A synthetic view of an analogue of the spiro-β-lactone-γ-lactam ring in oxazolomycins and lajollamycin

Article abstract of DOI:10.1055/s-0030-1257872

Herein, we describe a new synthetic strategy towards an analogue of the spiro-β-lactone-γ-lactam ring found in a class of potent antibiotics, the oxazolomycins and lajollamycin. The synthetic idea relies on the construction of two rings (β-lactone and pyr

Full text of DOI:10.1055/s-0030-1257872

PAPER
3301
A Synthetic View of an Analogue of the Spiro-b-lactone-g-lactam Ring in
Oxazolomycins and Lajollamycin
Dhananjoy Mondal,* Smritilekha Bera
Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
Fax +91(20)25902629; E-mail: dhananjoym@yahoo.com
Received 23 March 2010; revised 12 May 2010
lactam-based antibiotics, which have hitherto remained
clinically unexamined. In addition, it is obvious that the
bioactivities of the analogues change with substitution at
the b-lactone and oxazoline rings as well as changes in the
Abstract: Herein, we describe a new synthetic strategy towards an
analogue of the spiro-b-lactone-g-lactam ring found in a class of po-
tent antibiotics, the oxazolomycins and lajollamycin. The synthetic
idea relies on the construction of two rings (b-lactone and pyrrolid-
inone). The formation of the spiro-b-lactone was accomplished by E,Z-isomer in the triene moiety. These intriguing structur-
a crossed Cannizzaro reaction, while the 3,4-disubstituted pyrrolid-
al features together with the important bioactivities moti-
inone ring was constructed by a titanium(IV) chloride mediated
vated us to synthesize a new analogue with more potent
chelation-controlled double stereodifferentiating Crimmins aldol
and selective bioactivities. To date, the total synthesis of
reaction of Garner’s aldehyde.
1 has not yet been accomplished, although the only two
Key words: Garner’s aldehyde, pyrrolidine, crossed Cannizzaro
reaction, Crimmins aldol reaction, lactones, Mitsunobu reaction
total syntheses of neooxazolomycin have been reported in
the literature: one by Kende et al. in 1990 and the other by
Hatakeyama et al. in 2007.8 Most studies have focused on
the left and middle segments,9 while we10 and others11
The severe resistance of many organisms against tradi-
tional antibiotics is explosively intensifying in the medic-
have focused on the synthesis of the spiro-b-lactone-g-
lactam unit (Figure 2). Additional research needs to be
inal fields; this requires a daunting commitment from
pursued to install the requisite functionalities on the pyr-
academic and industrial laboratories to maintain the flow
of new classes of antibiotics in the market. One such class
of compounds is the novel spiro-b-lactone-g-lactam group
of antibiotics. This unusual class of compounds, the ox-
azolomycins, lajollamycin, and their analogues contain-
ing a spiro-b-lactone-g-lactam ring, are current synthetic
targets for determining details of the biological mode of
rolidine ring and modulate their behavior while forming
the spiro-bicyclic b-lactone-g-lactam system. To investi-
R1
O
N
action and studies of structure–activity relationships
8'
(SAR). Oxazolomycins 1 (Figure 1),1 first isolated from a
2 R3
5'
strain of Streptomyces in 1985 by Mori et al.,2 make up a
wider class of potent antibiotic compounds with inhibito-
ry activity against Gram-positive bacteria, antiviral activ-
ity against vaccinia, herpes simplex type I, and influenza
A (WSN; H1N1), as well as in vivo antitumor activity.3 In
addition, their analogues 16-methyloxazolomycin,4 curro-
mycin A and B,5 and KSM-26906 (Figure 1) are also re-
ported to be potent antibiotics. Lajollamycin (2),7 which
has been isolated more recently in 2005, is a new member
of a class of oxazolomycins showing activity against both
drug-sensitive and -resistant Gram-positive bacteria and
B16-F10 tumor cells. Although these compounds possess
a similar structural backbone, differing only at the oxazo-
line ring, the geometry of the triene moiety, or at the b-lac-
tone ring, these differences lead to different activities of
the analogues of oxazolomycins and lajollamycin.
4'
R
O
7'
MeO
O
O
6'
16
1'
HO
N
N
O
3
Me
5
HO
11
OH
1
oxazolomycin A (1a): R1 = H, R2 = H, R3 = H; 4'Z,6'Z,8'E
oxazolomycin B (1b): R1 = H, R2 = H, R3 = H; 4'E,6'E,8'E
oxazolomycin C (1c): R1 = H, R2 = H, R3 = H; 4'Z,6'E,8'E
16-methyloxazolomycin (1c): R1 = H, R2 = H, R3 = Me; 4'Z,6'Z,8'E
curromycin A (1d): R1 = Me, R2 = MOM, R3 = H; 4'Z,6'Z,8'E
curromycin B (1e): R1 = Me, R2 = H, R3 = Me; 4'Z,6'Z,8'E
KSM-2690 B (1f): R1 = H, R2 = H, R3 = Me; 4'Z,6'Z,8'E
–
O
O
+
N
To explore a new class of antibiotics to alleviate the well-
known bacterial resistance, we are interested in develop-
ing a new strategy to synthesize novel spiro-b-lactone-g-
O
O
O
OH
MeO
HO
N Me
O
N
H
OH
lajollamycin (2)
SYNTHESIS 2010, No. 19, pp 3301–3308
x
x.
x
x
.
2
0
1
0
Advanced online publication: 22.07.2010
DOI: 10.1055/s-0030-1257872; Art ID: M02410SS
Figure 1 Structures of oxazolomycins (1a–f) and lajollamycin (2)
© Georg Thieme Verlag Stuttgart · New York

3302
D. Mondal, S. Bera
PAPER
Figure 2 Segments of oxazolomycin A
gate the above features, in the work reported in this paper hydroxymethylated cyclic carbamate derivative 6 due to
we have focused on the synthesis of an unnatural spiro-b- the reaction of formaldehyde from the least hindered side.
lactone-g-lactam analogue present in the oxazolomycins The b-lactone ring 5 could be appropriately derived from
and lajollamycin for the study of the structure–activity re- 6 by conversion of the remaining free primary alcohol into
lationship (SAR), intending to synthesize a more potent the carboxyl group followed by cleavage of the cyclic car-
antibiotic, whereas in our earlier communication the syn- bamate and b-lactone formation with the Mitsunobu reac-
thesis of the natural spiro-b-lactone-g-lactam core of ox- tion.15 Finally, the pyrrolidinone skeleton 4 could be
azolomycin was reported.10
realized by using Taylor’s oxidation11a strategy from
spiro-b-lactone pyrrolidine derivative 5 on treatment with
ruthenium tetroxide (Scheme 1).
