 13C NMR (75 MHz, CDCl3):
d 19.5 (C(CH3)3), 27.2 (C(CH3)3), 34.4 (CH2Ph), 47.3 (C5),
48.8 (C1), 50.8 (NeCH2), 56.1, 56.2 (2ꢂOCH3), 64.3 (C7),
74.3 (C4), 111.2 (C20), 112.0 (C40), 120.9 (C60), 126.9,
128.2, 128.3, 130.0, 130.3, 135.9 (Cq, Bn, CH arom), 130.6
(C10), 132.5 and 133.0 (Cq arom, TBDPS), 148.6 (C30),
149.2 (C40), 172.5 (C]O lactone); HREIMS m/z calcd for
C37H41NNaO5Sþ [MþNa]þ: 630.2646, found 630.2664.
4.9.5. (1R,4S,5S )-4-((tert-Butyldiphenylsilyloxy)methyl)-6-
(3,4-dimethoxybenzyl)-1-methyl-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (17b)
Using general method A and methyl iodide (101 mL,
1.63 mmol) as the electrophile, compound 17b was obtained
from 14b in 10% yield (27 mg, 0.032 mmol) after flash chro-
matography (EtOAc/heptane 1:5) of the crude product
(114 mg). Rf 0.5 (EtOAc/heptane 3:4); [a]2D0 þ12 (c 1.22,
CHCl3); IR (film, cmꢀ1): 2933, 2858, 1774 (C]O lactone),
1
1516, 1464, 1264, 1112, 703; H NMR (250 MHz, CDCl3):
d 1.06 (s, 9H, SiC(CH3)3), 1.46 (s, 1H, CH3), 3.06 (1H, H5),
3.43e3.88 (m, 4H, NCH2Ar, H7, H70), 3.89 (s, 6H,
2ꢂOCH3), 4.33 (m, 1H, H4), 6.82e7.65 (m, 13H, H arom);
13C NMR (75 MHz, CDCl3): d 14.6 (CH3), 19.2 (SiC(CH3)3),
26.7 (SiC(CH3)3), 44.7 (C1), 48.2 (C5), 50.4 (NCH2Ar), 55.9
(OCH3), 63.9 (C7), 74.4 (C4), 111.1, 111.4 (C20, C50), 120.3
(C60), 127.9, 130.0, 132.2, 132.4, 135.5, 135.7 (Cq arom),
148.3, 149.0 (C30, C40), 172.9 (C]O lactone).
4.9.8. (1S,4S,5S )-1-(1-(tert-Butyldimethylsilyloxy)-
(phenyl)methyl)-6-(3,4-dimethoxybenzyl)-4-
(trityloxymethyl)-3-oxa-6-azabicyclo-
[3.1.0]hexan-2-one (19a)
Using general method A and benzaldehyde (59 mL,
0.58 mmol) as the electrophile, a crude product was obtained
from 14a after work-up, which was dried under vacuum and
then dissolved in CH2Cl2 (3 mL) under argon. Et3N (61 mL,
0.43 mmol) was added followed by TBSOTf (75 mL,
0.33 mmol) dropwise at 0 ꢁC. The solution was stirred for
2 h, diluted with CH2Cl2 (5 mL), and washed with saturated
aqueous NaCl (2ꢂ10 mL). The organic layer was dried over an-
hydrous MgSO4, filtered, and the solvent was removed in
vacuo. The crude product was then purified by column chroma-
tography on silica gel using a gradient of EtOAc/heptane 1:9 af-
fording compound 19a (75 mg, 0.10 mmol) as a colorless oil in
46% yield (51% yield based on recovery of starting material)
and as a 1.4:1 mixture of diastereomers. Rf 0.20 (EtOAc/hep-
tane 2:8); IR (film, cmꢀ1): 3061, 2928, 2855, 1772, 1595,
1515, 1447, 1260, 1060, 1028, 836, 760, 697; 1H NMR
4.9.6. (1R,4S,5S )-1-Benzyl-6-(3,4-dimethoxybenzyl)-4-
(trityloxymethyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one
(18a)
Using general method A and benzyl bromide (69 mL,
0.10 mmol) as the electrophile, compound 18a was obtained
from 14a in 17% yield (20 mg, 0.33 mmol; 25% yield based
on recovery of starting material) as a white solid after flash
chromatography (EtOAc/heptane 3:7) of the crude product.
Rf 0.60 (EtOAc/heptane 1:1); [a]2D0 ꢀ10.1 (c 0.50, CHCl3);
mp 155 ꢁC (decomp.); IR (film, cmꢀ1): 2959, 2918, 2871,
2850, 1765, 1752, 1592, 1517, 1450, 1323, 1267, 1230,

M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
427
(300 MHz, CDCl3): d ꢀ0.26, ꢀ0.16, ꢀ0.06, 0.07 (4ꢂs, 10.2H,
4ꢂCH3, TBS), 0.73, 0.79 (2ꢂs, 15.3H, 2ꢂC(CH3)3, TBS),
2.79, 3.00 (2ꢂs, 1.7H, H5), 3.07 (dd, J¼4.9, 10.4 Hz, 0.7H,
H7, minor diast.), 3.21 (dd, J¼6.4, 9.8 Hz, 1.0H, H7, major di-
ast.), 3.28 (dd, J¼4.9, 10.0 Hz, 0.7H, H7, minor diast.), 3.42 (d,
J¼13.4 Hz, 1H, NeCH2, major diast.), 3.47 (dd, J¼5.8, 9.5 Hz,
1.0H, H70, major diast.), 3.52 (d, J¼13.4 Hz, NeCH2, minor di-
ast.), 3.57 (d, J¼13.4 Hz, 1H, NeCH2, major diast.), 3.71 (d,
J¼13.4 Hz, NeCH2, minor diast.), 3.82, 3.85, 3.87, 3.89
(4ꢂs, 10.2H, 4ꢂOCH3), 3.82, 3.85, 3.87, 3.89 (4ꢂs, 10.2H,
4ꢂOCH3), 4.25, 4.34 (2ꢂt, J¼5.8 Hz, H4), 5.07, 5.2 (2ꢂs,
1.7H, CHOTBS), 6.69e7.51 (m, 39.1H, H arom); 13C NMR
(75 MHz, CDCl3): d ꢀ5.3, ꢀ5.0, ꢀ4.7, ꢀ4.5 (4ꢂCH3, TBS),
18.0, 18.2 (C(CH3)3), 25.7 (C(CH3)3), 44.9 (C1), 50.6, 52.4
(NeCH2), 55.7, 55.8, 55.9 (OCH3), 64.1, 64.7 (C7), 70.7,
71.1 (CHPh), 72.8, 73.0 (C4), 87.2 (CPh3), 110.8, 111.0
(C20), 111.9 (C50), 120.7, 120.8 (C60), 127.0, 127.3, 127.4,
128.0, 128.6 (CH arom), 130.2 (C10), 134.4, 139.7, 143.2,
143.3 (Cq, CPh3), 148.3, 148.5 (C30), 170.6, 170.8 (C]O);
HREIMS m/z calcd for C46H51NO6SiNaþ [MþNa]þ:
764.3339, found 764.3349.
