Approaches to the synthesis of enantiopure α-hydroxy-β-lactams with functionalized side chains

Article abstract of DOI:10.1016/j.tetasy.2007.08.012

We report a synthesis of pharmaceutically important α-hydroxy (or t-butyldimethylsilyl protected α-hydroxy)-β-lactams with functionalized chains in position 4 of the azetidinone ring. A convenient and high-yielding route to these compounds was developed and optimized. Preparation and characterization of several new enantiopure title compounds with various functional groups are discussed.

Full text of DOI:10.1016/j.tetasy.2007.08.012

Tetrahedron: Asymmetry 18 (2007) 2021–2029
Approaches to the synthesis of enantiopure a-hydroxy-b-lactams
with functionalized side chains
Yan Yang, Jianmei Wang and Margaret Kayser*
Department of Physical Sciences, University of New Brunswick, Saint John, NB, Canada E2L 4L5
Received 7 February 2007; accepted 2 August 2007
Abstract—We report a synthesis of pharmaceutically important a-hydroxy (or t-butyldimethylsilyl protected a-hydroxy)-b-lactams with
functionalized chains in position 4 of the azetidinone ring. A convenient and high-yielding route to these compounds was developed and
optimized. Preparation and characterization of several new enantiopure title compounds with various functional groups are discussed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
AcO
O
R'O
O
R
R
N
N
3-Hydroxy-b-lactams and their derivatives, b-amino-a-hy-
droxy acids, are key fragments of pharmaceutically impor-
tant compounds such as phenylisoserine analogues used in
the synthesis of new taxane anticancer drugs,1,2 or inhibi-
tors of enzymes renin3 and HIV-1 protease.4 Although
the biological importance and synthetic applications of
hydroxy-b-lactams led to the development of numerous
syntheses, the wide variety of functionality and substitution
patterns in the target compounds continues to drive the
search for new and practical stereoselective methods for
their preparation.5,6 We have been interested in the synthe-
sis of enantiopure 3-hydroxy-b-lactams substituted in posi-
tion 4 with side chains that carry both gem dimethyl and a
polar group such as OH, CHO, and morpholine (1a–e,
Fig. 1). Our goal was to develop an efficient and relatively
easy synthesis of racemic cis-3-acetoxy precursors 2a,b
and to access the corresponding enantiopure 3-hydroxy
or t-butyldimethylsilyl (TBS) protected 3-hydroxy
compounds 1a–e via lipase PS resolution.7,8 We also
intended to convert 1a to derivative 16 (vide infra), which
is directly attachable to baccatin III, to obtain access to
new paclitaxel analogues.
PMP
PMP
rac-2-cis
(3R,4S)-1
2a: R = COOEt
2b: R =CH2OBn
1a: R' = H; R = CH2OH
1b: R' =TBS; R = CH2OH
1c: R' =TBS; R = CHO
1d: R' =TBS; R = CH2-morpholine
1e : R' =TBS; R = OTBS
O
O
N
O
PMP
(1R,5S)-2c
Figure 1. Structure of product 1 and 2.
In an earlier paper we reported the synthesis of racemic 2a
as a mixture of cis and trans diastereomers in a 1:2 ratio.9
Since selective formation of cis b-lactam 2a is required for
the lipase PS resolution (the lipase does not accept trans b-
lactams), cis-selectivity needed to be improved. In this com-
munication we describe a modified protocol for the prepa-
ration of racemic 2a as a cis:trans (7:1) mixture (Scheme 1).
However, even with an improved access to rac-2a-cis, the
synthesis of 1a was found to be inefficient due to the forma-
tion of by-product 2c (Fig. 1) during lipase resolution step.6
To circumvent this problem we developed an alternative
route to enantiopure compound 1a and its derivatives
1b–e.
*
Corresponding author. Tel.: +1 506 648 5576; fax: +1 506 648 5948;
e-mail: kayser@unbsj.ca
Present address: Department of Chemistry, Southern Methodist Univer-
sity, Dallas, TX 75275, USA.
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.08.012

2022
Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
EtOOC
p-anisidine
CBr4
H
N
EtO
COOEt
COOEt
CH3CN-H2O
reflux at 76 ºC
MgSO4, CH2Cl2
AcO
O
OEt
O
OCH3
COOEt
PMP
Et3N
3
4
N
5
CH2Cl2, -5 ºC
O
2a
(cis: trans = 7:1)
Cl
O
O
6
Scheme 1. Synthesis of 3-acetoxy b-lactam 2a.
2. Results and discussion
reported in the literature,17 gave benzylidene acetal 9 in
essentially quantitative yield. In the following ring-opening
18
To obtain cis-2a as a principal product we focused on the
generation of E imine, since the structure of an imine plays
a crucial role in the stereochemical course of a Staudinger
cycloaddition reaction.10 In the original experiments imine
5 was prepared in a one-pot reaction by deprotection of
diethyl acetal 3 with TsOH at 145 ꢁC, followed by conden-
reaction, the reduction with LiAlH4/AlCl3 cleaved acetal
9 to benzyl ether alcohol 10 in excellent yield (93%). Subse-
quent Swern oxidation19 with oxalyl chloride yielded ben-
zyloxyaldehyde 11 in 92% yield (Scheme 2). In this case,
the condensation of aldehyde 11 with p-anisidine gave
1
exclusively E imine 12 as shown by H NMR of the crude
1
sation with p-anisidine. H NMR spectrum of the crude
product. The Staudinger reaction of imine 12 and acetoxy-
acetyl chloride 6 gave rac-cis-2b b-lactam in 75% yield. The
cycloaddition was fast (3 h) and free of the trans isomer.
product showed it to be a mixture of Z and E imines in
the ratio of 1.6:1, respectively. We thought that the ele-
vated temperature in the one-pot protocol may be respon-
sible for the high proportion of the Z imine and the
consequent increase in the formation of the trans b-lactam
during the condensation with the aldehyde.à To obtain
imine 5 at lower temperature we decided to prepare alde-
hyde 4 prior to the condensation with p-anisidine. Among
several deprotection methods11–13 refluxing of acetal 3 with
CBr4/H2O–CH3CN at 76 ꢁC14 turned out to be the most
effective and gave complete conversion after 6 h. The
resulting aldehyde 4 was used without purification in the
preparation of imine 5 at room temperature in the presence
of anhydrous MgSO4. In view of its low stability, imine 5
was used without purification in the following Staudinger
reaction. The condensation of 5 with acetoxyacetyl chlo-
ride 6 was performed at ꢀ5 ꢁC in the presence of excess tri-
ethylamine and produced b-lactam 2a in the ratio
cis:trans = 7:1 (Scheme 1). Unfortunately, the improved ac-
cess to rac-cis-2a did not save this synthesis since the fol-
lowing lipase resolution of rac-cis-2a gave a poor yield of
enantiopure 1a because of a spontaneous formation of cyc-
lic lactone 2c under the work-up conditions.9
With all reactions optimized, lipase PS-catalyzed kinetic
resolution provided a route to the enantiopure targets.