These compounds could be envisioned as an assembly of
three parts, namely the polyene (left-hand), diene (mid-
dle), and spiro-b-lactone-g-lactam (right-hand) fragments In our earlier published results,16 the fate of titanium(IV)
(Figure 2). The crucial coupling between the diene and chloride mediated double stereodifferentiating Crimmins
right-hand part could be mediated by a Wittig reaction fol- aldol reaction of 4-benzyl-N-propionyloxazolidinone and
lowed by a Sharpless asymmetric dihydroxylation with an Garner’s aldehyde in different enantiomeric combinations
appropriate chiral catalyst that would ensure installation was thoroughly described. This double stereodifferentiat-
of the two hydroxy groups present at C3 and C4 in oxazo- ing aldol reaction offered a mixture of two different non-
lomycins. In contrast, a peptide coupling reaction could be Evans anti,anti- and syn,syn-diastereoisomers in case of a
expected to assemble the polyene and diene parts to com- ‘mismatching’ pair in good yield, while it produced only
plete the total synthesis of the oxazolomycin series of one Evans syn,syn-diastereomer in case of a ‘matching’
molecules (Figure 2).
combination of an enantiomeric pair of 4-benzyl-N-propi-
onyloxazolidinone (4R/4S) derivative and Garner’s alde-
hyde (R/S) with high diastereomeric selectivity.
Described in this article is a synthetic strategy for the
right-hand segment via successful use of a Crimmins aldol
reaction12 between (4R)-benzyl-N-propionyloxazolidi- For the synthesis of the unnatural (4R,7S,8R)-spiro-b-lac-
none13 used as chiral auxiliary and (S)-Garner’s tone-g-lactam core, we performed the Crimmins aldol re-
aldehyde14 as chiral substrate to construct the contiguous action of the chiral auxiliary 9 with Garner’s aldehyde 10
triad stereogenic centers in the 3,4-disubstituted prolinol in the presence of titanium(IV) chloride at 0 °C to obtain
intermediate 7 (Scheme 1). The precursor for the spiro-bi- two isomers 8 and 11 in a 2:3 ratio and a combined yield
cyclic b-lactone ring system could be obtained by utiliz- of 82% (Scheme 2). Much to our delight, isomer 8 crystal-
ing an aldol followed by a crossed Cannizzaro reaction lized out in 40% yield, leaving compound 11 as a liquid in
with formaldehyde at C2 in 7 to produce exclusively the solution. The structure of 8 was unambiguously con-
OBn
OBn
OBz
OBz
4
3
OH
OH
5
O
O
2
O
N
1 N
N
N
O
O
Boc
O
Boc
Boc
O
5
6
7
4
O
O
OH
O
O
O
O
N
H
O
O
N
+
O
N
N
Bn
Boc
Boc
Bn
9
10
8
Scheme 1 Retrosynthetic analysis of analogue of spiro-b-lactone-g-lactam moiety
Synthesis 2010, No. 19, 3301–3308 © Thieme Stuttgart · New York

PAPER
Spiro-b-lactone-g-lactam Ring in Oxazolomycins and Lajollamycin
3303
O
O
O
O
O
OH
O
O
OH
a
H
N
O
N
O
N
O
+
+
O
O
O
82%
N
N
N
Boc
Bn
Bn
Bn
Boc
Boc
9
10
8
11
Scheme 2 Reagents and conditions: (a) TiCl4 (1.1 equiv), DIPEA (2.5 equiv), CH2Cl2, 0 °C, 2 h, 82%.
firmed, not only by spectroscopic and elemental data, but the selective protection of diol 12 with tert-butyldimeth-
also by a single-crystal X-ray diffraction study (CCDC ylsilyl chloride and triethylamine in dichloromethane at
615731),16 which conclusively proved the stereochemical 0 °C generated silyl compound 13 in 92% yield. On treat-
assignments as non-Evans anti,anti-adducts, and the ste- ment with benzyl bromide and sodium hydride in dimeth-
reochemistry of the liquid 11 was also proved to be the ylformamide at 0 °C, silyl derivative 13 formed benzyl
non-Evans syn,syn-product in the earlier published pa- ether 14 in 88% yield. Deprotection of the silyl function-
per.16 The stereochemical outcome of this reaction is an ality of 14 by using tetrabutylammonium fluoride in tet-
addition to the anomalous instances of the Crimmins aldol rahydrofuran at 0 °C to room temperature provided 15 in
reaction, although we are aware of some prior literature 91% yield (Scheme 3). Subsequently, the resulting prima-
precedents of such double stereodifferentiating reac- ry hydroxy group was protected as tosyl ester 16 by reac-
tions.17 These anomalous results could be explained by in- tion with tosyl chloride and triethylamine in
dependent (complementary or opposing) influences of the dichloromethane. On exposure of tosyl ester 16 to p-tolu-
oxazolidinone derivative or Garner’s aldehyde on the enesulfonic acid–methanol, the isopropylidene moiety
course of the aldol reaction.
was removed; this was followed by in situ cyclization to
give the substituted pyrrolidine derivative 7 in 78% yield
over two steps (Scheme 3).