(C]O); HREIMS m/z calcd for C38H41NNaOþ6 [MþNa]þ:
630.2832, found 630.2864.
4.9.10. (1S,4S,5S )-1-(1-(tert-Butyldimethylsilyloxy)-2-
methylpropyl)-6-(3,4-dimethoxybenzyl)-4-(trityloxymethyl)-
3-oxa-6-azabicyclo[3.1.0]hexan-2-one (21a)
Using general method A and isobutyraldehyde (53 mL,
0.58 mmol) as the electrophile, a crude product was obtained
from 14a after work-up, which was dried under vacuum and
then dissolved in CH2Cl2 (3 mL) under argon. Et3N (53 mL,
0.38 mmol) was added followed by dropwise addition of
TBSOTf (66 mL, 0.29 mmol) at 0 ꢁC. The solution was stirred
for 2 h, diluted with CH2Cl2 (5 mL) and washed with saturated
aqueous NaCl (2ꢂ10 mL). The organic layer was dried over
MgSO4, filtered and removed in vacuo. The crude product was
then purified by column chromatography on silica gel using
a gradient of EtOAc/heptane 1:9 affording compound 21a
(27 mg, 0.038 mmol) as a colorless oil in 22% yield (30% yield
based on recovery of starting material) and as 1.7:1 mixture of
diastereoisomers. Rf 0.60 (EtOAc/heptane 1:9); IR (film,
cmꢀ1): 3058, 2953, 2927, 2854, 1769, 1737, 1514, 1448,
1236, 1056, 1029, 834, 771, 703; 1H NMR (300 MHz,
CDCl3): d ꢀ0.16, ꢀ0.07, ꢀ0.02, 0.01 (4ꢂs, 9.6H, CH3, TBS),
0.78, 0.82, 0.83 (2ꢂC(CH3)3, 14.4H, TBS), 0.67, 0.90 (2ꢂd,
J¼6.7 Hz, 9.6H, 2ꢂCH(CH3)2), 1.88, 2.09 (m, 2.6H,
2ꢂCH(CH3)2, 1.6H), 3.10, 3.14 (2ꢂs, 1.6H, H5), 3.21, 3.22
(m, J¼6.4, 10.1 Hz, 1.6H, H7, major or minor diast.), 3.36,
3.81 (2ꢂd, J¼14.0 Hz, 2.0H, NeCH2, major diast.), 3.42,
3.89 (2ꢂd, J¼14.0 Hz, 1.2H, NeCH2, minor diast.), 3.46,
3.51 (2ꢂdd, J¼6.7, 10.1 Hz, 0.6H, H70, major or minor diast.),
3.75, 4.02 (2ꢂd, J¼4.3 Hz, 1.6H, CHOTBS, major or minor di-
ast.), 3.87, 3.88 (4ꢂOCH3, 10.9H, major or minor diast.), 4.33
(2ꢂt, J¼6.4, 6.1 Hz, 1.6H, H4, major or minor diast.), 6.78e
7.50 (m, 28.8H, H arom); 13C NMR (75 MHz, CDCl3):
d ꢀ4.6, ꢀ4.5, ꢀ4.0, ꢀ3.6 (4ꢂCH3, TBS), 16.9, 18.3, 19.6,
20.7 (CH(CH3)2), 17.3, 18.1 (C(CH3)3), 25.9 (C(CH3)3), 29.7,
31.3 (CH(CH3)2), 45.9, 46.4 (C1), 49.9, 50.8 (C5), 50.1, 51.3
(NeCH2), 55.9 (OCH3), 64.3, 64.9 (C7), 73.1 (C4), 72.5, 73.3
(CHOTBS), 87.3 (CPh3), 111.0, 111.1 (C20), 111.4 (C50),
120.3, 120.4 (C60), 127.3, 128.0, 128.1, 128.5, 128.8, 128.9
(CH arom), 130.4, 130.5 (C10), 143.2 (Cq, CPh3), 148.4 (C40),
149.0 (C30), 170.8, 171.6 (C]O); HREIMS m/z calcd for
C43H53NO6SiNaþ [MþNa]þ: 730.3534, found 730.3540.
Using general method B and isobutyraldehyde (58 mL,
51 mmol) as the electrophile, the crude product obtained
from 16a was treated with TBSOTf as above, affording com-
pound 21a (16 mg, 0.020 mmol) in 12% yield (19% yield
based on recovery of starting material) and as 1.7:1 mixture
of diastereoisomers and was identical in all respects to the
product prepared by method A.
Using general method B and benzaldehyde (61 mg,
0.58 mmol) as the electrophile, the crude product obtained
from 16a was treated with TBSOTf as above affording com-
pound 19a (75 mg, 0.10 mmol) in 46% yield (51% yield based
on recovery of starting material) and as a 1.4:1 mixture of di-
astereomers and was identical in all respects to the product
prepared by method A.