Thus, (3S,4R)-13 (>99% ee) was prepared via kinetic reso-
lution of rac-cis-2b, and its antipode (3R,4S)-13 was ac-
cessed by 2 M KOH hydrolysis of the unreacted (3R,4S)-
2b (>99% ee). Alcohol (3S,4R)-13 was oxidized to the cor-
responding ketone (4R)-14. Baker’s yeast reduction of
(4R)-14 gave (3R,4R)-13 in 90% yield, as shown in Scheme
3. A parallel synthesis of the (3S,4S)-13 enantiomer was
not attempted at this time since our earlier studies have
shown that neither whole cell baker’s yeast, nor any of
the available isolated yeast reductases, screened against
several racemic 3-keto b-lactams, was successful in produc-
ing a significant proportion of 3S,4S isomer.20,21
The absolute configuration of (3S,4R)-13 was assigned by
analogy to the related (3S,4R)-3-hydroxy-4-aryl-b-lactams
from lipase resolution, whose absolute configurations have
been confirmed by X-ray crystallographic analyses9,20,22
and proton NMR data.23 Furthermore, the three com-
pounds (3R,4S)-13, (3S,4R)-13, and (3R,4R)-13 are clearly
resolved on chiral HPLC (S,S)-Whelk-O 1 column and
each individual compound shows a single peak, indicating
>99% enantiomeric excess for each compound.§
To improve the synthesis of compound 1a, we switched to
a different strategy that employs benzyloxyaldehyde 1115 as
a key intermediate (Scheme 2). Selective monobenzylation
of glycols is an important protecting step in organic synthe-
sis. It can be achieved via direct monoalkylation with ben-
zyl chloride or via reductive cleavage of benzylidene
acetals.16 Benzylidenation of neopentyl glycol 7 with benz-
aldehyde dimethylacetal 8 in the presence of camphorsulf-
onic acid (CSA), performed according to a protocol
The cleavage of the benzyl group, particularly in sensitive
molecules such as b-lactams, can be difficult, and the com-
monly used H2–Pd/C hydrogenation24 was ineffective in
the deprotection of (3R,4S)-13. Among the deprotection
methods investigated, homogeneous hydrogenation with
ammonium formate as the hydrogen source turned out to
be fast and reliable25 (Scheme 3). The same deprotection
à This notion was supported by the observation that when the Staudinger
reaction was carried out with the imine that was purified by chroma-
tography during which a significant proportion of the Z imine was
removed the proportion of cis-b-lactam was greatly enhanced.
§ The enantiopurity of these compounds was initially established by the
NMR analysis of their Mosher33 derivatives.

Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
2023
O
O
OH
O
CSA
LiAlH4-AlCl3
CH2Cl2-Et2O
93%
Ph
HO
OH
PhCH(OCH3)2
Ph
+
CH2Cl2, 4Å MS
99%
7
8
9
10
O
BnO
DMSO
p-anisidine
CH2Cl2
C
H
N
Ph
(ClCO)2, TEA, -60 0C
92%
O
OCH3
O
12
11
OBn
Et3N
O
O
+
CH2Cl2
O
N
Cl
PMP
-10 oC
75%
O
O
rac-cis-2b
6
Scheme 2. Synthesis of 3-acetoxy b-lactam rac-cis-2b.
OBn
HO
OBn
OBn
O
O
HO
O
DMSO
P2O5
baker's yeast
N
N
N
O
PMP
PMP
PMP
AcO
O
OBn
(3R,4R)-13
(4R)-14
(3S,4R)-13
Lipase PS
N
> 99% ee, 90% yield
> 99% ee, 47% yield
10% CH3CN, pH=7.5
PMP
OH
OBn
rac-cis-2b
HO
AcO
OBn
HO
2 M KOH
Pd/C
HCOONH4
N
N
N
O
PMP
O
PMP
O
PMP
(3R,4S)-2b
(3R,4S)-1a
(3R,4S)-13
> 99% ee, 48% yield
Scheme 3. Preparation of (3R,4S)-13, (3S,4R)-13, and (3R,4R)-13.
method was also effective with the t-butyldimethyl silyl
(TBS) derivative (3R,4S)-17, making it suitable for the
preparation of compound (3R,4S)-1b (Scheme 4). Having
the resistant cancer cell lines expressing P-glycoproteins
(PC-12, PC-6/VCR29-9, and PC-6/VP1-1).27,28 In light of
the above, a paclitaxel analogue bearing a morpholine
group in the C-13 side chain became an attractive target
and we decided to extend our synthesis to incorporate mor-
pholine into the C-13 side chain of the precursor b-lactam
1d. The synthesis of the latter compound from (3R,4S)-13
was achieved in 30% yield after four steps, as shown in
Scheme 4. The 3-hydroxy group of (3R,4S)-13 was pro-
tected by TBSCl to give (3R,4S)-17 in 96% yield. The fol-
lowing debenzylation successfully produced (3R,4S)-1b,
although compared to the earlier described hydrogenation
of (3R,4S)-13 to (3R,4S)-1a, debenzylation of (3R,4S)-17
required more palladium and a longer reaction time. Sub-
sequent Swern oxidation (DMSO/(COCl)2)19 of (3R,4S)-
1b at ꢀ50 ꢁC to ꢀ60 ꢁC gave aldehyde (3R,4S)-1c in 92%
yield. To introduce the morpholine group we carried out
reductive amination using sodium triacetoxylborohydride
(NaBH(OAc)3),29 as reducing agent in the presence of ex-
cess morpholine. Under these conditions, aldehyde
identified
a good deprotection method, compounds
(3R,4S)-13 and (3R,4S)-17 were converted to (3R,4S)-1a
and (3R,4S)-1b, respectively, as shown in Scheme 4.
In the following steps, enantiomer (3R,4S)-1a was pro-
tected with two equivalents of TBSCl to (3R,4S)-1e and
the N-p-methoxyphenyl (PMP) group was removed with
ammonium cerium nitrate (CAN) to give (3R,4S)-15 in
high yield. The subsequent protection of the amide amine
group in (3R,4S)-15 as the corresponding N-Boc derivative
yielded (3R,4S)-16, which is poised for coupling with bacc-
atin III toward a new paclitaxel analogue (Fig. 2).
It has been shown that the introduction of a morpholine
group into four new taxane analogues (non-side chain)
provides enhanced biological activity of these analogues
compared to paclitaxel and docetaxel, especially vis a vis

2024
Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
O
OBn
Pd/C, HCOONH4
MeOH, reflux
TBSO
O
OH
TBSO
N
TBSO
TBSO
DMSO,(COCl)2
NaBH(OAc)3
CHO
N
N
N
N
PMP
-60 oC
THF, Morpholine
r.t.