To demonstrate the novel use of this intermediate in the
synthesis of the analogue of the spiro-fused b-lactone-g-
lactam substructure present in oxazolomycins and lajolla- Compound 7 was then set to perform the crossed
mycin, we thought to explore first the aldol adduct 8, from Cannizzaro reaction18 at the C2 position (Scheme 3). The
which we could achieve the synthesis of a new analogue primary hydroxy functionality in compound 7 was oxi-
of the right-hand segment (Scheme 3). The reductive dized with 2-iodoxybenzoic acid (IBX) in dimethyl sulf-
cleavage of the oxazolidinone ring in 8 with in situ gener- oxide to afford aldehyde 17, which was successively
ated lithium borohydride obtained when using a mixture treated with 37% aqueous formaldehyde in the presence
of sodium borohydride and lithium chloride in a mixture of two molar sodium hydroxide solution for four days at
of absolute ethanol and tetrahydrofuran produced diol 12 ambient temperature; this gave a mixture of bicyclic car-
in excellent yield at ambient temperature. Subsequently, bamate 6 and gem-hydroxymethyl derivative 18 in a 9:1
O
OH
OBn
OH
O
OH
c
d
b
a
TBSO
TBSO
HO
O
N
O
O
O
O
N
N
N
N
Boc
Bn
Boc
Boc
Boc
12
13
14
8
OBn
OBn
OBn
OBn
g
h
e
f
OH
HO
TsO
O
O
CHO
N
N
N
N
Boc
Boc
Boc
Boc
15
16
7
17
NOE
OBn
H
OBn
H
OH
OH
+
N
OH
N
O
O
O
18
O
6
i
9:1
Scheme 3 Reagents and conditions: (a) LiCl, NaBH4, EtOH–THF (2:1), 0 °C to r.t., 7 h, 96%; (b) TBSCl, Et3N, DMAP (cat.), CH2Cl2, 0 °C,
6 h, 92%; (c) NaH, BnBr, DMF, 0 °C to r.t., 1 h, 88%; (d) TBAF, THF, 0 °C to r.t., 3 h, 91%; (e) TsCl, Et3N, DMAP, CH2Cl2, 0 °C, 6 h, 95%;
(f) PTSA, MeOH, r.t., 4 h, 78% (over two steps); (g) IBX, DMSO, THF, r.t., 4 h, 89% (crude); (h) HCHO, 2 N NaOH, THF–H2O (7:1), r.t., 4
d, 55% (combined yield); (i) 4 N NaOH, THF–MeOH (1:2), r.t., 4 h.
Synthesis 2010, No. 19, 3301–3308 © Thieme Stuttgart · New York

3304
D. Mondal, S. Bera
PAPER
ratio and a combined yield of 55%. Compound 18 was The final oxidation of 23 to the corresponding pyrrolidi-
then converted immediately into a single bicyclic carbam- none derivative 4 turned out to be a difficult proposition.
ate compound 6 in high diastereoselectivity in four hours The ruthenium(III) chloride–sodium periodate catalyzed
on treatment with four molar sodium hydroxide in a tet- oxidation,20 as described by Taylor, on 23 produced only
rahydrofuran–methanol mixture (Scheme 3). The struc- the O-benzoate derivative 5 after one hour, while a longer
ture of 6 was assigned on the basis of NOESY NMR reaction time provided an intractable mixture of products.
experiments. At a later stage, this key intermediate would The presence of two sets of signals in the 1H NMR spec-
help in the stereoselective formation of the b-lactone ring trum also supported the formation of two rotamers in
found in the oxazolomycin series of molecules. The ex- compound 5. The characteristic downfield shift (d = 5.86)
clusive formation of 6 could be explained by taking into of the H3-proton-bearing benzoate group in compound 5
1
account the strong steric hindrance imparted by the b-sub- was visible in the H NMR spectrum. Other literature
stituent present at the C3 and C4 positions, which strongly methods21 for the pyrrolidine–pyrrolidinone transforma-
biases the facial selectivity of the bicyclic system for re- tion did not succeed; in most of the cases starting material
action with formaldehyde at the least hindered face. As a was recovered. Although Taylor’s model compound did
result of this, the b-hydroxymethyl group at the C2 posi- provide 25%11a of the pyrrolidinone from the spiro-b-lac-
tion underwent cyclization, leaving an a-hydroxymethyl tone-based pyrrolidine derivative with ruthenium(III)
free in carbamate 6 (Scheme 3).
chloride–sodium periodate, we believe that in our case the
densely substituted pyrrolidine moiety spiro-fused with
an acid-labile b-lactone unit carrying an active methylene
group22 at the a-position of the oxygen atom in 23 pre-
cluded this oxidation step (Scheme 4).
The free hydroxymethyl group of 6 was then modified
into a carbomethoxy group in a two-step protocol involv-
ing successive Swern oxidation (oxalyl chloride, DMSO,
Et3N, CH2Cl2, –78 °C) of the primary hydroxy moiety
followed by treatment with bromine–methanol of the re- In conclusion, we have successfully developed a general
sulting aldehyde 19 to furnish the methyl ester 20 in a and flexible synthetic route for the epi-spiro-b-lactone-
combined yield of 80% over two steps (Scheme 4).19 Sub- based substituted pyrrolidine derivative 5, which will al-
sequent treatment of 20 with six molar sodium hydroxide low the synthesis not only of the natural products, but also
solution in ethanol hydrolyzed both the ester and the cy- their analogues for the understanding of their biological
clic carbamate ring to form amino alcohol 21 in good mode of action and the therapeutic potential of this class
yield. The secondary amine in compound 21 was then pro- of compounds. Constructing a pyrrolidinone ring at the
tected with a tert-butoxycarbonyl group to form 22 by us- end of the synthetic sequence, based on Taylor’s report,
ing di-tert-butyl dicarbonate and N,N-diisopropyl- was found to be unattainable, particularly with densely
ethylamine in acetonitrile at ambient temperature in 99% substituted pyrrolidine spiro-fused with b-lactone. On the
yield. The thus formed N-Boc derivative 22 was then sub- basis of our findings, it is pertinent to mention that the
jected to b-lactonization under Mitsunobu condition with most appropriate strategy would be to initiate the synthe-
triphenylphosphine and diethyl azodicarboxylate at –78 °C sis with the already installed pyrrolidinone ring system,
to room temperature to give the epi-spiro-b-lactone deriv- which was already shown in our earlier publication.10
ative 2315 as two rotamers, the presence of which was con-
firmed by two sets of signals in the NMR spectra. Apart
NMR spectra were recorded on a Brucker Avance 200 spectrometer
from compatible 1H and 13C NMR spectra and elemental
analysis, 23 showed in its IR spectrum the characteristic
signal due to a b-lactone carbonyl at 1833 cm–1.
