Preparation of fused β-lactams through Weinreb amide α-anions

Article abstract of DOI:10.1016/j.tet.2014.05.054

Enantiomerically pure β-lactams bearing a Weinreb amide functionality at the C3 position have been shown to be excellent substrates for α-alkylation reactions, generating C3 quaternary centers with predictable absolute stereochemistry. In addition, oxidative coupling of C3/C4 dianions affords entry to fused β,γ-bislactam systems.

Full text of DOI:10.1016/j.tet.2014.05.054

Tetrahedron xxx (2014) 1e8
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Preparation of fused b-lactams through Weinreb amide a-anions
y
z
*
William M. Hewitt, Michael Egger , Nathaniel B. Zuckerman , Joseph P. Konopelski
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA 95064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically pure
b
-lactams bearing a Weinreb amide functionality at the C3 position have been
Received 16 April 2014
Received in revised form 15 May 2014
Accepted 15 May 2014
Available online xxx
shown to be excellent substrates for
predictable absolute stereochemistry. In addition, oxidative coupling of C3/C4 dianions affords entry to
fused -bislactam systems.
a-alkylation reactions, generating C3 quaternary centers with
b,g
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Weinreb amide
b
-lactams
Allylation
CeC coupling
a
-substitution
1. Introduction
Azetidin-2-ones (b-lactams) are among the most highly in-
vestigated heterocyclic ring systems. Beyond the obvious impact on
antibiotic research and treatment,1
-lactams have expressed bi-
ological activity in cholesterol absorption2 and as a target of viral
b
proteases.3 As synthetic organic reagents,4,5
b-lactams offer a well-
Scheme 1. Previous work.
defined stereochemical relationship between the adjacent sp3
centers and an amide carbonyl that is reactive by virtue of the 4-
continuing studies on this b-lactam system, with the goal of artic-
membered ring strain. In peptide chemistry
employed as turn mimics6,7 and as precursors to
and their related polymers10 -foldamers11,12) that have been the
b
-lactams have been
ulating reaction pathways toward synthetic building blocks offer-
ing myriad (orthogonal) functionalities around the EP four-
membered ring. The specific focus of the present studies was on
functionalization of the C3 center. In particular, we have found that
alkylation reactions occur with predictable stereochemistry at this
activated carbon. In addition, we present our results on the oxi-
dative coupling of the dianion formed from deprotonation of the C3
position and a C4 pendant NeH amide functionality, resulting in
the formation of a diazabicyclo[3.2.0]heptane structure.
b
-amino acids8,9
(b
focus of much study. New synthetic methods for the preparation of
this ring system continue to appear in the literature with great
frequency.13,14
Recently, we presented a new route to enantiomerically pure
(EP)
b-lactams, such as 1 and 2, from readily available a-amino
acids in a process that is efficient both in the use of photochemistry
for the key reaction and in the dearth of chromatographic separa-
tions (Scheme 1).15 In addition, the
b
-lactam Weinreb amide
functionality is able to effectively undergo reactions with Grignard
and alkyllithium reagents without opening of the -lactam ring due
2. Results and discussion
b
Generally, Weinreb amides have not been effective
a-anion-
to the steric presence of the N-Tr group. Herein we report our
stabilizing functionalities16; they are more often introduced into
the molecule of interest and directly reacted with alkyllithium or
Grignard reagents, or hydride reducing agents. Indeed, our pub-
* Corresponding author. Fax: þ1 831 459 2935; e-mail address: joek@ucsc.edu (J.
lished work documents this technology within the context of
b-
P. Konopelski).
lactam 1.15 Furthermore, our synthetic path to
b
-lactams involves
y
Present address: tesa SE, Quickbornstr. 24, 20253 Hamburg, Germany.
Present address: Lawrence Livermore National Laboratory, 7000 East Avenue
z
the anion of commercial N-methoxy-N-methylacetamide reacting
with an acylating agent that proceeds in excellent yield (vide infra).
#283, Livermore, CA 94551, USA.