O
PMP
O
PMP
O
PMP
(3R,4S)-17
(3R,4S)-1b
(3R,4S)-1c
(3R,4S)-1d
TBSCl
DMF, imidazole
OTBS
OTBS
TBSO
TBSO
OBn
HO
O
OH
TBSCl
HO
O
Pd/C
CAN/MeCN
N
N
H2O -5 oC
N
DMF, imidazole
N
HCOONH4
PMP
O
PMP
O
H
PMP
(3R,4S)-15
,DMAP
(3R,4S)-1e
(3R,4S)-1a
(3R,4S)-13
(Boc)2O
Et3N,CH2Cl2
OTBS
TBSO
N
O
Boc
(3R,4S)-16
Scheme 4. Synthesis of (3R,4S)-1b–e and (3R,4S)-16.
TBSO
R1
AcO
AcO
O
O
OH
OH
N
O
R2
Boc
O
NH
R1
HO
O
O
H
H
OH
OH
OH
OBzAcO
OBzAcO
baccatin III
paclitaxel analogue
Figure 2. Paclitaxel analogues with novel C-13 side chains are formed by coupling baccatin III with suitably substituted b-lactams according to Holton’s
protocol.26 Several protection and deprotection steps are involved.
(3R,4S)-1c was converted to (3R,4S)-1d in 53% yield. Other
reductive amination methods employing toxic NaBH3CN30
or neat Ti(OiPr)4 in the presence of NaBH3CN31 gave low-
er yields.
4. Experimental
4.1. General
Melting points were determined on a Fisher–Johns melting
point apparatus and are uncorrected. Optical rotations
were measured on a Perkin–Elmer 241 polarimeter operat-
ing at room temperature. IR spectra were recorded as thin
films on NaCl plates on a Mattson Satellite FTIR spec-
trometer. 1H and 13C NMR spectra were recorded in
CDCl3 solution at room temperature on a Bruker 250,
400, and 500 MHz FT-NMR spectrometer; chemical shifts
are reported in ppm using Me4Si as internal standard. J
values are expressed in Hertz. Enantiomeric excess was
determined by chiral HPLC analysis or by NMR analysis
of the Mosher [(R)-MTPA-Cl] derivatives [compounds
(3R,4S)-13, (3S,4R)-13, and (3R,4R)-13]. Chiral-phase
HPLC analyses were performed on a (S,S)-Whelk-O 1 col-
umn (25 cm · 4.6 mm, Regis Technologies Inc.) using hex-
ane–isopropanol (90:10) as the mobile phase on an Agilent
3. Conclusion
Useful chiral building blocks for the synthesis of paclitaxel
analogues and other pharmaceutically important com-
pounds were prepared in enantiopure form (99% ee) via a
simple and efficient synthesis followed by lipase-catalyzed
kinetic resolution. A protocol was established for oxidation
of compound (3S,4R)-13 to the corresponding 3-oxo-b-lac-
tam (4R)-14 and its subsequent conversion by baker’s yeast
to the trans-(3R,4R) isomer. The synthesis of the morphol-
ine substituted b-lactam 1d was carried out. However, to
obtain the corresponding N-Boc derivative, ready for cou-
pling with baccatin III, several protection and deprotection
steps will need to be optimized.

Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
2025
HPLC 1100. A UV detector set at 254 nm was used to
monitor the reactions.
three-neck round-bottom flask equipped with a thermome-
ter and two pressure-equalizing dropping funnels contain-
ing dimethyl sulfoxide (3.6 mL, 0.051 mol) dissolved in
methylene chloride (12 mL) and benzyl ether alcohol 10
(4.9 g, 0.025 mol) dissolved in methylene chloride
(25 mL), respectively. The reaction mixture was cooled to
ꢀ60 ꢁC and the DMSO solution was added over a period
of 5 min, followed by the alcohol solution (10 min). After
stirring at ꢀ60 ꢁC for 30 min, triethylamine (18 mL,
0.13 mol) was added and stirring was continued for an
additional 45 min when GC shows a complete conversion.
After the reaction was warmed to room temperature, water
(40 mL) was added and stirred for 10 min, followed by
addition of 2 M HCl (30 mL). The solution was extracted
with methylene chloride, washed with brine, dried over
magnesium sulfate, and filtered. Evaporation under vac-
uum gave 11 (6.0 g, 92% yield) as a colorless oil; IR
(CHCl3) cmax/cmꢀ1 3349, 2982, 2940, 2839, 1725, 1513,
All solvents and chemicals were purchased from Sigma–
Aldrich and Fisher Scientific (Canada). All solvents used
were purified and dried by standard methods. Lipase PS
was a gift from Amano Enzyme USA Co. Baker’s yeast
was purchased from the bulk food store Bulkbarn.
4.2. 5,5-Dimethyl-2-phenyl-1,3-dioxane 932
Camphorsulfonic acid (0.22 g, 0.95 mol) was added to a
solution of neopentyl glycol 7 (8.32 g, 0.08 mol) and benz-
aldehyde dimethyl acetal 8 (12.8 mL, 0.09 mol) in methy-
˚
lene chloride (220 mL) containing activated 4 A
molecular sieves (10 g). GC and TLC show complete con-
version after 30 min of reaction. The molecular sieves were
filtered and washed with methylene chloride (20 mL · 3).
The filtrate was washed with 10% sodium bicarbonate
and brine, dried over magnesium sulfate, and filtered.
Evaporation under vacuum afforded 9 (14.9 g, 99% yield)
as colorless crystals; mp 30–31 ꢁC; IR (CHCl3) cmax/cmꢀ1
1
1249, 1173; H NMR (250 MHz, CDCl3) d 1.09 (6H, s,
(CH3)2), 3.45 (2H, s, OCH2), 4.51 (2H, s, OCH2Ph), 7.30
(5H, s, ArH), 9.57 (1H, s, CHO); 13C NMR (126 MHz,
CDCl3) d 22.3 (CH3), 43.4 (CMe2), 73.4 (CH2O), 76.5
(OCH2Ph), 127.5, 127.6, 128.3, 138.0, 182.2; HRMS:
C12H16O2 (M+), calcd: 192.1150, found: 192.1142.
1
3066, 3036, 2953, 2868, 1456, 1390, 1216, 1105, 1022; H
NMR (400 MHz, CDCl3) d 0.80 (3H, s, CH3), 1.30 (3H,
s, CH3), 3.65 (2H, d, J = 10.8, CH2), 3.77 (2H, d,
J = 11.0, CH2), 5.39 (1H, s, CH), 7.37 (3H, dd, J = 6.7,
J = 8.1, ArH), 7.51 (2H, d, J = 6.7, ArH); 13C NMR
(126 MHz, CDCl3) d 21.9 (CH3), 23.1 (CH3), 30.2
(CMe2), 77.7 (OCH2), 101.8 (HCPh), 126.2, 128.3, 128.7,
138.8; HRMS: C12H16O2 (M+), calcd: 192.11504, found:
192.11502.
4.5. (E)-N-(3-(Benzyloxy)-2,2-dimethylpropylidene)-4-meth-
oxybenzenamine 12
To a 5% solution of the corresponding aldehyde 11
(4.239 g, 0.022 mol), in methylene chloride (18 mL) were
˚
added p-anisidine (2.883 g, 0.022 mol) and 4 A molecular
sieves (9 g). The resulting suspension was stirred at room
temperature for 2 h until TLC shows complete conversion.