(200 MHz for 1H NMR, 50 MHz for 13C) and an AMX 500 spec-
trometer (500 MHz for 1H NMR). Optical rotation was measured at
a concentration of g/100 mL, with a Perkin-Elmer polarimeter (ac-
curacy (0.002°). GC-MS analyses were performed on a Perkin-
OBn
OBn
COOMe
OBn
OBn
CHO
a
b
c
OH
OH
COOH
N
H
N
N
N
O
O
O
O
O
O
6
19
20
21
OR
O
OBn
OR
d
f
X
e
O
O
OH
COOH
O
N
N
Boc
22
N
Boc
4
O
Boc
23 R = Bn
5 R = Bz
f
Scheme 4 Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, Et3N, –78 °C, 3 h, 92%; (b) Br2, NaHCO3, MeOH, H2O, r.t., 4 h, 87%; (c)
6 N NaOH, EtOH, reflux, 2 h, 83%; (d) Boc2O, DIPEA, MeCN, r.t., 4 h, 99%; (e) DEAD, Ph3P, THF, –78 °C to r.t., 1 h, 88%; (f) RuCl3, aq
NaIO4, EtOAc, r.t., 3 h, 89%.
Synthesis 2010, No. 19, 3301–3308 © Thieme Stuttgart · New York

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Spiro-b-lactone-g-lactam Ring in Oxazolomycins and Lajollamycin
3305
Elmer Turbomass-Autosystem XL. Analytical TLC was performed
on precoated aluminum silica gel plates. Visualization was per-
formed by use of UV light and/or by staining with ninhydrin and
anisaldehyde soln in EtOH. Chromatographic separations were per-
formed by flash chromatography on a silica gel column (Kieselgel
40, 0.040–0.063 mm; Merck). Yields are given after purification,
unless differently stated. When reactions were performed under an-
hyd conditions, the mixtures were maintained under N2. Com-
pounds were named following IUPAC rules as applied by the
Beilstein Institute AutoNom (version 2.1) software for systematic
names in organic chemistry.
tert-Butyl (4S)-4-[(1R,2R)-1,3-Dihydroxy-2-methylpropyl]-2,2-
dimethyloxazolidine-3-carboxylate (12)
A mixture of LiCl (3.3 g, 76.8 mmol) and NaBH4 (3.0 g, 76.8 mmol)
in absolute EtOH (100 mL) was stirred vigorously for 1 h at 0 °C,
and then a soln of aldol adduct 8 (5.3 g, 11.5 mmol) in THF (20 mL)
was added. The reaction mixture was stirred for another 6 h at r.t.,
the solid was collected by filtration, and the filtrate was neutralized
to pH ~7 by dropwise addition of sat. aq NH4Cl soln. The solvent
was removed and the aqueous residue was partitioned between
EtOAc (3 × 50 mL) and H2O. The combined organic extract was
washed with brine (30 mL), dried (Na2SO4), and concentrated to af-
ford a crude residue, which was purified by column chromatogra-
phy (silica gel; EtOAc–hexane, 2:3); this gave diol 12.
Compounds 8 and 11
TiCl4 (5.6 mL, 50.9 mmol) was added by syringe to a stirred soln of
(4R)-4-benzyl-N-propionyl-2-oxazolidinone (9; 10.8 g, 46.3 mmol)
in CH2Cl2 (220 mL) at 0 °C under a N2 atmosphere; DIPEA (20.2
mL, 115.8 mmol) addition followed. The resultant deep red soln
was stirred for 30 min at 0 °C, and then freshly distilled Garner’s al-
dehyde 10 (11.7 mL, 50.9 mmol) was added. The reaction mixture
was maintained at 0 °C for 2 h. Sat. aq NH4Cl soln (100 mL) was
added and the reaction mixture was extracted with CH2Cl2 (2 × 100
mL). The combined organic layer was washed with brine (2 × 50
mL), dried (Na2SO4), and concentrated under reduced pressure. The
residue was purified by flash chromatography (silica gel; EtOAc–
hexane, 1:4); this gave aldol products 8 and 11 in a 2:3 ratio.
Yield: 3.2 g (11.0 mmol, 96%); [a]D25 –42.0 (c 1.55, CHCl3).
IR (CHCl3): 1653 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.90 (d, J = 7.3 Hz, 3 H), 1.49 (br
s, 12 H), 1.59 (br s, 3 H), 1.65–1.87 (m, 1 H), 2.84 (m, 2 H), 3.61–
3.71 (m, 2 H), 3.78–3.86 (m, 1 H), 3.94 (dd, J = 6.5, 8.9 Hz, 1 H),
4.02–4.17 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 14.0, 24.0, 26.5, 28.2 (3 C), 36.9,
59.6, 63.3, 66.1, 75.2, 80.2, 93.7, 152.7.
Anal. Calcd for C14H27NO5: C, 58.11; H, 9.40; N, 4.84. Found: C,
57.94; H, 9.38; N, 4.87.
Yield (8): 7 g (15.1 mmol); yield (11): 10.6 g (22.9 mmol); com-
bined yield: 82% (ratio 8/11, 2:3).
tert-Butyl (4S)-4-[(1R,2R)-3-(tert-Butyldimethylsiloxy)-1-hy-
droxy-2-methylpropyl]-2,2-dimethyloxazolidine-3-carboxylate
(13)
A mixture of diol 12 (3.5 g, 12.1 mmol), Et3N (2.0 mL, 14.52
mmol), TBSCl (2.36 g, 15.7 mmol), and DMAP (54 mg) in CH2Cl2
(50 mL) was stirred for 6 h at 0 °C. After completion of the reaction,
the reaction mixture was diluted with CH2Cl2 (50 mL), washed with
H2O (25 mL) and brine (15 mL), dried (Na2SO4), and concentrated.
The residue was purified by column chromatography (silica gel;
EtOAc–hexane, 1:16); this gave TBS ether derivative 13.
tert-Butyl (4S)-4-[(1R,2S)-3-{(4R)-4-Benzyl-2-oxooxazolidin-3-
yl}-1-hydroxy-2-methyl-3-oxopropyl]-2,2-dimethyloxazolidine-
3-carboxylate (8)
[a]D25 –38.0 (c 1.5, CHCl3).