4.9.9. (1S,4S,5S )-6-(3,4-Dimethoxybenzyl)-1-(1-hydroxy-
2,2-dimethylpropyl)-4-(trityloxymethyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (20a)
Using general method
A and pivaldehyde (62 mL,
0.57 mmol) as the electrophile, compound 20a was obtained
from 14a as a colorless oil and as a mixture of diastereoisomers
(1:1.7) in 66% yield (57 mg, 0.094 mmol) following flash chro-
matography of the crude product on silica gel (EtOAc/heptane
2:8). Rf 0.60 (EtOAc/heptane 1:1); IR (film, cmꢀ1): 3516, 3058,
2953, 1767, 1593, 1514, 1490, 1448, 1263, 1235, 1156, 1138,
1
1056, 1027, 903; H NMR (300 MHz, CDCl3): d 0.76, 0.88
(2ꢂs, 15.3H, C(CH3)3), 3.00 (s, 0.6H, H5, minor diast.), 3.20
(dd, J¼7.4, 9.8 Hz, 0.8H, H7, minor diast.), 3.28 (s, 1.0H,
H5, major diast.), 3.37 (dd, 0.9H, J¼5.7, 10.0 Hz, H7, major di-
ast.), 3.45 (dd, J¼3.6, 10.2 Hz, H7, major diast.), 3.47 (d,
J¼14.9 Hz, 1H, NeCH2, major diast.), 3.52 (d, J¼5.09 Hz,
CH(CH3)3), 3.53 (d, J¼13.4 Hz, NeCH2, minor diast.), 3.62
(dd, J¼6.4, 9.80 Hz, minor diast.), 3.68 (d, J¼13.4 Hz,
NeCH2), 3.87 (s, 10.2H, OCH3), 4.41 (t, J¼5.6 Hz, 1.0H,
H4, major diast.), 4.52 (t, J¼6.8 Hz, 0.6H, H4, minor diast.),
6.72e7.61 (m, 30.6H, H arom); 13C NMR (75 MHz, CDCl3):
d 22.7 (C(CH3)3), 26.3, 26.6 (C(CH3)3), 35.3, 35.9 (C1), 46.1,
47.7 (C5), 49.7, 50.3 (NeCH2), 55.7, 55.9, 56.0, 56.2
(4ꢂOCH3), 63.7 (C7), 70.2 (C(CH3)3), 73.1, 73.3 (C4), 87.4,
87.5 (CPh3), 111.2, 111.4 (C20), 111.7 (C50), 120.4, 120.6
(C60), 127.4, 127.7, 127.8, 128.0, 128.3, 128.5, 128.6, 128.8,
128.9, 129.2 (CH arom), 142.9, 143.0 (Cq, CPh3), 130.1
(C1), 148.5, 148.6 (C40), 149.0, 149.1 (C30), 170.8, 172.2
4.9.11. (1S,4S,5S )-1-(1-(tert-Butyldimethylsilyloxy)butyl)-6-
(3,4-dimethoxybenzyl)-4-(trityloxymethyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (22a)
Using general method A and n-butyraldehyde (51 mL,
0.58 mmol) as the electrophile, a crude product was obtained
from 14a after work-up, which was dried under vacuum and

428
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
then dissolved in CH2Cl2 (3 mL) under argon. Et3N (53 mL,
0.38 mmol) was added followed by dropwise addition of
TBSOTf (66 mL, 0.29 mmol) at 0 ꢁC. The solution was stirred
for 2 h, diluted with CH2Cl2 (5 mL), and washed with saturated
aqueous NaCl (2ꢂ10 mL). The organic phase was dried over
anhydrous MgSO4, filtered, and the solvent was removed in va-
cuo. The crude product was then purified by column chroma-
tography on silica using a gradient of EtOAc/heptane 1:9
affording compound 22a (14 mg, 0.038 mmol) as a colorless
oil in 10% yield (15% yield based on recovery of starting ma-
terial) and as a 1:1 mixture of diastereomers. Rf 0.80 (EtOAc/
heptane 1:1); IR (film, cmꢀ1): 2954, 2928, 2855, 1770, 1593,
1514, 1448, 1259, 1137, 1029, 834, 773, 704; 1H NMR
(300 MHz, CDCl3): d 0.77 (s, 6H, 2ꢂCH3, TBS), 0.84 (m,
6H, 2ꢂ(CH2)2CH3), 0.88 (s, 18H, 2ꢂC(CH3)3, TBS), 1.21e
1.44 (m, 8H, 2ꢂe(CH2)2CH3), 3.02 (s, 1H, H1), 3.22 (dd,
J¼7.6, 9.8 Hz, 1H, H7), 3.62 (dd, J¼6.1, 9.8 Hz, 1H), 3.30
(s, 1H, H1), 3.38 (dd, J¼5.8, 10.1 Hz, 1H, H7), 3.43 (d,
J¼5.2 Hz, 1H, CHOTBS), 3.44 (m, 1H, H7), 3.48 (d,
J¼13.7 Hz, 1H, NeCH2), 3.53 (d, J¼5.2 Hz, 1H, CHOTBS),
3.54 (d, J¼13.4 Hz, 1H, NeCH2), 3.68 (d, J¼13.4 Hz, 1H,
NeCH2), 3.79 (d, J¼13.7 Hz, 1H, NeCH2), 3.87 (2ꢂs, 12H,
4ꢂOCH3), 4.41 (t, J¼5.2 Hz, 1H, H4), 4.52 (t, J¼6.7 Hz, 1H,
H4), 6.53e7.52 (m, 26H, CH arom); 13C NMR (75 MHz,
CDCl3): d ꢀ4.8, ꢀ4.5, ꢀ4.2 (SiC(CH3)3(CH3)2), 14.1, 14.2
(OTBSCH(CH2)2CH3), 18.0 (SiC(CH3)3(CH3)2), 18.7, 18.9
(CHOTBSCH2CH2CH3), 25.7, 25.8, 25.9 (SiC(CH3)3(CH3)2,
TBS), 29.3, 29.7 (CHOTBSCH2CH2CH3), 36.3, 36.5 (CHOT-
BS(CH2)2CH3), 45.9, 46.5 (C1), 50.4, 50.5 (C5), 51.1, 51.6
(NeCH2), 55.8, 56.0 (OCH3), 64.6, 64.9 (C7), 68.0, 69.7
(C8), 73.0, 73.3 (C4), 87.3, 87.4 (CPh3), 111.0, 111.1 (C20),
111.7, 111.8 (C50), 120.6, 120.7 (C60), 127.3, 127.7, 128.0,
128.6, 128.9 (CH arom), 130.3, 130.4 (C10), 143.2, 143.3
(Cq, CPh3), 148.4, 148.5 (C40), 149.0, 149.1 (C30), 170.5,
171.4 (C]O); HREIMS m/z calcd for C43H53NO6SiNaþ
[MþNa]þ: 730.3540, found 730.3555.
H70), 3.54 (d, J¼8.3 Hz, CHOH, 1H, H8), 3.44 (d,
J¼13.6 Hz, 1H, NeCH2), 3.79 (d, J¼13.6 Hz, 1H, NeCH2),
3.88 (s, 6H, 2ꢂOCH3), 4.41 (t, J¼5.46 Hz, 1H, H4), 6.79e
7.00 (m, J¼18.8 Hz, 4H, H9, H10, H arom), 7.14e7.47 (m,
15H, H arom); HREIMS m/z calcd for C42H39NNaO6þ
[MþNa]þ: 676.2675, found 676.2701.
4.9.13. (1S,4S,5S )-6-(3,4-Dimethoxybenzyl)-1-
(1-hydroxycyclopentyl)-4-(trityloxymethyl)-3-
oxa-6-azabicyclo[3.1.0]hexan-2-one (24a)
Using general method A and cyclopentanone (51 mL,
0.57 mmol) as the electrophile, compound 24a (32 mg,
0.053 mmol) was obtained from 14a as a colorless oil in 31%
yield (44% yield based on recovery of starting material) after
flash chromatography (EtOAc/heptane 3:7) of the crude prod-
uct. Rf 0.55 (EtOAc/heptane 1:1); [a]2D0 þ16.5 (c 0.30,
CHCl3); IR (film, cmꢀ1): 3528, 2932, 2868, 1762, 1593, 1514,
1
1448, 1262, 1027, 761, 704; H NMR (300 MHz, CDCl3):
d 1.58 (m, 4H, COH(eCH2CH2e)2), 1.80 (m, 4H, COH
(eCH2CH2e)2), 3.21 (s, 1H, H5), 3.40 (dd, J¼4.5, 10.4 Hz,
1H, H7), 3.47 (dd, J¼5.1, 10.5 Hz, 1H, H70), 3.57 (d,
J¼13.2 Hz, 1H, NeCH2), 3.72 (d, J¼13.2 Hz, 1H, NeCH2),
3.89 (s, 6H, 2ꢂOCH3), 4.39 (t, J¼4.9 Hz, 1H, H4), 6.8e7.55
(m, 18H, H arom); 13C NMR (75 MHz, CDCl3): d 23.9 (eCH2-
CH2e), 24.3 (eCH2CH2e), 36.6 (eCH2COHCH2e), 37.2
(eCH2COHCH2e), 47.1 (C1), 50.6 (NeCH2), 52.2 (C5), 55.9
(2ꢂOMe), 63.9 (C7), 72.9 (eCH2COHCH2e), 78.5 (C4),
87.5 (CPh3), 111.1 (C40), 112.0 (C50), 120.9 (C60), 127.3,
128.0, 128.7 (CH arom), 130.0 (Cq arom), 143.1 (Cq, CPh3),
148.6 (C30), 149.0 (C40), 171.1 (C]O); HREIMS m/z calcd
for C38H39O6NNaþ [MþNa]þ: 628.2675, found 628.2702.