The molecular sieves were filtered and thoroughly washed
with methylene chloride (20 mL). The combined organic
solutions were concentrated under vacuum to give imine
12 (6.2 g, 95% yield) as a light yellow liquid; IR (CHCl3)
4.3. 3-(Benzyloxy)-2,2-dimethylpropan-1-ol 1032
Lithium aluminum hydride (1.98 g, 0.052 mol) was added
to a solution of 9 (10.0 g, 0.052 mol) in 1:1 diethyl ether
and methylene chloride (200 mL) cooled to ꢀ10 ꢁC. Alumi-
num chloride (6.95 g, 0.052 mol) in 40 mL of diethyl ether
was then added and the resulting mixture was stirred at
ꢀ10 ꢁC for 10 min. The reaction was allowed to warm to
room temperature, then it was heated at reflux. Reflux
was continued until GC shows complete conversion (4 h).
After the reaction was cooled to ꢀ10 ꢁC and diluted with
50 mL of ethyl acetate the reaction was hydrolyzed with
water (150 mL) and extracted with ethyl acetate. The com-
bined organic layers were washed sequentially with 10%
sodium bicarbonate solution and brine, dried over
magnesium sulfate, and filtered. Evaporation under vac-
uum gave 10 (9.35 g, 93% yield) as a colorless oil; IR
(CHCl3) cmax/cmꢀ1 3349, 2982, 2940, 2839, 1725, 1513,
c
max/cmꢀ1 3031, 2961, 2930, 2858, 3708, 1731, 1648,
1504, 1454, 1244, 1101, 1034; 1H NMR (400 MHz, CDCl3)
d 1.15 (6H, s, CH3), 3.51 (2H, s, OCH2), 3.83 (3H, s,
OCH3), 4.56 (2H, s, CH2Ph), 6.85 (2H, d, J = 8.9, ArH),
7.00 (2H, d, J = 8.8, ArH), 7.32 (5H, s, ArH), 7.89 (1H,
s, N@CH). 13C NMR (126 MHz, CDCl3) d 22.7 (CH3)2,
28.4 (CMe2), 55.9 (OCH3), 75.3 (OCH2Ph), 80.0 (CH2O),
163.7 (CH@N), 127.5, 127.6, 128.3, 138.0 (C–Ph), 115.6,
123.3, 141.3, 159.2 (C–Ph–OMe).
4.6. cis-( )-3-Acetoxy-4-(2-benzyloxy-1,1-dimethylethyl)-1-
(4-methoxyphenyl)azetidin-2-one rac-cis-2b
1
1249, 1173; H NMR (400 MHz, CDCl3) d 0.93 (6H, s,
Crude imine 12 (10.8 g, 0.036 mol) and dry triethylamine
(25 mL, 0.18 mol) in dry methylene chloride (100 mL) were
cooled to ꢀ10 ꢁC and treated under a nitrogen atmosphere
with carboxylic acid chloride 6 (12.3 g, 0.09 mol) in dry
methylene chloride (65 mL). After complete addition, the
solution was warmed to room temperature and stirred for
3 h. The reaction mixture was hydrolyzed with 2 M HCl,
and extracted with methylene chloride (100 mL · 2). The
combined organic layers were washed with saturated
sodium carbonate solution (50 mL · 2), dried over magne-
sium sulfate, filtered, and evaporated to dryness.
Crystallization from hexane and ethyl acetate gave rac-
(CH3)2), 2.68 (1H, s, OH), 3.32 (2H, s, CH2), 3.45 (2H, s,
CH2), 4.51 (2H, s, OCH2Ph), 7.32 (5H, m, ArH); 13C
NMR (126 MHz, CDCl3) d 21.8 (CH3), 36.2 (CMe2),
71.6 (CH2OH), 73.5 (CH2Ph), 79.3 (CH2OCH2Ph), 127.4,
127.6, 128.4, 138.2; HRMS: C12H18O2 (M+), calcd:
194.13068, found: 194.13067.
4.4. 3-(Benzyloxy)-2,2-dimethylpropanal 1119
A solution of oxalyl chloride (4.9 g, 0.025 mol) in dry meth-
ylene chloride (63 mL) was placed in a flame-dried 250 mL

2026
Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
2b-cis (11.9 g, 75% yield) as white crystals; mp 78–79 ꢁC;
IR (CHCl3) cmax/cmꢀ1 2961, 2934, 2871, 1758, 1513,
1373, 1221, 1112; 1H NMR (250 MHz, CDCl3) d 1.03
(3H, s, CH3), 1.04 (3H, s, CH3), 2.15 (3H, s, CH3CO),
3.17 (2H, dd, J = 9.1, J = 9.0, CCH2), 3.79 (3H, s,
OCH3), 4.39 (2H, q, J = 11.9, OCH2Ph), 4.69 (1H, d,
J = 5.5, NCH), 6.17 (1H, d, J = 5.5, CHO), 6.83 (2H, d,
J = 9.0, ArH), 7.34–7.38 (7H, m, ArH); 13C NMR
(126 MHz, CDCl3) d 20.4 (CH3), 20.8 (CH3), 21.5
(CH3CO), 38.4 (CMe2), 55.4 (OCH3), 61.7 (NCH), 73.1
(OCH2Ph), 73.4 (CHO), 77.6 (CCH2O), 114.2, 121.2,
127.4, 127.7, 128.4, 130.3, 138.1, 157.1, 163.9, 169.1;
HRMS: C23H27NO5 (M+), calcd: 397.18893, found:
397.18891.
The reaction mixture was slowly treated with 2 M KOH
(20 mL) and stirred at 0 ꢁC until TLC indicated complete
conversion (2 h). The reaction was quenched with water
(20 mL) and extracted with ethyl acetate (40 mL · 2). The
combined organic layers were washed with brine, and dried
over magnesium sulfate, filtered, and concentrated. Crys-
tallization from hexane and ethyl acetate yielded (3R,4S)-
(+)-13 (1.65 g, 92% yield) as colorless crystals; mp 138–
20
140 ꢁC; ½aꢁD ¼ þ78:0 (c 1.0, CH2Cl2). Spectra are identical
to those of (3S,4R)-(ꢀ)-13.