IR (CHCl3): 1688, 1781 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.40 (d, J = 7.2 Hz, 3 H), 1.48 (s,
9 H), 1.50 (s, 3 H), 1.60 (s, 3 H), 2.73 (dd, J = 11.2, 13.8 Hz, 1 H),
3.48 (dt, J = 2.8, 11.2 Hz, 1 H), 3.67 (dd, J = 2.8, 13.8 Hz, 1 H), 3.83
(dq, J = 2.8, 7.2 Hz, 1 H), 3.94 (dd, J = 5.6, 9.0 Hz, 1 H), 4.0 (d,
J = 10.9 Hz, 1 H), 4.09 (dd, J = 5.6, 9.0 Hz, 1 H), 4.13–4.18 (m, 2
H), 4.29 (d, J = 9.0 Hz, 1 H), 4.57–4.63 (m, 1 H), 7.26–7.36 (m, 5
H).
13C NMR (50 MHz, CDCl3): d = 15.8, 24.0, 27.9, 28.4 (3 C), 37.1,
37.8, 55.7, 59.9, 65.1, 65.8, 75.4, 80.2, 93.7, 126.9, 128.7 (2 C),
129.1 (2 C), 136.5, 152.2, 153.2, 177.8.
Yield: 4.5 g (11.1 mmol, 92%); [a]D25 –37.0 (c 0.90, CHCl3).
IR (CHCl3): 1657 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.07 (s, 6 H), 0.90 (s, 9 H), 0.98
(d, J = 6.5 Hz, 3 H), 1.48 (s, 9 H), 1.51 (br s, 3 H), 1.59 (br s, 3 H),
1.64–1.75 (m, 1 H), 3.00 (br s, 1 H), 3.67 (dd, J = 5.4, 10.1 Hz, 1
H), 3.73–3.84 (m, 1 H), 3.91 (dd, J = 6.3, 8.3 Hz, 2 H), 3.95–4.09
(m, 1 H), 4.16 (dd, J = 1.8, 8.3 Hz, 1 H).
13C NMR (50 MHz, CDCl3): d = –5.7 (2 C), 14.3, 18.0, 23.7, 25.7
(3 C), 26.5, 28.2 (3 C), 37.1, 69.7, 63.3, 66.2, 74.4, 79.6, 93.7,
152.2.
Anal. Calcd for C24H34N2O7: C, 62.32; H, 7.41; N, 6.06. Found: C,
62.20; H, 7.45; N, 6.10.
Anal. Calcd for C20H41NO5Si: C, 59.51; H, 10.24; N, 3.47. Found:
C, 59.43; H, 10.10; N, 3.55.
tert-Butyl (4S)-4-[(1S,2S)-3-{(4R)-4-Benzyl-2-oxooxazolidin-3-
yl}-1-hydroxy-2-methyl-3-oxopropyl]-2,2-dimethyloxazolidine-
3-carboxylate (11)
[a]D25 –74.0 (c 1.6, CHCl3).
tert-Butyl (4S)-4-[(1R,2R)-1-(Benzyloxy)-3-(tert-butyldimethyl-
siloxy)-2-methylpropyl]-2,2- dimethyloxazolidine-3-carboxy-
late (14)
IR (CHCl3): 1678, 1789 cm–1.
1H NMR (200 MHz, CDCl3): d = 1.39 (d, J = 6.8 Hz, 3 H), 1.50 (s,
12 H), 1.55 (s, 3 H), 2.78 (dd, J = 9.5, 13.3 Hz, 1 H), 3.26 (dd,
J = 3.3, 13.3 Hz, 1 H), 3.60–3.80 (m, 1 H), 3.80–3.95 (m, 2 H),
4.07–4.15 (m, 2 H), 4.15–4.30 (m, 3 H), 4.69 (m, 1 H), 7.28 (m, 5
H).
13C NMR (50 MHz, CDCl3): d = 12.1, 24.0, 26.9, 28.2 (3 C), 37.6,
39.5, 54.9, 59.2, 64.4, 65.9, 71.7, 80.8, 93.8, 127.2, 128.8 (2 C),
129.3 (2 C), 134.9, 152.5, 153.1, 177.3.
The TBS ether derivative 13 (4.2 g, 10.4 mmol) in anhyd DMF (50
mL) was cooled to 0 °C and NaH (60% dispersion in oil, 0.50 g,
12.48 mmol) was added portionwise at 0 °C. After 25 min, BnBr
(1.5 mL, 12.48 mmol) was added. After stirring at r.t. for 1 h, the
reaction mixture was quenched with sat. aq NH4Cl soln (25 mL) and
diluted with EtOAc (50 mL). The reaction mixture was then extract-
ed with EtOAc (2 × 25 mL). The combined organic layer was dried
over Na2SO4, filtered and the solvent was removed under vacuum
to give the residue, which was purified by column chromatography
(silica gel; EtOAc–hexane, 1:24); this gave 14.
Anal. Calcd for C24H34N2O7: C, 62.32; H, 7.41; N, 6.06. Found: C,
62.22; H, 7.39, N; 5.88.
Yield: 4.5 g (9.2 mmol, 88%); colorless liquid; [a]D25 –42.0 (c 1.0,
CHCl3).
IR (CHCl3): 1687 cm–1.
Synthesis 2010, No. 19, 3301–3308 © Thieme Stuttgart · New York

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D. Mondal, S. Bera
PAPER
1H NMR (200 MHz, CDCl3): d = 0.01 (s, 6 H), 0.90 (s, 9 H), 0.97
(d, J = 6.8 Hz, 3 H), 1.53 (s, 16 H), 3.32–3.78 (m, 2 H), 3.92– 4.19
(m, 4 H), 4.43–4.79 (m, 2 H), 7.25–7.35 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = –5.7 (2 C), 14.2, 18.0, 23.6, 25.7
(4 C), 28.2 (3 C), 38.9, 58.8, 62.8, 64.5, 74.5, 78.9, 79.2, 93.9,
127.0, 127.3 (2 C), 127.8 (2 C), 138.6, 151.9.
purified by column chromatography (silica gel; EtOAc–hexane,
1:4); this gave 7.
25
Yield: 1.6 g (5.1 mmol, 78% over two steps); viscous liquid; [a]D
+55.0 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 1.07 (d, J = 6.4 Hz, 3 H), 1.46 (s,
9 H), 2.20–2.38 (m, 1 H), 3.17 (t, J = 10.3 Hz, 1 H), 3.46 (dd,
J = 7.3, 10.3 Hz, 1 H), 3.58–3.84 (m, 3 H), 4.05 (m, 2 H), 4.45 (d,
J = 11.9 Hz, 1 H), 4.65 (d, J = 11.9 Hz, 1 H), 7.23–7.42 (m, 5 H).