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.054
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2
W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
Given the generally modest results when standard strong bases
have been employed for Weinreb amide -deprotonation, we de-
a
cided to employ KH, a base that we have used effectively in the
past.17 In the event, alkylation of the anion of 1 with both EtI and
allyl bromide/NaI afforded the expected products 3 and 4, re-
spectively, in good yield (Scheme 2). The major product derived
from approach of the electrophile from the least hindered face,
opposite to the eCH2OBn group, as evidenced by a single crystal X-
ray analysis of 4.18,19
Scheme 3. Bicyclo[3.2.0] framework.
biologically active core structure to the corresponding b-lactone
natural product proteasome inhibitors exemplified by salinospor-
amide A (Fig. 1).
Scheme 2.
a-Alkylation.
Reduction of the Weinreb amide with MeLi proceeded in ex-
cellent yield in the presence of the adjacent quaternary center,
affording methyl ketone 5. Elaboration of the allyl functionality in 4
proceeded by treatment with catalytic OsO4 followed by NaIO4 to
provide the chain-shortened aldehyde 6, which was reduced in
good yield with NaBH4 to afford the corresponding alcohol 7
(Scheme 2).
Our inability to remove the benzyl group in the presence of the
allyl double bond in 4 necessitated a change in the C4 protection
scheme (Scheme 3). We had published the standard deprotection of
1 to provide 8 previously,15 and introduction of both the eTBS and
the eTBDPS group on the primary alcohol proceeded in excellent
yield to give 9 (86%) and 10 (>99%), respectively. Allyl introduction
employing the same methodology as found in Scheme 2 afforded
vastly different yields, with 9 providing only 22% yield of the ex-
pected product 11 while 10 returned 12 in 82% as a single di-
astereomer. Deprotection of 12 with TBAF in refluxing THF afforded
fused bicyclic lactone 13, thereby confirming the cis relationship
between the Weinreb amide and hydroxymethyl side chain. Com-
pound 13 was also identified in the reaction mixture that produced
11, suggesting instability of the eTBS group to the reaction condi-
tions. Ketone production from 12 via methyllithium treatment
proceeded without incident to deliver 14 and deprotection of the
hydroxymethyl group again led to collapse of the alkoxide onto the
cis-C3 carbonyl functionality with production of lactol 15.
Fig. 1. Diazabicyclo[3.2.0] retrosynthesis.
In designing our approach to 16 we were also cognizant of one
perceived shortcoming in our published work with b-lactam 2. In
that previous effort, both the C4 carbomethoxy and C3 Weinreb
amide groups reacted competitively with methyllithium. While we
were able to provide a satisfactory solution through selective lith-
ium complexation of the Weinreb amide,15 it was decided to de-
velop an alternative approach that would result in the production
of a unique
b
-lactam with a reduced two-carbon substituent at C4,
-methionine was subjected to
i.e., -lactam 17. Toward this end,
b
L
van der Donk’s protocol,21 followed by trityl protection to provide
known22 crystalline lactone 18 on multigram scale in 70% yield.
Treatment of 18 with the anion of N-methyl-N-methoxyacetamide
proceeded to give the corresponding lactol 19 (stereochemistry not
defined). Protection of the primary alcohol functionality with TBSCl
Our success in accessing and reacting the
b-lactam Weinreb
amide -anion, together with our ability to manipulate the C4
a
substituent, presented alternative possibilities for generating
bicyclo[3.2.0] systems beyond compounds 13 and 15. Our attention
turned to diazabicyclo[3.2.0]heptane 16, a ring system that was m
ost recently described in the primary literature20 as an alternative
under standard conditions released the b-ketoamide functionality
to give 20 in 92% yield for the two steps. Diazo transfer afforded 21
in 97% yield, ready for diazo decomposition, Wolff rearrangement
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W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
3
Table 1
and amine collapse onto the transiently formed ketene. This cas-
Oxidative coupling of lactam dianion
cade of reactions was accomplished under both photolytic (4.5 h,
92%) and thermal (1 h, 89%) conditions, each providing excellent
yield of the desired product 22. Removal of the eTBS protection
group led to free alcohol 17 in 91% yield. Oxidation to acid 23 and
amide formation to give 24 proceeded without incident and in
excellent yield (Scheme 4).