Using general method B and cyclopentanone (45 mL,
0.51 mmol) as the electrophile, compound 24a (15 mg,
0.025 mmol) was obtained from 16a in 14% yield (21% yield
based on recovery of starting material) after flash chromato-
graphy (EtOAc/heptane 3:7) of the crude product and was iden-
tical in all respects to the compound prepared by method A.
Using general method B and n-butyraldehyde (45 mL,
51 mmol) as the electrophile, the crude product obtained
from 16a was treated with TBSOTf as above affording com-
pound 22a (9 mg, 0.012 mmol) in 6% yield (10% yield based
on recovery of starting material) and as a 1:1 mixture of dia-
stereomers and was identical in all respects to the product pre-
pared by method A.
4.9.14. (1S,4S,5S )-4-((tert-Butyldiphenylsilyloxy)methyl)-6-
(3,4-dimethoxybenzyl)-1-(1-hydroxycyclopentyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (24b)
Using general method A and cyclopentanone (52 mL,
0.58 mmol) as the electrophile, compound 24b (38 mg,
0.063 mmol) was obtained from 14b as a colorless oil in
33% yield after flash chromatography (EtOAc/heptane 3:7)
of the crude product: Rf 0.60 (EtOAc/heptane 1:1); [a]D20
þ10.1 (c 1.30, CHCl3); IR (film, cmꢀ1): 3513, 2930, 1764,
1590, 1514, 1462, 1263, 1104, 1027, 821, 700; 1H NMR
(300 MHz, CDCl3): d 1.06 (s, C(CH3)3, 9H), 1.41e1.94 (m,
8H, e(CH2)4e), 2.34 (br s, OH, 1H), 3.26 (s, 1H, H5), 3.55
(d, J¼13.1 Hz, 1H, NeCH2), 3.68 (d, J¼13.1 Hz, 1H, Ne
CH2), 3.75e3.86 (m, J¼5.46 Hz, 2H, H7, H70), 3.85 (s, 6H,
2ꢂOMe), 4.35 (t, J¼5.09 Hz, 1H, H4), 6.73e7.78 (m, 13H,
H arom); 13C NMR (125 MHz, CDCl3): d 19.2 (C(CH3)3),
23.9 (eCH2CH2e), 24.3 (eCH2CH2e), 26.8 (C(CH3)3),
36.6 (eCH2COHCH2e), 37.1 (eCH2COHCH2e), 46.9 (C1),
50.6 (NeCH2), 52.2 (C5), 55.9 (2ꢂOMe), 64.4 (C7), 73.8
4.9.12. (1S,4S,5S )-6-(3,4-Dimethoxybenzyl)-1-((E )-1-
hydroxy-3-phenylallyl)-4-(trityloxymethyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (23a)
Using general method A and trans-cinnamaldehyde (72 mL,
0.57 mmol) as the electrophile, compound 23a was obtained
from 14a as a yellow oil in 28% yield (30 mg, 0.046 mmol)
after flash chromatography (EtOAc/heptane 3:7) of the crude
product. Only one diastereoisomer of the 1:1 mixture was iso-
lated for characterization (15 mg, 0.023 mmol). Rf 0.55
(EtOAc/heptane 1:1); IR (film, cmꢀ1): 3410, 2955, 2932,
1730, 1674, 1516, 1448, 1264, 1237, 1138, 1026, 747, 764,
1
632; H NMR (300 MHz, CDCl3): d 3.28 (s, 1H, H5), 3.36
(dd, J¼5.5, 9.5 Hz, 1H, H7), 3.44 (dd, J¼5.5, 9.4 Hz, 1H,

M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
429
(eCH2COHCH2e), 78.6 (C4), 111.0 (C40), 111.9 (C50), 120.8
(C60), 127.8, 129.9 (CH arom), 132.5 (C10), 132.6 (Cq arom),
135.6 (CH arom), 148.5 (C30), 149.0 (C40), 171.1 (C]O);
HREIMS m/z calcd for C35H43NO6SiNaþ [MþNa]þ:
624.2757, found 624.2749.
(Cq, CPh3), 148.7 (C30), 149.1 (C40), 170.1 (C]O); HREIMS
m/z calcd for C38H41NO6Naþ [MþNa]þ: 630.2832, found
630.2794.
Using general method
B and 3-pentanone (54 mL,
0.51 mmol) as the electrophile, compound 26a (23 mg,
0.038 mmol) was obtained from 16a as a colorless oil in
22% yield (30% yield based on recovery of starting material)
after flash chromatography (EtOAc/heptane 3:7) of the crude
product and was identical in all respects to the product pre-
pared by method A.
4.9.15. (1S,4S,5S )-6-(3,4-Dimethoxybenzyl)-1-
(1-hydroxycyclohexyl)-4-(trityloxymethyl)-3-
oxa-6-azabicyclo[3.1.0]hexan-2-one (25a)
Using general method A and cyclohexanone (60 mL,
0.58 mmol) as the electrophile, compound 25a (54 mg,
0.087 mmol) was obtained from 14a as a white solid in 45%
yield (56% yield based on recovery of starting material) after
flash chromatography (EtOAc/heptane 3:7) of the crude prod-
uct. Rf 0.55 (EtOAc/heptane 1:1); [a]2D0 þ19.1 (c 1.00, CHCl3);
IR (film, cmꢀ1): 3483, 2932, 2863, 1748, 1513, 1446, 1259,
4.9.17. (1S,4S,5S )-4-((tert-Butyldiphenylsilyloxy)methyl)-6-
(3,4-dimethoxybenzyl)-1-(3-hydroxypentan-3-yl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (26b)
Using general method
A and 3-pentanone (61 mL,
0.58 mmol) as the electrophile, compound 26b (41 mg,
0.068 mmol) was obtained from 14b as a colorless oil in 35%
yield (40% yield based on recovery of starting material) after
flash chromatography (EtOAc/heptane 3:7) of the crude prod-
uct. Rf 0.60 (EtOAc/heptane 1:1); [a]2D0 ꢀ15.9 (c 0.50,
CHCl3); IR (film, cmꢀ1): 3493, 2932, 2857, 1766, 1681, 1589,
1514, 1462, 1427, 1265, 1427, 1265, 1237, 1135, 1105, 1057,
1
1029, 762, 707, 631; H NMR (300 MHz, CDCl3): d 0.8e
1.71 (m, e(CH2)5e, 10H), 3.19 (s, 1H, H5), 3.37 (d,
J¼5.2 Hz, 2H, H7, H70), 3.54 (d, J¼13.2 Hz, 1H, NeCH2),
3.65 (d, J¼13.2 Hz, 1H, NeCH2), 3.87 (s, 6H, 2ꢂOCH3),
4.35 (t, J¼5.0 Hz, 1H, H4), 6.77e7.40 (m, 18H, H arom);
13C NMR (75 MHz, CDCl3): d 21.0, 25.4, 32.8, 33.3
(COH(CH2)5e), 46.4 (C1), 50.6 (NeCH2), 54.2 (C5), 55.9
(2ꢂOCH3), 64.0 (C7), 68.1 (COH(CH2)5e), 72.7 (C4), 87.7
(CPh3), 111.1 (C20), 112.0 (C30), 121.0 (C60), 127.3, 128.0,
128.7 (CH arom), 129.9 (C10), 143.1 (Cq, CPh3), 148.6
(C30), 149.0 (C40), 170.6 (C]O); HREIMS m/z calcd for
C39H41NO6Naþ [MþNa]þ: 642.2832, found 642.2842.