4.9. (3R,4S)-(+)-3-Hydroxy-4-1,1-dimethyl-2-hydroxy-
ethyl)-1-(4-methoxyphenyl)azetidin-2-one 1a
Ammonium formate (0.41 g, 0.006 mol) and palladium on
activated carbon (1.2 g, 10 wt %) were added to a solution
of b-lactam (3R,4S)-(+)-13 (1.1 g, 0.03 mol) in dry metha-
nol (15 mL). The reaction was stirred at reflux for 20 min
when TLC indicated complete conversion. The mixture
was acidified with 2 M HCl to pH ꢂ 3, and then extracted
with ethyl acetate (40 mL · 3). The organic layers were
combined and washed with brine, dried over magnesium
sulfate, filtered, and evaporated to dryness to give crude
product. Crystallization with methylene chloride yielded
4.7. General procedure for lipase resolution of racemic cis
3-acetoxy-b-lactams
Amano PS lipase (2 g) was suspended in a 0.2 M potassium
phosphate buffer (pH 7.5) (27 mL). 3-Acetoxy-b-lactam
rac-2b-cis (2 g, 0.005 mol) in 10% acetonitrile (3 mL) was
added to the reaction mixture. The reaction was vigorously
stirred at room temperature for 72 h until the reaction pro-
ceeded to 48% conversion (by chiral HPLC analysis). The
mixture was extracted with ethyl acetate (30 mL · 3) and
the combined ethyl acetate layers were washed with brine
and dried over magnesium sulfate. Removal of the solvent
afforded a mixture of unreacted 3-acetoxy-b-lactam and
hydrolyzed product 3-hydroxy-b-lactam. Separation by
flash chromatography on a silica gel column (hexane–ethyl
acetate = 4:1 to 2:1) gave enantiopure 3-hydroxy-b-lactam
(3S,4R)-(ꢀ)-13 (0.83 g, 47% yield) and the unreacted 3-
acetoxy-b-lactam (3R,4S)-(+)-2b (0.95 g, 48% yield).
Chemical hydrolysis of the latter gave (3R,4S)-(+)-13 in
92% yield.
products (3R,4S)-(+)-1a (0.398 g, 50% yield) as colorless
20
crystals; mp 162–164 ꢁC; ½aꢁD ¼ þ70:2 (c 1.0, CH2Cl2).
IR (CHCl3) cmax/cmꢀ1 3369, 2960, 2933, 1727, 1512,
1247, 1126, 1033; 1H NMR (500 MHz, CDCl3) d 0.87
(3H, s, CH3), 1.13 (3H, s, CH3), 3.26 (1H, d, J = 10.5,
NCH), 3.72 (3H, s, OCH3), 3.73 (1H, d, J = 10.2, CHOH),
4.23 (2H, d, J = 5.3, CH2), 4.94 (1H, s, OH), 6.30 (1H, s,
OH), 6.83 (2H, d, J = 10.0, ArH), 7.23 (2H, d, J = 10.0,
ArH); 13C NMR (62.9 MHz, CDCl3) d 21.5 (CH3), 26.5
(CH3), 39.4 (C), 55.5 (OCH3), 66.6 (NCH), 67.5 (OHCH),
76.5 (CH2), 114.3, 122.4, 129.4, 157.3, 169.7 (CO); HRMS:
C14H19NO4 (M+), calcd: 265.1001, found: 265.1006.
4.7.1.
3-hydroxy-1-(4-methoxyphenyl)azetidin-2-one 13. White
(3S,4R)-(ꢀ)-4-(2-Benzyloxy-1,1-dimethylethyl)-
20
crystals; mp 133–134 ꢁC; ½aꢁD ¼ ꢀ77:1 (c 1.0, CH2Cl2).
5. (3R,4S)-(+)-4-(2-Benzyloxy-1,1-dimethylethyl)-
3-(tert-butyldimethylsilanyloxy)-1-(4-methoxyphenyl)-
azetidin-2-one 17
IR (CHCl3) cmax/cmꢀ1 3344, 2943, 2876, 1726, 1512,
1243; H NMR (500 MHz, CDCl3) d 0.97 (3H, s, CCH3),
1
1.20 (3H, s, CCH3), 3.10 (1H, d, J = 9.5, CCH2), 3.48
(1H, d, J = 9.3, CCH2), 3.78 (3H, s, OCH3), 4.24 (1H, d,
J = 5.5, NCH), 4.57 (2H, s, OCH2Ph), 4.95 (1H, dd,
J = 5.4, J = 11.5, OHCH), 5.40 (1H, d, J = 11.3, OH),
6.83 (2H, d, J = 9.0, ArH), 7.19 (2H, d, J = 9.0, ArH),
7.39 (5H, m, ArH); 13C NMR (126 MHz, CDCl3) d 21.6
(CH3), 27.2 (CH3), 38.9 (CCH3), 55.4 (OCH3), 66.8
(NCH), 74.1 (HOCH), 74.6 (OCH2Ph), 77.3 (CCH2O),
114.2, 121.6, 128.3, 128.6, 128.7, 130.3, 136.2, 156.8,
168.4; HRMS: C21H25NO4 (M+), calcd: 355.1783, found:
355.1776.
3-Hydroxy-b-lactam (3R,4S)-(+)-13 (1.1 g, 0.03 mol) was
dissolved in dimethylformamide (2 mL). tert-Butyldimeth-
ylsilyl chloride (0.73 g, 0.036 mol) and imidazole
(2.5 equiv) were added. The mixture was stirred at 35 ꢁC
until TLC indicated complete conversion (4 h). The reac-
tion was quenched with water and extracted with methy-
lene chloride (15 mL · 3). The combined organic extracts
were washed three times with water and brine, dried over
magnesium sulfate. Filtration and concentration gave
(3R,4S)-(+)-17 (1.3 g, 97% yield) as a colorless oil;
20
½aꢁD ¼ þ52:1 (c 1.2, CH2Cl2); IR (CHCl3) cmax/cmꢀ1
4.7.2. (3R,4S)-(+)-4-(2-Benzyloxy-1,1-dimethylethyl)-3-acet-
oxy-1-(4-methoxyphenyl)azetidin-2-one
2955, 2931, 2857, 1753, 1513, 1248, 1132; 1H NMR
(250 MHz, CDCl3) d 0.97 (3H, s, CH3), 1.20 (3H, s,
CH3), 3.11 (1H, d, J = 9.3, OCH2), 3.47 (1H, d, J = 9.3,
CCH2), 3.78 (3H, s, OCH3), 4.35 (1H, d, J = 5.5, NCH),
4.57 (2H, s, OCH2Ph), 4.96 (1H, dd, J = 5.4, J = 11.3,
CHOH), 5.40 (1H, d, J = 11.3, OH), 6.83 (2H, d, J = 9.0,
ArH), 7.20 (2H, d, J = 9.0, ArH), 7.39 (5H, m, ArH);
13C NMR (126 MHz, CDCl3) d ꢀ5.4 (SiCH3), ꢀ4.6
(SiCH3), 18.1 (Me3CSi), 20.4 ((CH3)2C), 21.2 ((CH3)2C),
2b. Colorless
crystals; mp 85–86 ꢁC; ½aꢁD ¼ þ51:0 (c 1.0, CH2Cl2).
20
4.8. (3R,4S)-(+)-3-Hydroxy-4-(2-benzyloxy-1,1-dimethyl-
ethyl)-1-(4-methoxyphenyl)azetidin-2-one 13
3-Acetoxy-b-lactam (3R,4S)-(+)-2b (2 g, 0.005 mol) was
dissolved in tetrahydrofuran (40 mL) and cooled to 0 ꢁC.

Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
2027
25.7 ((CH3)3CSi), 39.6 (C(CH3)2), 55.4 (OCH3), 61.9
(NCH), 73.0 (HOCH), 76.1 (OCH2Ph), 78.0 (CCH2O),
114.0, 120.6, 127.3, 127.5, 128.4, 131.2, 138.4, 156.5,
167.4; HRMS: C27H39NO4Si (M+), calcd: 469.2648,
found: 469.2648.