Anal. Calcd for C27H47NO5Si: C, 65.68; H, 9.59; N, 2.84. Found: C,
65.70; H, 9.48; N, 2.80.
13C NMR (50 MHz, CDCl3): d = 11.3, 28.4 (3 C), 35.7, 52.1, 64.7,
tert-Butyl (4S)-4-[(1R,2R)-1-(Benzyloxy)-3-hydroxy-2-methyl-
propyl]-2,2-dimethyloxazolidine-3-carboxylate (15)
A 1.0 M soln of TBAF in THF (16 mL, 16.0 mmol) was added to a
soln of benzyl ether 14 (4.4 g, 8.9 mmol) in THF (30 mL), and the
mixture was stirred for 3 h at r.t. The reaction mixture was quenched
with H2O (15 mL), extracted with EtOAc (2 × 50 mL), dried
(MgSO4), and concentrated; this gave a crude residue, which was
purified by column chromatography (silica gel; EtOAc–hexane,
1:3) to give 15.
Yield: 3.1 g (8.1 mmol, 91%); colorless liquid; [a]D25 –58.0 (c 1.0,
CHCl3).
IR (CHCl3): 1686 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (d, J = 6.8 Hz, 3 H), 1.49 (s,
3 H), 1.50 (s, 9 H), 1.53 (s, 3 H), 1.89–1.98 (m, 1 H), 3.54 (d, J = 6.0
Hz, 2 H), 3.94 (t, J = 8.2 Hz, 1 H), 3.98 (br s, 1 H), 4.03 (br d, J = 4.4
Hz, 1 H), 4.11 (m, 1 H), 4.21 (dd, J = 4.0, 8.4 Hz, 1 H), 4.59 (d,
J = 11.5 Hz, 1 H), 4.67 (d, J = 11.5 Hz, 1 H), 7.34 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 13.1, 24.9, 26.7, 28.5 (3 C), 37.9,
58.2, 63.3, 65.8, 74.1, 80.4 (2 C), 93.7, 127.8 (3 C), 128.4 (2 C),
138.4, 153.2.
65.5, 71.1, 80.2, 81.7, 127.6, 127.7 (2 C), 128.4 (2 C), 138.0, 156.9.
Anal. Calcd for C18H27NO4: C, 67.26; H, 8.47; N, 4.36. Found: C,
67.29; H, 8.76; N, 4.16.
(6R,7R,7aR)-7-(Benzyloxy)-7a-(hydroxymethyl)-6-methyltet-
rahydropyrrolo[1,2-c]oxazol-3(1H)-one (6)
IBX (0.31 g, 1.12 mmol) was added to a soln of 7 (0.26 g, 0.8 mmol)
in DMSO (3 mL). After 4 h, the reaction mixture was diluted with
H2O (20 mL), filtered, and extracted with Et2O (2 × 10 mL). The
combined organic layers were washed with NaHCO3 (2 × 5 mL) fol-
lowed by brine (5 mL). Finally the organic layer was dried (Na2SO4)
and concentrated in vacuo to produce crude aldehyde 17 as a pale
yellow liquid which was used as such for the next reaction.
Yield: 0.23 g (0.7 mmol, 89%).
A 37% aq soln of formaldehyde (0.8 mL) and 2 N NaOH (1.8 mL)
were added to a stirred soln of crude aldehyde 17 (0.23 g, 0.7 mmol)
in H2O (1.6 mL). The reaction mixture was stirred at r.t. for 4 d, pro-
ducing a mixture of 6 and 18 (9:1). Then 4 N NaOH (2.0 mL) and
MeOH (1.0 mL) were added and the reaction mixture was stirred at
r.t. for 4 h; compound 6 was obtained exclusively. The reaction mix-
ture was quenched with formic acid, extracted with CH2Cl2 (3 × 10
mL), washed with brine (10 mL), and concentrated in vacuo. The
residue was purified by chromatography (silica gel; EtOAc); this
gave 6.
Anal. Calcd for C21H33NO5: C, 66.46; H, 8.76; N, 3.69. Found: C,
66.57; H, 8.63; N, 3.58.
tert-Butyl (4S)-4-[(1R,2R)-1-(Benzyloxy)-2-methyl-3-(p-tolu-
enesulfonyloxy)propyl]-2,2-dimethyloxazolidine-3-carboxylate
(16)
Yield: 0.110 g (0.4 mmol, 55% over two steps); viscous liquid;
[a]D25 +29.0 (c 2.6, CHCl3).
TsCl (2.81 g, 14.74 mmol) was added to a stirred soln of alcohol 15
(2.8 g, 7.4 mmol), Et3N (4.0 mL, 29.48 mmol), and DMAP (40 mg)
in CH2Cl2 (30 mL) at 0 °C. The reaction mixture was stirred for 6 h
at r.t., washed with H2O (2 × 15 mL) and brine (20 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography (silica gel; EtOAc–hexane, 3:17); this gave 16.
Yield: 3.7 g (7.0 mmol, 95%); colorless liquid; [a]D25 +13.0 (c 1.0,
CHCl3).
IR (CHCl3): 1686 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.97 (d, J = 6.8 Hz, 3 H), 1.50 (br
s, 15 H), 1.72–1.82 (m, 1 H), 2.40 (s, 3 H), 3.85–4.11 (m, 6 H), 4.35
(d, J = 10.7 Hz, 1 H), 4.60–4.72 (m, 1 H), 7.18–7.42 (m, 7 H), 7.71
(d, J = 8.3 Hz, 2 H).
IR (CHCl3): 1741 cm–1 (NC=O).
1H NMR (500 MHz, CDCl3): d = 1.11 (d, J = 7.2 Hz, 3 H), 1.97 (br
s, 1 H), 2.70–2.60 (m, 1 H), 3.34 (d, J = 7.8 Hz, 2 H), 3.46 (d,
J = 11.4 Hz, 1 H), 3.56 (d, J = 11.4 Hz, 1 H), 3.71 (d, J = 4.6 Hz, 1
H), 4.28 (d, J = 8.5 Hz, 1 H), 4.46 (d, J = 8.5 Hz, 1 H), 4.53 (d,
J = 11.4 Hz, 1 H), 4.64 (d, J = 11.4 Hz, 1 H), 7.40–7.25 (m, 5 H);
13C NMR (CDCl3, 125 MHz): d 12.6, 39.2, 51.7, 64.9, 67.1, 73.2,
74.1, 81.5, 127.6, 128.1 (2 C), 128.6 (2 C), 137.2, 162.4.