1
1026, 822, 700; H NMR (300 MHz, CDCl3): d 0.79, 0.84
(2ꢂt, J¼7.5 Hz, 4H, COH(CH2CH3)2), 1.05 (s, 9H, C(CH3)3),
1.68, 1.82 (m, 4H, COH(CH2CH3)2), 3.27 (s, 1H, H5), 3.46 (d,
J¼13.8 Hz, 1H, NeCH2), 3.74 (dd, J¼6.8, 10.9 Hz, H7), 3.86
(m, 1H, NeCH2), 3.88 (dd, J¼7.5 Hz, 1H, H70), 6.87e7.66
(m, 13H, H arom); 13C NMR (75 MHz, CDCl3): d 7.6
(COH(CH2CH3)2), 19.1 (C(CH3)3), 26.8 (C(CH3)3), 29.3
(COH(CH2CH3)2), 45.5 (C1), 49.8 (NeCH2), 52.6 (C5), 55.9
(2ꢂOCH3), 63.9 (C7), 70.6 (COH(CH2CH3)2), 73.6 (C4),
111.1 (C40), 111.4 (C50), 120.4 (C60), 127.7, 127.9, 129.8,
130.0 (CH arom), 132.3 (C10), 135.5 (Cq arom), 148.5 (C30),
149.1 (C40), 170.0 (C]O); HREIMS m/z calcd for
C35H45NO6SiNaþ [MþNa]þ: 626.2908, found 626.2908.
Using general method B and cyclohexanone (52 mL,
0.50 mmol) as the electrophile, compound 25a (32 mg,
0.026 mmol) was obtained from 16a in 30% yield (43% yield
based on recovery of starting material) after flash chromato-
graphy (EtOAc/heptane 3:7) of the crude product and was
identical in all respects to the product prepared by method A.
4.9.16. (1S,4S,5S )-6-(3,4-Dimethoxybenzyl)-1-
(3-hydroxypentan-3-yl)-4-(trityloxymethyl)-3-
oxa-6-azabicyclo[3.1.0]hexan-2-one (26a)
4.9.18. (1S,4S,5R)-6-(3,4-Dimethoxybenzyl)-1-
(phenylsulfonyl)-4-(trityloxymethyl)-3-oxa-6-
Using general method
A
and 3-pentanone (60 mL,
azabicyclo[3.1.0]hexan-2-one (27a)
0.58 mmol) as the electrophile, compound 26a (76 mg,
0.13 mmol) was obtained from 14a as a colorless oil in 33%
yield (45% yield based on recovery of starting material) after
flash chromatography (EtOAc/heptane 3:7) of the crude prod-
uct. Rf 0.60 (EtOAc/heptane 1:1); [a]2D0 ꢀ12.6 (c 2.00, CHCl3);
IR (film, cmꢀ1): 3511, 2928, 2876, 1765, 1681, 1593, 1514,
1448, 1263, 1236, 1155, 1137, 1057, 1027, 763, 746, 704;
1H NMR (300 MHz, CDCl3): d 0.73, 0.83 (2ꢂt, J¼7.8 Hz,
6H, COH(CH2CH3)2), 1.58 (m, 4H, COH(CH2CH3)2), 3.23
(s, 1H, H5), 3.29 (dd, J¼6.6, 9.8 Hz, 1H, H7), 3.51 (dd,
J¼5.7, 9.8 Hz, 1H, H70), 3.53 (d, J¼13.1 Hz, 1H, NeCH2),
3.82 (d, J¼13.1 Hz, 1H, NeCH2), 3.91 (s, 6H, 2ꢂOMe), 4.4
(t, J¼6.3 Hz, 1H, H4), 6.81e7.60 (m, 18H, H arom); 13C
NMR (75 MHz, CDCl3): d 7.5, 7.8 (COH(CH2CH3)2), 29.1,
29.3 (COH(CH2CH3)2), 45.9 (C1), 49.8 (NeCH2), 52.4
(C5), 56.0 (2ꢂOMe), 63.7 (C7), 70.6 (COH(CH2CH3)2),
72.5 (C4), 87.5 (CPh3), 111.2 (C20), 111.5 (C50), 120.5
(C60), 127.4, 128.0, 128.6 (CH arom), 129.9 (C10), 143.1
Using general method A and benzenesulfonyl fluoride
(69 mL, 0.58 mmol) as the electrophile, compound 27a
(63 mg, 0.095 mmol) was obtained from 14a as a white solid
in 50% yield (62% yield based on recovery of starting material)
after flash chromatography (EtOAc/heptane 3:7) of the crude
product. Rf 0.45 (EtOAc/heptane 1:1); IR (film, cmꢀ1): 3060,
2927, 1778, 1593, 1515, 1448, 1330, 1266, 1239, 1155, 1063,
1
1027, 750, 704, 632; H NMR (300 MHz, CDCl3): d 3.23 (s,
1H, H5), 3.45 (dd, J¼4.0, 10.9 Hz, H7), 3.62 (dd, J¼4.3,
10.9 Hz, 1H, H70), 3.85 (s, 6H, 2ꢂOMe), 4.34 (t, J¼4.3 Hz,
1H, H4), 6.45e7.75 (m, 23H, H arom); HREIMS m/z calcd
for C39H35NO7SNaþ [MþNa]þ: 684.2032, found 684.2041.
Using general method B and benzenesulfonyl fluoride
(61 mL, 0.51 mmol) as the electrophile, compound 27a (17 mg,
0.026 mmol) was obtained from 16a in 15% yield (32% yield
based on recovery of starting material) after flash chromatogra-
phy (EtOAc/heptane 3:7) of the crude product and was identical
in all aspects to the product prepared by method A.