(3H, s, CH3Si), 0.92 (9H, s, (CH3)3CSi), 1.21 (3H, s,
CH3C), 1.24 (3H, s, CH3C), 3.78 (3H, s, OCH3), 4.55
(1H, d, J = 5.5, NCH), 5.02 (1H, d, J = 5.5, CHOH),
6.85 (2H, d, J = 8.6, ArH), 7.27 (2H, d, J = 8.6, ArH),
9.64 (1H, s, CHO); 13C NMR (126 MHz, CDCl3) d ꢀ5.5
(SiCH3), ꢀ4.8 (SiCH3), 18.1 (Me3CSi), 19.3 (CH3C), 22.1
(CH3C), 25.6 ((CH3)3CSi), 48.0 (C(CH3)2), 55.4 (OCH3),
64.1 (NCH), 76.2 (OCH), 114.3, 114.5, 121.1, 122.7,
130.3, 156.9 (C–Ph), 166.3 (CO), 204.3 (CHO); HRMS:
C21H33NO4Si (M+), calcd: 391.21787, found: 391.21824.
5.1. (3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(1,1-
dimethyl-2-hydroxy-ethyl)-1-(4-methoxyphenyl)azetidin-
2-one 1b
Ammonium formate (820 mg, 13 mmol) and palladium on
activated carbon (1.5 g, 10 wt %) were added to a solution
of (3R,4S)-(+)-17 (499 mg, 1 mmol) in dry methanol
(20 mL). The reaction was stirred under reflux for 30 min
when TLC indicated complete conversion. The mixture
was acidified with 2 M HCl to pH ꢂ 3, and then extracted
with ethyl acetate (40 mL · 3). The organic layers were
combined and washed with brine, dried over magnesium
sulfate, filtered, and evaporated to dryness. Separation of
the crude residue by flash column chromatography (hex-
ane–ethyl acetate = 6:1 to 4:1) followed by crystallization
5.3. (3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(1,1-
dimethyl-2-morpholinethyl)-1-(4-methoxyphenyl)azetidin-
2-one 1d30
Aldehyde (3R,4S)-(+)-1c (541 mg, 1.43 mmol) was dis-
solved in MeOH (4 mL), to this solution were added mor-
pholine (0.36 mL, 4.2 mmol), AcOH (0.075 mL,
1.43 mmol), and NaBH(OAc)3 (417 mg, 2 mmol). With
ice cooling, the mixture was stirred at room temperature
for 3 h. The reaction mixture was quenched with saturated
NaHCO3 solution (20 mL) and extracted with ethyl acetate
(20 mL · 3). The combined organic layer was washed with
brine and dried over MgSO4. The solvent was removed un-
der reduced pressure and the residue was purified by flash
chromatography on silica gel (hexane–ethyl acetate = 4:1)
with methylene chloride yielded (3R,4S)-(+)-1b (230 mg,
20
57%) as colorless crystals; mp 103–104 ꢁC; ½aꢁD ¼ þ53:7
(c 1.0, CH2Cl2); IR (CHCl3) cmax/cmꢀ1 3417, 2956, 2931,
1
2858, 1738, 1513, 1248, 836; H NMR (500 MHz, CDCl3)
d 0.97 (9H, s, C(CH3)3), 1.02 (3H, s, CH3), 1.11 (3H, s,
CH3), 3.40 (2H, q, OCH2), 3.78 (1H, s, OCH3), 4.39 (1H,
d, J = 5.5, NCH), 5.02 (1H, d, J = 5.5), 6.86 (2H, d,
J = 9.0, ArH), 7.37 (2H, d, J = 9.0, ArH), 7.39; 13C
NMR (126 MHz, CDCl3) d ꢀ5.4 (SiCH3), 84.6 (SiCH3),
18.1 (Me3CSi), 20.8 ((CH3)2C), 21.1 ((CH3)2C), 25.7
((CH3)3CSi), 39.5 (C(CH3)2), 55.5 (OCH3), 62.9 (NCH),
69.8 (HOCH), 114.2, 121.0, 131.0, 156.8, 167.1 (CON);
HRMS: C20H33NO4Si (M+), calcd: 379.21790, found:
379.21787.
to give (3R,4S)-(+)-1d (340 mg, 53% yield) as a colorless
20
solid; mp 90–91 ꢁC; ½aꢁD ¼ þ48:7 (c 1.5, CH2Cl2); IR
(CHCl3) cmax/cmꢀ1 2956, 2931, 2857, 1749, 1512, 1378,
1247, 1131, 1036, 888, 836, 782; 1H NMR (500 MHz,
CDCl3) d 0.16 (3H, s, SiCH3), 0.25 (3H, s, SiCH3), 0.95
(6H, s, (CH3)3CSi), 1.01 (3H, s, CH3CC), 1.04 (3H, s,
CH3CC), 2.21 (1H, J = 13.8, OCH2Ph), 2.56 (1H, d,
J = 13.8, OCH2Ph), 2.43–2.48 (4H, m, CH2NCH2), 3.65–
3.66 (4H, m, CH2OCH2), 3.77 (3H, s, OCH3), 4.27 (1H,
d, J = 5.5, NCH), 4.96 (1H, d, J = 5.5, OCH), 6.83 (2H,
d, J = 8.8, ArH), 7.28 (2H, d, J = 8.8, ArH); 13C NMR
(126 MHz, CDCl3) d ꢀ5.4 (SiCH3), ꢀ4.4 (SiCH3), 18.1
(Me3CSi), 22.4 ((CH3)2C), 25.2 ((CH3)2C), 25.7
((CH3)3CSi), 40.3 (CMe2), 55.4 (OCH3), 56.2 (CH2NCH2),
65.7 (NCH), 76.5 (HOCH), 65.0 (CCH2O), 67.3
(CH2OCH2), 114.0, 121.7, 130.9, 156.6 (C–Ph), 167.4
(CO); HRMS: C24H40N2O4Si (M+), calcd: 448.27572,
found: 448.27602.
5.2. (3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(1-
formyl-1,1-dimethylmethyl)-1-(4-methoxyphenyl)azetidin-
2-one 1c19
A solution of oxalyl chloride (0.134 mL, 1.74 mmol) in dry
methylene chloride (12 mL) was placed in a 50 mL three-
neck round-bottom flask equipped with two dropping fun-
nels containing DMSO (0.265 mL, 3.76 mmol) dissolved in
methylene chloride (4 mL) and (3R,4S)-(+)-1b (660 mg,
1.88 mmol) dissolved in methylene chloride (8 mL), respec-
tively. When the reaction mixture was cooled to ꢀ60 ꢁC,
the DMSO solution was added to the mixture, stirred for
5 min; then, the alcohol solution was added over a period
of 10 min. After stirring at ꢀ60 ꢁC for 1 h, triethylamine
(1.368 mL, 9.88 mmol) was added and stirred for an addi-
tional 4 h at room temperature. When TLC indicated com-
plete conversion, water (10 mL) was added and stirred for
10 min, followed by addition of saturated ammonium chlo-
ride solution (10 mL). The solution was extracted with
methylene chloride (25 mL · 3), washed with brine, dried
over magnesium sulfate, and filtered. Evaporation under
5.4. (3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(2-(tert-
butyldimethylsilanyloxy)-1,1-dimethylethyl)-1-(4-methoxy-
phenyl)azetidin-2-one 1e
Hydroxy-b-lactam (3R,4S)-(+)-1a (1.06 g, 0.004 mol)
(1.0 equiv) was dissolved in dimethylformamide (2 mL).
tert-Butyldimethylsilyl chloride (1.32 g, 0.009 mol) and
imidazole (4 equiv) were added. The mixture was stirred
at 35 ꢁC until TLC indicated complete conversion (4 h).