Reagents
Conditions
Yield
PhI(OAc)2
PhIO, TBAI
1) LHMDS
2) PhI(OAc)2
1) LHMDS
2) I2
CH3CN, RT
Toluene, RT
THF,
NR
5%
5%
ꢀ78 to 0 ꢁC
THF,
32%
NR
ꢀ78 to 0 ꢁC
THF,
1) LHMDS
2) Cu(OAc)2
1) LHMDS
2) Fe(OAc)2
1) LHMDS
2) NBS
ꢀ78 to 0 ꢁC
THF,
NR
ꢀ78 to 0 ꢁC
THF,
28%
ꢀ78 to 0 ꢁC
transformed under standard conditions to provide building blocks
for future synthetic ventures. In addition, the dianion of 24, pre-
pared from L-methionine in high yield, has been shown to undergo
oxidative coupling to the corresponding diazabicyclo[3.2.0]heptane
16. Further optimization of this transformation and elaboration of
the product toward various products are ongoing and will be
communicated in due course.
4. Experimental section
4.1. General procedures
Melting point determinations are uncorrected. Infrared spectra
were recorded as thin films on salt plates, with nmax in inverse
centimeters (cmꢀ1). High-resolution mass measurements were
obtained on an ESITOF mass spectrometer. Flash chromatography
was performed on Silica Gel 60, 40e63 mesh using EtOAc/hexanes
mixtures as solvent unless otherwise indicated. Thin layer chro-
matography (TLC) was carried out on silica gel plates with UV de-
tection. Proton (1H NMR) and carbon (13C NMR) magnetic resonance
spectra where obtained in CDCl3 at 500 MHz, unless otherwise
noted, and 125 MHz, respectively. The following abbreviations were
utilized to describe peak patterns: br¼broad, s¼singlet, d¼doublet,
t¼triplet, q¼quartet, quin¼quintet, sex¼sextet, app¼apparent, and
m¼multiplet. All air and moisture sensitive reactions were carried
out under an atmosphere of dry nitrogen using oven-dried or flame-
dried glassware and standard syringe techniques. Triethylamine
(NEt3), N,N-dimethylpropyleneurea (DMPU), benzylamine, and
hexamethyldisilizane (HMDS) were distilled from calcium hydride.
Allyl bromide was passed through a column of basic alumina im-
mediately before use. N,N-Dimethylformamide was distilled se-
quentially from calcium hydride, then calcium oxide to remove trace
amounts of dimethylamine. N-Bromosuccinimide was recrystal-
lized from water. Tetrahydrofuran (THF), acetonitrile (CH3CN),
methylene chloride (CH2Cl2) and toluene were freshly obtained
from the solvent purification system. Compounds 115 and 1821,22
were prepared according to literature procedures. N-Methoxy-N-
methylacetamide was prepared by a procedure described in the
literature.25 Single crystal data were recorded using a Bruker SMART
Scheme 4. L-Met to b-lactam.
The key reaction for the formation of 16 was the oxidative
coupling between the anion at C3 and the anion produced by
deprotonation of the benzyl amide appended to C4 in 24. While
there are numerous examples of CeC bond formation through
oxidative coupling,23 fewer CeN bond forming events have been
described.24 Furthermore, we are unaware of the use of the
of a Weinreb amide in this technology.
a-anion
Table 1 provides our results to date. The use of hypervalent io-
dine compounds without preformation of the dianion species gave
minimal desired product, and classic copper and iron complexes
likewise led to poor results. Consistent, albeit modest, success came
from treatment of the dianion of 24 with I2. Treatment of the dia-
nion with NBS also resulted in desired material.