430
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
4.9.19. (1S,4S,5R)-6-(3,4-Dimethoxybenzyl)-1-
(tri-n-butylstannyl)-4-(trityloxymethyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (28a)
4.9.21. (1S,4S,5R)-6-(3,4-Dimethoxybenzyl)-1-iodo-4-
(trityloxymethyl)-3-oxa-6-azabicyclo[3.1.0]hexan-
2-one (29a)
Using general method
A
and n-Bu3SnCl (157 mM,
Using general method A and iodine (145 mg, 0.57 mmol)
as the electrophile, compound 29a (32 mg, 0.049 mmol) was
obtained from 14a as a white solid in 25% yield (41% based
on recovery of starting material) after flash chromatography
(EtOAc/heptane 3:7) of the crude product. Rf 0.65 (EtOAc/
heptane 1:1); [a]2D0 ꢀ0.2 (c 0.50, CHCl3); mp¼157e159 ꢁC;
IR (film, cmꢀ1): 2931, 1774, 1681, 1593, 1514, 1447, 1418,
1331, 1263, 1155, 1023, 999, 761, 703, 631; 1H NMR
(300 MHz, CDCl3): d 2.90 (s, 1H, H5), 3.19 (dd, J¼2.4,
11.0 Hz, 1H, H7), 3.67 (dd, J¼2.47, J¼11.5 Hz, 1H, H70),
3.67 (d, J¼13.8 Hz, 1H, NeCH2), 3.72 (d, J¼14.0 Hz, 1H,
NeCH2), 3.86, 3.88 (2ꢂs, 6H, 2ꢂOCH3), 4.43 (t, J¼2.5 Hz,
1H, H4), 6.77e7.56 (m, 18H, H arom); 13C NMR (75 MHz,
CDCl3): d 46.7 (C1), 49.8 (NeCH2), 53.3 (C5), 55.9, 56.0
(2ꢂOMe), 62.8 (C7), 87.3 (CPh3), 111.1 (C20), 111.5 (C50),
120.3 (C60), 127.3, 128.0, 128.7 (CH arom), 143.0
(Cq, CPh3), 148.6 (C30), 149.1 (C40), 192.5 (C]O); HREIMS
m/z calcd for C33H30INO5Naþ [MþNa]þ: 670.1061, found
670.1077.
0.58 mmol) as the electrophile, the crude product obtained
from 14a was first purified by passage through a small column
comprising 10% w/w of finely ground KF and 90% w/w of silica
gel, developed with CH2Cl2 to remove organotin impurities and
then with EtOAc to elute the product.21 Flash chromatography
of the latter (EtOAc/heptane 1:9) afforded compound 28a
(75 mg, 0.093 mmol) as a colorless oil in 55% yield. Rf 0.60
(EtOAc/heptane 1:4); [a]2D0 þ22.6 (c 1.50, CHCl3); IR (film,
cmꢀ1): 2953, 2922, 1754, 1592, 1513, 1448, 1263, 1154,
1074, 1029, 761, 703, 631; 1H NMR (300 MHz, CDCl3):
d 0.80e0.91 (m, 9H, 3ꢂ(CH2)2CH3), 0.93e1.54 (m, 18H,
3ꢂ(CH2)2CH3), 2.80 (s, 1H, H5), 3.11 (dd, J¼6.8, 9.8 Hz, 1H,
H7), 3.28 (d, J¼13.4 Hz, 1H, NeCH2), 3.37 (dd, J¼6.8,
9.8 Hz, 1H, H70), 3.76 (d, 1H, NeCH2), 3.90 (m, 6H,
2ꢂOCH3), 4.56 (dd, J¼5.09, 6.41 Hz, 1H, H4), 6.74e7.78
(m, 18H, H arom); 13C NMR (75 MHz, CDCl3): d 9.4, 11.0,
13.5 (3ꢂ(CH2)3CH3), 27.2, 28.7, 28.8, 28.9, 29.6 (3ꢂ
(CH2)3CH3), 40.5 (C1), 48.4 (NeCH2), 51.4 (C5), 55.8, 55.9
(2ꢂOCH3), 63.7 (C7), 79.3 (C4), 87.1 (CPh3), 110.8 (C20),
111.1 (C50), 119.6 (C60), 127.3, 127.9, 128.6 (CH arom),
130.6 (C10), 143.4 (Cq, CPh3), 148.4 (C30), 149.2 (C40), 176.9
(C]O); HREIMS m/z calcd for C45H57NO5SnNaþ [MþNa]þ:
834.3156, found 834.3149.
Using general method B and iodine (129 mg, 0.51 mmol)
as the electrophile, compound 29a (11 mg, 0.017 mmol) was
obtained from 16a as a white solid in 10% yield (16% based
on recovery of starting material) after flash chromatography
(EtOAc/heptane 3:7) of the crude product and was identical
in all respects to the product prepared by method A.
4.9.20. (1S,4S,5R)-4-((tert-Butyldiphenylsilyloxy)methyl)-6-
(3,4-dimethoxybenzyl)-1-(tri-n-butylstannyl)-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (28b)
4.9.22. (1S,4S,5R)-6-Benzyloxycarbonyl-4-((tert-
butyldiphenylsilyloxy)methyl)-1-(trimethylsilyl)-3-
Using general method
A
and n-Bu3SnCl (157 mL,
oxa-6-azabicyclo[3.1.0]hexan-2-one (30)
0.58 mmol) as the electrophile, the crude product obtained
from 14b was first purified by passage through a small column
comprising 10% w/w of finely ground KF and 90% w/w of silica
gel, developed with CH2Cl2 to remove organotin impurities and
then with EtOAc to elute the product. Flash chromatography of
the latter (EtOAc/heptane 1:9) afforded compound 28b (61 mg,
0.075 mmol) as a colorless oil in 45% yield (48% yield based on
recovery of starting material). Rf 0.65 (EtOAc/heptane 1:4);
[a]2D0 þ26.4 (c 1.00, CHCl3); IR (film, cmꢀ1): 2953, 2929,
2854, 1756, 1515, 1463, 1427, 1337, 1264, 1236, 1111, 1030,
823; 1H NMR (300 MHz, CDCl3): d 0.75e0.91 (m, 9H,
3ꢂ(CH2)2CH3), 0.93e1.60 (m, 18H, 3ꢂ(CH2)2CH3), 1.05 (s,
9H, C(CH3)3), 2.88 (s, 1H, H5), 3.27 (d, J¼13.4 Hz, 1H, Ne
CH2), 3.56 (dd, J¼7.7, 10.6 Hz, 1H, H7), 3.76 (d, 1H, Ne
CH2), 3.81 (dd, J¼4.9, 10.6 Hz, 1H, H70), 3.88 (2ꢂs, 6H,
2ꢂOCH3), 4.50 (dd, J¼4.9, 7.7 Hz, 1H, H4), 6.74e7.72 (m,
18H, H arom); 13C NMR (75 MHz, CDCl3): d 9.4, 11.0, 13.5
(3ꢂ(CH2)3CH3), 19.2 (C(CH3)3), 26.8 (C(CH3)3), 27.2, 27.6,
28.7, 28.8, 29.0 (3ꢂ(CH2)3CH3), 40.3 (C1), 48.2 (NeCH2),
51.4 (C5), 55.9 (2ꢂOCH3), 63.7 (C7), 80.0 (C4), 110.8 (C20),
111.1 (C50), 119.6 (C60), 127.8, 127.8, 129.9 (CH arom),
130.6 (C10), 132.6, 132.8 (Cq arom), 148.3 (C30), 149.1 (C40),
176.9 (C]O); HREIMS m/z calcd for C42H61NO5SiSnNaþ
[MþNa]þ: 830.3239, found 830.3260.