The reaction was quenched with water and extracted with
methylene chloride (20 mL · 3). The combined organic ex-
tracts were washed with water (15 mL · 3) and brine, and
dried over magnesium sulfate. Filtration and concentration
vacuum gave (3R,4S)-(+)-1c (600 mg, 83%) as colorless
20
crystals; mp 110–111 ꢁC; ½aꢁD ¼ þ56:4 (c 1.05, CH2Cl2);
gave (3R,4S)-(+)-1e (1.4 g, 72% yield) as colorless crystals;
20
IR (CHCl3) cmax/cmꢀ1 2955, 2932, 2857, 1756, 1724,
1513, 1466, 1384, 1249, 1180, 1129, 894, 837, 783; 1H
NMR (500 MHz, CDCl3) d 0.15 (3H, s, CH3Si), 0.22
mp 82–83 ꢁC; ½aꢁD ¼ þ34:8 (c 1.0, CH2Cl2); IR (CHCl3)
1
c
max/cmꢀ1 2955, 2931, 2857, 1753, 1513, 1248, 1132; H
NMR (500 MHz, CDCl3) d 0.17 (6H, s, CH3Si), 0.24

2028
Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
(6H, s, CH3Si), 0.95 (18H, s, (CH3)3C), 3.15 (1H, d,
J = 10.1, CHOBn), 3.32 (1H, d, J = 10.1, CHOBn), 3.77
(3H, s, OCH3), 4.42 (1H, d, J = 5.5, NCH), 4.98 (1H, d,
J = 5.5, CHO), 6.80 (2H, d, J = 8.9, ArH), 7.30 (2H, d,
J = 8.9, ArH); 13C NMR (126 MHz, CDCl3) d ꢀ5.5
(CH3Si), ꢀ5.4 (CH3Si), ꢀ5.4 (CH3Si), ꢀ4.6 (CH3Si), 18.1
(Me3C), 18.3 (Me3C), 19.5 (CH3C), 20.8 (CH3C), 25.7
((CH3)3C), 25.9 ((CH3)3C), 39.3 (C(Me)2), 55.4 (OCH3),
61.3 (NCH), 76.0 (OCH), 70.5 (CH2), 113.9, 120.3, 131.5,
156.4 (C–Ph), 167.5 (CO). HRMS: C26H47NO4Si2 (M+),
calcd: 493.30435, found: 493.30518.
raphy on silica gel (hexane–ethyl acetate = 8:1) to afford
(3R,4S)-(+)-16 (917 mg, 94% yield) as a colorless oil;
20
½aꢁD ¼ þ57:1 (c 1.01, CH2Cl2); IR (CHCl3) cmax/cmꢀ1
2956, 2931, 2858, 1808, 1729, 1472,1318, 1256, 1156,
1095, 838, 780; 1H NMR (500 MHz, CDCl3) d ꢀ0.17
(3H, s, CH3Si), ꢀ0.18 (6H, s, CH3Si), ꢀ0.05 (3H, s,
CH3Si), 0.70 (9H, s, (CH3)3CSi), 0.72 (9H, s, (CH3)3CSi),
0.82 (1H, s, CH3C), 0.85 (1H, s, CH3C), 1.31 (9H, s,
(CH3)3CO), 3.20 (1H, d, J = 9.5, (CH)2O), 3.41 (1H, d,
J = 9.5, (CH)2O), 3.93 (1H, d, J = 6.6, NCH), 4.72 (1H,
d, J = 6.6, CHO); 13C NMR (126 MHz, CDCl3) d ꢀ5.5
((CH3)2Si), ꢀ5.5 (CH3Si), ꢀ4.7 (CH3Si), 18.0 (Me3CSi),
18.3 (Me3CSi), 20.1 (CH3C), 22.7 (CH3C), 25.6
((CH3)3CSi), 25.9 ((CH3)3CSi), 27.9 ((CH3)3CO), 39.4
(C(Me)2), 63.2 (NCH), 76.1 (OCH), 83.0 (Me3CO), 69.6
(CH2), 149.1 (COO), 167.8 (CO); HRMS: C24H49NO5Si2
(M+), calcd: 487.31491, found: 487.31496.
5.5. (3R,4S)-(+)-3-(tert-Butyldimethylsilanyloxy)-4-(2-
(tert-butyldimethylsilanyloxy)-1,1-dimethylethyl)azetidin-
2-one 15
A solution of b-lactam (3R,4S)-(+)-1e (262 mg, 0.531
mmol) in acetonitrile (25 mL) was cooled to ꢀ10 ꢁC.
CAN (1.016 g, 1.858 mmol) (3.5 equiv) in distilled water
(14 mL) was added dropwise to the solution over the peri-
od of 1 h. The reaction mixture was diluted with distilled
water (10 mL) and stirred at ꢀ10 ꢁC for 20 min. Then,
the mixture was extracted with ethyl acetate (50 mL · 3),
and the combined organic layers were washed with 5% so-
dium bisulfite solution (25 mL), 10% sodium carbonate
solution (25 mL), 5% sodium bisulfite solution (25 mL),
and brine (25 mL). The organic layers were dried over mag-
nesium sulfate, filtered, and concentrated under vacuum.
Purification of the crude products by flash chromatography
on silica gel (hexane–ethyl acetate = 7:1) as eluting solvent
5.7. (4R)-(+)-4-(2-Benzyloxy-1,1-dimethylethyl)-1-(4-meth-
oxyphenyl)azetidin-2,3-dione 14
Phosphorus pentoxide (568 mg, 1.5 equiv) was added to
dry DMSO (15 mL) and stirred at room temperature for
10 min. The starting material (3S,4R)-(ꢀ)-13 (710 mg,
2 mmol) dissolved in 6 mL of DMSO, was added dropwise.