APEX II CCD area detector X-ray diffractometer using graphite
ꢀ
monochromated Mo-K
a
radiation (
l
¼0.71073 A). The structures
were solved by direct methods and expanded routinely. The models
were refined by full-matrix least-squares analysis of F2 against all
reflections. All non-hydrogen atoms were refined with anisotropic
thermal displacement parameters. Thermal parameters for the hy-
drogen atoms were tied to the isotropic thermal parameter of the
atom to which they are bonded. Programs used: APEX-II v2.1.4;26
SHELXTL v6.14.27,28
3. Conclusions
In conclusion, we have demonstrated that
are amenable to -alkylation of the Weinreb amide functionality,
generating a quaternary center with predictable stereochemistry.
The functional groups at C3 and C4 of the resultant -lactams are
Please cite this article in press as: Hewitt, W. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.054
b-lactams, such as 1
a
4.1.1. (2R,3R)-2-(Benzyloxymethyl)-3-ethyl-N-methoxy-N-methyl-4-
b
oxo-1-tritylazetidine-3-carboxamide (3). To
a
suspension of

4
W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
potassium hydride (30e35% in mineral oil, 141 mg, 1.056 mmol,
30 min, after which TLC (30% EtOAc/hexane) showed complete
consumption of starting material. The solution was quenched with
methanol, warmed to room temperature, and concentrated. The
residue was partitioned between dichloromethane (25 mL) and sat.
NH4Cl (25 mL) and the aqueous layer extracted with dichloro-
methane (2ꢂ15 mL). The combined organic layers were washed with
brine (25 mL), dried (MgSO4) and concentrated to obtain the product
1.1 equiv) in THF (10 mL) at ꢀ78 ꢁC was added the trans-
b-lactam 1
(500 mg, 0.960 mmol, 1 equiv). The solution was stirred for 30 min,
after which ethyl iodide (84 mL, 1.06 mmol, 1.1 equiv) was added.
The resulting solution was stirred overnight while slowly warming
to room temperature, after which TLC (30% EtOAc/Hexanes) in-
dicated consumption of starting material. The reaction was
quenched with sat. NH4Cl (10 mL) and the aqueous phase extracted
with dichloromethane (3ꢂ10 mL). The combined organics were
washed with brine (5 mL), dried (MgSO4), and concentrated to
obtain the title compound (268 mg) and its C3 epimer (116 mg) as
colorless solids (dr¼2.3:1, 73% combined yield). Major isomer:
(539 mg, 96% yield) as a colorless solid. Mp¼96e99 ꢁC; ½a D26
ꢀ35.7 (c
ꢃ
0.28, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d (ppm) 7.37e7.22 (m,
20H), 5.96 (dddd, J¼6.7, 8.1, 10.1, 16.9 Hz, 1H), 5.12 (d, J¼17.0 Hz, 1H),
5.07 (d, J¼10.5 Hz,1H), 4.03 (d, J¼10.0 Hz,1H), 3.86 (d, J¼10.5 Hz,1H),
3.73 (s, 1H), 3.12 (d, J¼10.5 Hz,1H), 2.71 (dd, J¼8.5, 14.0 Hz,1H), 2.60
(dd, J¼6.5, 13.5 Hz, 1H), 2.19 (s, 3H), 1.97 (d, J¼10.0 Hz, 1H); 13C NMR
mp¼118e122 ꢁC; ½a D24
ꢃ
62.8 (c 0.382, CH2Cl2) 1H NMR (500 MHz,
(ppm) 7.30e7.17 (m, 20H), 4.09 (d, J¼11.0 Hz, 1H), 3.90 (d,
CDCl3):
d
(125 MHz, CDCl3): d (ppm) 205.2, 168.6, 142.7, 137.1, 132.3, 130.2,
J¼11.5 Hz, 1H), 3.55 (s, 1H), 3.39 (s, 3H), 3.17 (m, 1H), 2.92 (s, 3H),
129.0,128.5,128.2,127.8,127.7, 119.4, 74.1, 73.2, 65.2, 64.0, 39.2, 31.2;
2.34e2.22 (m, 2H), 1.76 (m, 1H), 1.00 (t, J¼7.5 Hz, 3H); 13C NMR
IR (thin film) [cmꢀ1]:
1598, 1494, 1444, 1350, 699; HRMS for C35H33NO3Na [MþNa] calcd,
538.2353, found, 538.2362 (Error¼1.66 ppm).