Anal. Calcd. for C15H19NO4: C, 64.97; H, 6.91; N, 5.05. Found: C,
65.02; H, 6.84; N, 5.04.
Methyl (6R,7R,7aR)-7-(Benzyloxy)-6-methyl-3-oxohexahydro-
pyrrolo[1,2-c]oxazole-7a-carboxylate (20)
Oxalyl chloride (315 mg, 1.5 mmol) was added over 5 min to a
cooled (–78 °C) soln of DMSO (125 mg, 1.6 mmol) in CH2Cl2 (10
mL). A soln of 6 (139 mg, 0.5 mmol) in CH2Cl2 (5 mL) was added
over 10 min and the mixture was stirred at –78 °C for 3 h. Et3N (268
mg, 2.7 mmol) was introduced to the soln. The mixture was stirred
at –78 °C for 1.5 h and allowed to warm to r.t. The product was ex-
tracted with CH2Cl2 (3 × 20 mL). The combined organic phase was
washed with H2O (10 mL) and brine (10 mL) and dried (Na2SO4).
After removal of the solvent, the residue was separated by column
chromatography (silica gel; EtOAc) to give aldehyde 19.
13C NMR (50 MHz, CDCl3): d = 14.3, 21.5, 25.0, 26.0, 28.4, 36.5,
58.9, 62.8, 72.0, 74.8, 78.8, 80.1, 94.0, 127.5, 127.6 (2 C), 127.8 (2
C), 128.1 (2 C), 129.6 (2 C), 133.2, 138.0, 144.3, 152.4.
Anal. Calcd for C28H39NO7S: C, 63.02; H, 7.37; N, 2.62. Found: C,
62.97; H, 7.53; N, 2.86.
tert-Butyl (2S,3R,4R)-3-(Benzyloxy)-2-(hydroxymethyl)-4-
methylpyrrolidine-1-carboxylate (7)
A soln of tosyl ester 16 (3.5 g, 6.6 mmol) in MeOH (15 mL) was
treated with PTSA (0.113 g, 0.66 mmol) for 4 h at r.t., and quenched
with sat. aq NaHCO3 (10 mL). MeOH was removed under reduced
pressure, and the resulting aqueous phase was extracted with EtOAc
(3 × 30 mL). The combined organic soln was washed with brine
(25 mL), dried (Na2SO4), and concentrated. The crude residue was
Yield: 127 mg (0.46 mmol, 92%); colorless liquid.
Excess Br2 (5 equiv), prepared as a 2.0 M stock soln in MeOH–H2O
(9:l) was added to a soln of aldehyde 19 (0.5 M) in MeOH–H2O (9:l)
buffered with NaHCO3 (20.0 equiv). The reaction was continuously
monitored by TLC, and the mixture was stirred at r.t. for 4 h. Solid
Synthesis 2010, No. 19, 3301–3308 © Thieme Stuttgart · New York

PAPER
Spiro-b-lactone-g-lactam Ring in Oxazolomycins and Lajollamycin
3307
Na2S2O3 was added to quench excess Br2. The reaction mixture was
diluted with H2O (5 mL) and extraction with Et2O (3 × 10 mL) fol-
lowed. The combined organic layers were dried (Na2SO4) and con-
centrated in vacuo, and the crude product was purified by flash
chromatography (silica gel; EtOAC–hexane, 3:7); this gave 20.
removed and the residue was purified by column chromatography
(silica gel; EtOAc–hexane, 1:4); this gave 23.
25
Yield: 54 mg (0.157 mmol, 88%); white liquid; [a]D –46.0 (c 1,
CHCl3).
IR (CHCl3): 1833, 1705 (C=O) cm–1.
Yield: 87%; [a]D25 –26.0 (c 1.0, CHCl3).
1H NMR (500 MHz, CDCl3): d (2 rotamers) = 0.94 (d, J = 7.2 Hz,
2.2 H), 0.98 (d, J = 7.2 Hz, 0.8 H), 1.47 (s, 3 H), 2.45–2.37 (m, 1 H),
1.48 (s, 6 H), 3.12 (q, J = 7.1 Hz, 0.3 H), 3.15 (dd, J = 2.4, 10.3 Hz,
0.3 H), 3.24 (dd, J = 1.6, 11 Hz, 0.7 H), 3.45 (dd, J = 5.6, 10.3 Hz,
1 H), 4.25 (d, J = 5.3 Hz, 0.3 H), 4.26 (d, J = 5.3 Hz, 0.7 H), 4.38
(d, J = 5.0 Hz, 0.7 H), 4.62 (br q, J = 5.0 Hz, 0.4 H), 4.65–4.63 (m,
2 H), 4.66 (d, J = 5.0 Hz, 0.6 H), 7.40–7.25 (m, 5 H).
1H NMR (200 MHz, CDCl3): d = 1.11 (d, J = 6.9 Hz, 3 H), 2.50 (m,
1 H), 3.25 (dd, J = 9.3, 10.3 Hz, 1 H), 3.50 (dd, J = 8.5, 10.3 Hz, 1
H), 3.80 (s, 3 H), 3.98 (d, J = 3.9 Hz, 1 H), 4.40 (ABq, J = 9.4 Hz,
2 H), 4.60–4.72 (m, 2 H), 7.40–7.42 (m, 5 H).
13C NMR (50 MHz, CDCl3): d = 12.3, 39.9, 51.7, 53.0, 66.2, 74.9,
75.7, 83.5, 127.8, 128.3 (2 C), 128.7 (2 C), 137.0, 160.4, 171.1.
Anal. Calcd. for C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C,
63.12; H, 6.54; N, 4.64.
13C NMR (125 MHz, CDCl3): d = 12.9/12.8, 28.4/28.2 (3 C), 34.8/
33.5, 51.4/50.8, 68.0/67.0, 73.4/73.1, 75.9/76.4, 80.9/80.6, 82.5/
81.4, 128.3 (2 C), 127.8, 128.7 (2 C), 137.0/136.9, 153.6/153.2,
172.2/171.9.