The resulting mixture was stirred at room temperature, un-
til TLC indicated complete conversion (24 h). The reaction
was quenched with cooled saturated NaHCO3 solution and
extracted with ethyl acetate (25 mL · 3). The combined
organic layers were washed with water (20 mL · 3) to remove
excess DMSO, then, washed with brine, dried over MgSO4,
filtered, and concentrated under vacuum. The residue was
purified by flash chromatography on silica gel (hexane–
ethyl acetate = 8:1) and crystallized from hexane and ethyl
gave the N-H-lactam (3R,4S)-(+)-15 (152.3 mg, 74% yield)
20
as colorless crystals; mp 97–98 ꢁC; ½aꢁD ¼ þ47:1 (c 0.25,
CH2Cl2); IR (CHCl3) cmax/cmꢀ1 3232, 2955, 2930, 2858,
1
1763, 1472, 1254, 1190, 196, 890, 837, 729, 668; H NMR
(500 MHz, CDCl3) d 0.14 (6H, s, CH3Si), 0.19 (6H, s,
CH3Si), 0.87 (9H, s, (CH3)3C), 0.92 (9H, s, (CH3)3C),
1.02 ((CH3)2C), 3.26 (1H, d, J = 9.6, (CH)2O), 3.40 (1H,
d, J = 9.6, (CH)2O), 3.56 (1H, d, J = 5.0, NCH), 4.87
(1H, d, J = 5.0, CHO), 5.88 (NH); 13C NMR (126 MHz,
CDCl3) d ꢀ5.6 ((CH3)2Si), ꢀ5.5 (CH3Si), ꢀ4.6 (CH3Si),
18.0 (Me3CSi), 18.3 (Me3CSi), 19.3 (CH3C), 19.9 (CH3C),
25.7 ((CH3)3C), 25.9 ((CH3)3C), 37.3 (C(Me)2), 60.5
(NCH), 78.3 (OCH), 73.2 (CH2), 169.5 (CO); HRMS:
C19H41NO3Si2 (M+), calcd: 387.26251, found: 387.26272.
acetate to give (4R)-(+)-14 (310 mg, 55% yield) as yellow
20
crystals; mp: 137–138 ꢁC; ½aꢁD ¼ þ48:7 (c 0.75, CH2Cl2);
IR (CHCl3) cmax/cmꢀ1 2962, 2930, 2874, 1813, 1759,
1512, 1464, 1251, 1113, 1030, 978, 830, 739, 604; 1H
NMR (500 MHz, CDCl3) d 1.10 (3H, s, CH3), 1.14 (3H,
s, CH3), 3.19 (1H, s, OCH2Ph), 3.20 (1H, s, OCH2Ph),
3.86 (3H, s, OCH3), 4.49 (1H, s, CH2OBn), 4.51 (1H, s,
CH2OBn), 4.78 (1H, s, NCH), 6.92 (2H, d, J = 9.2,
ArH), 7.45 (2H, d, J = 9.2, ArH), 7.30–7.43 (5H, m,
ArH); 13C NMR (126 MHz, CDCl3) d 21.3 (CH3), 23.7
(CH3), 39.4 (CMe2), 55.6 (OCH3), 73.4 (OCH2Ph), 75.8
(NCH), 76.9 (CCH2O), 114.4, 121.1, 127.8, 128.5, 129.8,
137.6, 158.0 (C–Ph), 161.4 (CON), 194.4 (COC); HRMS:
C20H21NO4 (M+), calcd: 339.14706, found: 339.14711.
5.6. (3R,4S)-(+)-1-(tert-Butoxycarbonyl)-3-(tert-butyldi-
methylsilanyloxy)-4-(2-(tert-butyldimethylsilanyloxy)-
1,1-dimethylethyl)azetidin-2-one 16
Triethylamine (4 equiv) was added dropwise to a stirred
solution of N-H-b-lactam (3R,4S)-(+)-15 (775 mg,
2 mmol), di-tert-butyl-dicarbonate (808 mg, 4 mmol)
(2 equiv), and DMAP (0.3 equiv) in 15 mL of dry methyl-
ene chloride at room temperature. After the addition of
amine, the reaction mixture was monitored by TLC until
complete conversion was indicated. The reaction was
quenched with saturated aqueous NH4Cl solution
(15 mL), and extracted with ethyl acetate (30 mL · 3).
The combined organic layers were washed with saturated
aqueous NH4Cl (50 mL · 2) and brine solution, dried over
anhydrous MgSO4, filtered, and concentrated under vac-
uum. The crude material was purified by flash chromatog-
5.8. (3R,4R)-(+)-3-Hydroxy-4-(1,1-dimethyl-2-benzyloxy-
ethyl)-1-(4-methoxyphenyl)azetidin-2-one 13
Dry baker’s yeast (7 g) was added to a solution of sucrose
(26 g) in sterilized water (250 mL) contained in a 1 L flask
with 500 mL working volume. The mixture was stirred vig-
orously at 30 ꢁC for 30 min in order to activate the yeast.
Compound (4R)-(+)-14 (300 mg, 0.89 mmol), finely
ground with 300 mg of b-cyclodextrin, was added to a fer-
menting yeast and the reaction was monitored by TLC.
When the reaction reached 100% conversion (48 h), the
reaction was stopped. The reaction mixture was saturated
with sodium chloride and centrifuged at 3000g for 10 min

Y. Yang et al. / Tetrahedron: Asymmetry 18 (2007) 2021–2029
2029
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in order to remove yeast cells. The cell pellet was washed
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for 24 h and the combined extracts were washed with brine
and dried over anhydrous MgSO4. After removing the sol-
vent under reduced pressure, the crude residue was purified
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20
96 ꢁC; ½aꢁD ¼ þ39:5 (c 0.25, CH2Cl2); IR (CHCl3) cmax
/
1
cmꢀ1 3350, 2960, 2930, 2870, 1750, 1510, 1250; H NMR
(500 MHz, CDCl3) d 0.88 (3H, s, CH3), 1.02 (3H, s,
CH3), 3.10 (1H, s, CH2OBn), 3.11 (1H, s, CH2OBn), 3.75
(3H, s, OCH3), 4.13 (1H, s, NCH), 4.80 (1H, s, CHOH),
4.40 (1H, s, OCH2Ph), 4.42 (1H, s, OCH2Ph), 6.75 (2H,
d, J = 8.5, ArH), 7.16 (2H, d, J = 8.5, ArH), 7.24–7.39
(5H, m, ArH); 13C NMR (126 MHz, CDCl3) d 21.6
(CH3), 27.3 (CMe2), 5.5 (OCH3), 66.8 (NCH), 74.0
(HOCH), 74.6 (OCH2Ph), 77.2 (CCH2O), 114.2, 121.6,
128.3, 128.6, 128.7, 130.3, 136.2, 156.8, 168.4; HRMS:
C21H25NO4 (M+), calcd: 355.17857, found: 355.17838.
´
´ ´
´
18. Liptak, A.; Imre, J.; Harangi, J.; Nanasi, P.; Neszmelyi, A.
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´
20. Yang, Y.; Kayser, M. M.; Rochon, F. D.; Rodrıguez, S.;
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Financial support by the Natural Sciences and Engineering
Research Council of Canada (M.M.K.), and the Medical
Research Fund of New Brunswick (M.M.K.) are gratefully
acknowledged. The authors are deeply grateful to Dr. D. L.
Hooper for the NMR spectra recorded at the Atlantic
Regional Magnetic Resonance Centre at Dalhousie
University, Halifax, Canada.
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