To a solution of 16b (188 mg, 0.32 mmol) in CH2Cl2
(3.2 mL) and H2O (0.32 mL) was added DDQ (73 mg,
0.32 mmol) at room temperature. After 8 h of stirring, pyridine
(0.38 mL, 3.7 mmol), benzylchloroformate (91 mL, 0.64 mmol),
and DMAP (8 mg, 0.06 mmol) were added. After 15 h, the
mixture was diluted in CH2Cl2 (3 mL) and an aqueous solu-
tion of HCl 10% (5 mL) was added. The organic phase was
washed successively with water (2ꢂ5 mL) and with a satu-
rated aqueous solution NaHCO3 (5 mL), dried over MgSO4,
filtered, and evaporated in vacuo. The crude product was pu-
rified by flash chromatography (EtOAc/heptane 1:5) to afford
30 (38 mg, 0.07 mmol, 21%) as a colorless oil. Rf 0.7
(EtOAc/heptane 2:3); [a]2D0 þ25 (c 0.9, CHCl3); IR (film,
cmꢀ1): 3071, 2958, 2858, 1777 (C]O lactone), 1730
(C]O carbamate), 1264, 1196, 844, 700; 1H NMR
(300 MHz, CDCl3): d 0.07 (s, 9H, Si(CH3)3), 1.03 (s, 9H,
OSiC(CH3)3), 3.46 (s, 1H, H5), 3.68, 3.76 (2H,
J7,7¼11.3 Hz, J7,4¼3.6 Hz, H7, H70), 4.69 (m, 1H, H4),
5.09 (2H, J¼12.2 Hz, CH2Ph), 7.15e7.62 (m, 15H, H
arom); 13C NMR (75 MHz, CDCl3): d ꢀ3.5 (Si(CH3)3),
19.3 (OSiC(CH3)3), 26.9 (2ꢂSiC(CH3)3), 39.5 (C1), 46.7
(C5), 64.1 (C7), 68.9 (CH2Ar), 75.3 (C4), 127.9, 128.1,
128.5, 128.6, 130.1, 132.4, 135.0, 135.1, 135.5 (Cq arom),
158.9 (C]O carbamate), 171.7 (C]O lactone); HREIMS

M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
431
m/z calcd for C32H39NO5Si2Naþ [MþNa]þ: 596.2265, found
43.3 (C5), 64.3 (C7), 78.7 (C4), 127.9, 130.0, 132.6, 135.5
(Cq arom), 171.9 (C]O lactone); HREIMS m/z calcd for
C24H33NO3Si2Naþ [MþNa]þ: 462.1897, found 462.1904.
596.2228.
4.9.23. (1R,4S,5S )-1-Benzyl-6-benzyloxycarbonyl-
4-((tert-butyldiphenylsilyloxy)methyl)-3-oxa-6-
4.9.25. (1R,4S,5S )-1-Benzyl-6-benzyloxycarbonyl-4-
azabicyclo[3.1.0]hexan-2-one (31)
(hydroxymethyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-
one (34)
A solution of aziridine 18b (860 mg, 1.65 mmol) and DDQ
(449 mg, 1.98 mmol) in a 10:1 mixture of CH2Cl2 (60 mL) and
water (6 mL) was stirred for 24 h at room temperature. Pyridine
(269 mL, 3.30 mmol), benzyl chloroformate (469 mL,
3.30 mmol), and DMAP (40 mg, 0.33 mmol) were then succes-
sively added. The reaction mixture was stirred for 2 h at room
temperature and CH2Cl2 (10 mL) was added followed by aque-
ous 10% v/v HCl (20 mL). The aqueous layer was separated
and the organic layer was washed successively with aqueous
10% v/v of HCl (30 mL), saturated aqueous NaHCO3
(30 mL), and water (30 mL). The organic phase was dried
over MgSO4 and evaporated to dryness under vacuum. The re-
sulting residue was purified by column chromatography on sil-
ica gel (EtOAc/heptane 2:8) affording compound 31 (829 mg,
2.57 mmol) in 85% yield as a colorless oil. Rf 0.55 (EtOAc/hep-
tane 3:7); [a]2D0 ꢀ35.6 (c 0.70, CHCl3); IR (film, cmꢀ1): 3031,
2928, 2856, 1786 (C]O lactone), 1728 (C]O carbamate),
1426, 1379, 1227, 1103, 1055, 697; 1H NMR (300 MHz,
CDCl3): d 1.12 (s, 9H, C(CH3)3), 3.19 (d, J¼14.7 Hz, 1H,
CH2Ph), 3.24 (s, 1H, H5), 3.45 (d, J¼14.7 Hz, 1H, CH2Ph),
3.72 (dd, J¼2.3, 11.9 Hz, 1H, H7), 3.87 (dd, J¼4.0, 11.3 Hz,
1H, H70), 4.69 (t, J¼2.6 Hz, 1H, H4), 5.13 (d, J¼13.0 Hz,
1H, CH2 carbamate), 5.19 (d, J¼13.0 Hz, 1H, CH2 carbamate),
7.10e7.71 (m, 20H, H arom); 13C NMR (75 MHz, CDCl3):
d 19.2 (C(CH3)3), 26.8 (C(CH3)3), 31.8 (C5), 45.6 (CH2Ph),
48.3 (C1), 63.6 (C7), 68.9 (CH2 carbamate), 74.8 (C4), 127.0,
127.5, 127.8, 128.4, 130.0, 130.1, 131.8, 132.6, 134.6, 134.8,
135.4 (Cq, CH arom), 135.6 (Cq, Bn), 158.1 (C]O carbamate),
170.2 (C]O lactone); HREIMS m/z calcd for C36H37NO5-
SiNaþ [MþNa]þ: 614.2339, found 614.2366.