(2R,3R,4R)-3-(Benzyloxy)-2-(hydroxymethyl)-4-methylpyrroli-
dine-2-carboxylic Acid (21)
NaOH (400 mg, 10.0 mmol) was added to a soln of ester 20 (305
mg, 1 mmol) in EtOH (5.0 mL). The soln was stirred at reflux for 2
h, then cooled, and subsequently quenched with formic acid. The
residue was passed through a column of Dowex 50w × 4 (100–200
mesh) ion exchange resin (H2O, then 1 N aq NH3); this gave 21.
Anal. Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03. Found: C,
65.46; H, 7.21; N, 3.95.
tert-Butyl (4R,7R,8R)-8-(Benzoyloxy)-7-methyl-1-oxo-2-oxa-5-
azaspiro[3.4]octane-5-carboxylate (5)
A soln of 23 (0.19 g, 0.54 mmol), EtOAc (9 mL), 10% aq NaIO4
(0.92 g, 4.29 mmol), and RuCl3·2H2O (23.0 mg, 0.10 mmol) was
vigorously stirred at r.t. for 3 h. A 1 M aq soln of KHSO4 (5 mL)
was added and the layers were separated. The aqueous layer was ex-
tracted with EtOAc (3 × 10 mL). The combined organic layer was
washed with brine (5 mL), dried (Na2SO4), and concentrated to give
a crude residue which was purified by chromatography (silica gel;
EtOAc–hexane, 3:17); this gave 5 instead of the expected spiro-b-
lactone-g-lactam derivative 4.
Yield: 220 mg (0.83 mmol, 83%); colorless liquid.
1H NMR (200 MHz, D2O): d = 0.94 (d, J = 6.9 Hz, 3 H), 2.29 (m, 1
H), 2.94 (br t, J = 11.5 Hz, 1 H), 3.45 (dd, J = 8.5, 12.2 Hz, 1 H),
3.96 (ABq, J = 12.3 Hz, 2 H), 4.29 (d, J = 4.5 Hz, 1 H), 4.54 (s, 2
H), 7.25–7.34 (m, 5 H).
13C NMR (50 MHz, D2O): d = 12.7, 39.6, 51.9, 63.8, 77.5, 82.7,
86.9, 131.6, 139.9 (5 C), 175.3.
Anal. Calcd. for C14H19NO4: C, 63.38; H, 7.22; N, 5.28. Found: C,
63.52; H, 7.44; N, 5.14.
Yield: 0.176 g (0.487 mmol, 89%); colorless liquid.
IR (CHCl3): 1840, 1695, 1708 (C=O) cm–1.
(2R,3R,4R)-3-(Benzyloxy)-1-(tert-butoxycarbonyl)-2-(hy-
droxymethyl)-4-methylpyrrolidine-2-carboxylic Acid (22)
Et3N (280 mL, 1.5 mmol) and Boc2O (327 mg, 1.5 mmol) were add-
ed to a soln of 21 (305 mg, 1.15 mmol) in EtOH (10 mL). The mix-
ture was stirred for 4 h. The solvent was removed in vacuo, and the
crude residue was dissolved in sat. aq NH4Cl soln (10 mL). The
product was extracted with EtOAc (5 × 15 mL). The organic layers
were combined, dried (Na2SO4), and concentrated in vacuo. The
crude product was purified by flash column chromatography (silica
gel; EtOAc–hexanes, 1:4); this gave 22.
1H NMR (200 MHz, CDCl3): d (2 rotamers) = 1.04 (d, J = 8.0 Hz,
3 H), 1.51 (s, 9 H), 2.61–2.76 (m, 1 H), 3.20 –3.32 (m, 1 H), 3.76–
3.94 (m, 1 H), 4.37 (d, J = 6 Hz, 0.4 H), 4.42 (d, J = 10.0 Hz, 0.6 H),
4.64 (d, J = 6.0 Hz, 0.6 H), 4.90 (d, J = 10.0 Hz, 0.4 H), 5.86 (d,
J = 10.0 Hz, 1 H), 7.45–7.67 (m, 3 H), 8.04 (d, J = 6.0 Hz, 2 H).
Anal. Calcd for C19H23NO6: C, 63.15; H, 6.41; N, 3.88. Found: C,
63.55; H, 6.31; N, 3.85.
Acknowledgment
Yield: 416 mg (1.14 mmol, 99%); pale yellow liquid.
We thank Dr. Mukund K. Gurjar and Dr. Debendra K. Mohapatra
who provided significant support, advice, and suggestions in this
area, and CSIR, New Delhi, India for funding.
1H NMR (500 MHz, CDCl3): d = 1.08 (d, J = 6.9 Hz, 3 H), 1.50 (s,
9 H), 2.29 (m, 1 H), 2.50 (br s, 1 H), 3.19 (dd, J = 10.3, 10.8 Hz, 1
H), 3.67 (dd, J = 8.5, 9.5 Hz, 1 H), 4.15 (ABq, J = 12.3 Hz, 2 H),
4.33 (d, J = 3.6 Hz, 1 H), 4.70 (ABq, J = 10.7 Hz, 2 H), 7.30–7.41
(m, 5 H).
References
13C NMR (125 MHz, CDCl3): d = 11.4, 28.5, 35.4, 53.4, 63.6, 75.7,
76.6, 81.2, 87.0, 128.2, 128.3 (2 C), 128.6 (2 C), 137.3, 156.4,
173.1.
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Anal. Calcd. for C19H27NO6: C, 62.45; H, 7.45; N, 3.83. Found: C,
62.72; H, 7.54; N, 4.04.
tert-Butyl (4R,7R,8R)-8-(Benzyloxy)-7-methyl-1-oxo-2-oxa-5-
azaspiro[3.4]octane-5-carboxylate (23)
A soln of Ph3P (60 mg, 0.23 mmol) in anhyd THF (1.3 mL) was
cooled to –78 °C. Freshly distilled DEAD (43 mg, 0.25 mmol) in
THF (0.5 mL) was added dropwise. After 15 min, a soln of 22 (65
mg, 0.178 mmol) in anhyd THF (1.5 mL) was added over 5 min and
the mixture was stirred for a further 10 min at –78 °C. The reaction
mixture was then allowed to warm to r.t. After 1 h, the solvent was
Synthesis 2010, No. 19, 3301–3308 © Thieme Stuttgart · New York

3308
D. Mondal, S. Bera
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