Aziridine 31 (240 mg, 0.406 mmol) was dissolved in anhy-
drous THF (5 mL) and a solution of TBAF in THF (1 M,
608 mL, 0.608 mmol) was added at ꢀ20 ꢁC under argon. The
reaction mixture was stirred for 2 h and then allowed to warm
to room temperature over 1 h. The mixture was washed succes-
sively with saturated aqueous NaHCO3 (2ꢂ20 mL) and satu-
rated aqueous NaCl (2ꢂ20 mL). The organic layer was dried
over anhydrous MgSO4, filtered, and the solvent was removed
in vacuo. The crude product was then purified by chromatogra-
phy on silica gel (EtOAc/heptane 7:3) affording compound 34
in 68% yield (95 mg, 0.179 mmol) as a white solid. Rf 0.30
(EtOAc/heptane 1:1); [a]2D0 ꢀ72.9 (c 0.50, CHCl3); mp 115e
117 ꢁC; IR (film, cmꢀ1): 3448, 3062, 3032, 2961, 1789 (C]O
lactone), 1718 (C]O carbamate), 1494, 1408, 1268, 1224,
1
1165, 1073, 693; H NMR (300 MHz, CDCl3): d 3.32 (s, 1H,
H5), 3.24 (d, J¼14.7 Hz, 1H, CH2Ph), 3.40 (d, J¼14.7 Hz, 1H,
CH2Ph), 3.67 (dd, J¼2.4, 12.5 Hz, 1H, H7), 3.90 (dd, J¼3.0,
12.6 Hz, 1H, H70), 4.69 (t, J¼2.8 Hz, 1H, H4), 5.13 (d,
J¼12.2 Hz, 1H, CH2 carbamate), 5.20 (d, 1H, J¼12.1 Hz, CH2
carbamate), 7.17e7.48 Hz (m, 10H, H arom); 13C NMR
(75 MHz, CDCl3): d 32.1 (CH2, Bn), 45.5 (C5), 48.7 (C1),
62.1 (CH2OH), 69.0 (CH2 carbamate), 75.5 (C4), 127.1, 128.3,
128.6, 130.0 (CH arom), 134.3 (Cq, Bn), 134.7 (Cq carbamate),
158.4 (C]O carbamate), 170.8 (C]O lactone); HREIMS m/z
calcd for C20H19NNaOþ5 [MþNa]þ: 376.1161, found 376.1143.
4.9.26. (1R,4S,7R)-1-Benzyl-7-benzyloxycarbonylamino-
2,5-dioxabicyclo[2.2.1]heptan-6-one (35)
To a solution of compound 34 (50 mg, 0.141 mmol) in
CH3CN (14.1 mL, 0.01 M) at 0 ꢁC under argon was added
BF3$OEt2 (20 mL, 0.156 mmol). The reaction mixture was
warmed to room temperature and stirred for 4 h. The mixture
was washed successively with saturated aqueous NaHCO3
(2ꢂ10 mL) and saturated aqueous NaCl (2ꢂ10 mL), the or-
ganic layer was dried over anhydrous MgSO4, filtered, and
the solvent was removed in vacuo. The crude product was pu-
rified by chromatography on silica gel (EtOAc/heptane 2:8) af-
fording the bicyclic lactone 35 in 56% yield (27 mg,
0.057 mmol) as a colorless oil. Rf 0.60 (EtOAc/heptane 1:1);
[a]2D0 ꢀ47.8 (c 0.55, CHCl3); IR (film, cmꢀ1): 3379 (fine
band, NH), 2959, 2924, 1799 (C]O lactone), 1722 (C]O
4.9.24. (1S,4S,5R)-4-((tert-Butyldiphenylsilyloxy)methyl)-1-
(trimethylsilyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (32)
To a solution of 30 (78 mg, 0.14 mmol) in thiophenol
(0.6 mL) was added boron trifluoride etherate (17 mL,
0.14 mmol) at 0 ꢁC under argon. The reaction mixture was
then gradually allowed to reach room temperature under con-
stant stirring. After 4 days, the solution was diluted with EtOAc
(5 mL) and neutralized with a 10% aqueous NaHCO3 solution.
After separation of the phases, the aqueous phase was extracted
with EtOAc (2ꢂ5 mL). The combined organic phases were
dried over MgSO4, filtered, and evaporated in vacuo. The crude
oil obtained was purified by flash chromatography (EtOAc/hep-
tane 6:1) to give 32 (21 mg, 0.05 mmol, 35%) as a colorless oil.
Rf 0.3 (EtOAc/heptane 1:2); IR (film, cmꢀ1): 3266 (NH), 3071,
2956, 2930, 2857, 1762 (C]O lactone), 1250, 1114, 844, 701;
1H NMR (300 MHz, CDCl3): d 0.11 (s, 9H, Si(CH3)3, 1.07 (s,
9H, OSi(CH3)3), 3.13 (s, 1H, H5), 3.64, 3.83 (2H, J¼10.9, 6.4,
4.1 Hz, H7, H70), 4.48 (dd, 1H, J¼6.3, 4.1 Hz, H4), 7.36e7.67
(m, 10H, H arom); 13C NMR (75 MHz, CDCl3): d ꢀ3.1
(Si(CH3)3), 19.3 (OSiC(CH3)3), 26.9 (SiC(CH3)3), 31.5 (C1),
1
carbamate), 1515, 1244, 1142, 1023, 980, 895, 744, 696; H
NMR (300 MHz, C6D6): d 2.97 (d, J¼15.0 Hz, 1H, CH2Ph),
3.04 (br d, J¼8.2 Hz, 1H, H5), 3.15 (d, J¼9.2 Hz, 1H, H50),
3.34 (d, J¼15.0 Hz, 1H, 1H, CH2Ph), 3.83 (sl, 1H, H7), 4.09
(s, 1H, H4), 4.59 (br s, 1H, NH), 5.06 (s, 2H, CH2 carbamate),
7.10e7.44 (m, 10H, H arom); 13C NMR (75 MHz, C6D6):
d 31.6 (CH2, Bn), 60.3 (C7), 67.4 (CH2 carbamate), 68.2
(C5), 80.1 (C4), 83.3 (C1), 127.8, 128.0, 128.2, 128.3,
128.7, 130.8, 134.5 (Cq Bn), 136.4 (Cq carbamate), 155.4

432
M.S. Valle et al. / Tetrahedron 64 (2008) 419e432
8. Tarrade, A.; Dauban, P.; Dodd, R. H. J. Org. Chem. 2003, 68, 9521e9524.
9. (a) Dauban, P.; De Saint-Fuscien, C.; Dodd, R. H. Tetrahedron 1999, 55,
´
7589e7600; (b) Dauban, P.; De Saint-Fuscien, C.; Acher, F.; Prezeau, L.;
(C]O carbamate), 171.5 (C]O lactone); HREIMS m/z calcd
for C20H19NNaOþ5 [MþNa]þ: 376.1161, found 376.1135.
Brabet, I.; Pin, J.-P.; Dodd, R. H. Bioorg. Med. Chem. Lett. 2000, 10,
129e133.
10. Manuscript submitted for publication.
Acknowledgements
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59, 434e441; (b) Dauban, P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd,
R. H. J. Org. Chem. 1995, 60, 2035e2043; (c) Dauban, P.; Chiaroni,
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12. De Saint-Fuscien, C.; Tarrade, A.; Dauban, P.; Dodd, R. H. Tetrahedron
Lett. 2000, 41, 6393e6397.
We thank the Institut de Chimie des Substances Naturelles
and the French Ministry of Education for fellowships (M.S.V.
and A.T.M.).
References and notes
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