n
¼3063, 3032, 2926, 2867, 1747, 1705, 1640,
(125 MHz, CDCl3):
d
(ppm) 168.3, 142.9, 138.0, 130.2, 128.3, 127.9,
127.8, 127.6, 127.5, 73.7, 73.2, 66.1, 64.4, 62.1, 61.8, 33.1, 29.9, 9.5; IR
(thin film) [cmꢀ1]:
699; HRMS for C35H36N2O4Na [MþNa] calcd, 571.2567, found,
571.2539 (error¼ꢀ4.88 ppm).
n
¼3056, 2879, 1748, 1639, 1452, 1275, 1104, 749,
4.1.5. (2R,3R)-2-((Benzyloxy)methyl)-N-methoxy-N-methyl-4-oxo-3-
(2-oxoethyl)-1-tritylazetidine-3-carboxamide (6). To a solution of
allyl
was added N-methylmorpholine-N-oxide (53 mg, 0.45 mmol,
1.7 equiv) and osmium tetroxide (as a solution in t-BuOH, 67 L,
5.3 mol, 0.02 equiv) and the resulting solution was allowed to stir
b-lactam 4 (149 mg, 0.27 mmol) in acetone/H2O (2.5 mL, 9:1)
4.1.2. (2R,3R)-3-Allyl-2-((benzyloxy)methyl)-N-methoxy-N-methyl-
4-oxo-1-tritylazetidine-3-carboxamide (4). To a suspension of po-
tassium hydride (110 mg, 0.960 mmol, 2 equiv) and sodium iodide
(7 mg, 0.096 mmol, 0.1 equiv) in tetrahydrofuran (10 mL) at room
m
m
overnight in the dark. TLC (50% EtOAc/hexane) showed complete
consumption of starting material. Sodium periodate (114 mg,
0.53 mmol, 2 equiv) was added and the solution was stirred for an
additional 2.5 h. The suspended solid was removed by vacuum
filtration and the solution concentrated under vacuum. The residue
was resuspended in water (10 mL) and extracted with EtOAc
(3ꢂ15 mL). The combined organic layers were washed with sat.
sodium thiosulfate (30 mL), brine (30 mL), dried (MgSO4), and
concentrated to obtain 6 (120 mg, 81% yield) as a colorless solid.
temperature was added b-lactam 1. The solution was stirred for
30 min, then cooled to ꢀ78 ꢁC and allyl bromide (45
mL, 0.502 mmol,
1.1 equiv) was added. The solution was stirred overnight while
slowly being allowed to warm to room temperature. TLC (50%EtOAc/
Hex) indicated complete consumption of starting material. The re-
action was quenched with sat. NH4Cl (20 mL). The mixture was
concentrated and extracted with EtOAc (3ꢂ20 mL) and the com-
bined organic layers were washed with brine (50 mL) and dried
(MgSO4). Concentration and purification by flash chromatography
(50% EtOAc/Hex) afforded 215 mg of 4 as a colorless solid and 34 mg
of its C3-epimer as a colorless solid (93% combined yield, dr¼6:1).
Mp¼56 ꢁC (decomposition); ½a 2D5
ꢃ
þ38.1 (c 0.173, CH2Cl2); 1H NMR
(500 MHz, CDCl3):
d
(ppm) 9.83 (dd, J¼1.0, 2.5 Hz, 1H), 7.37e7.26
(m, 20H), 4.18 (d, J¼11.0 Hz, 1H), 4.10 (d, J¼11.0 Hz, 1H), 3.99 (dd,
J¼2.0, 5.5 Hz, 1H), 3.54 (s, 3H), 3.06 (s, 3H), 2.98 (d, J¼9.5 Hz, 1H),
2.92 (d, J¼16.0 Hz, 1H), 2.87e2.82 (m, 2H); 13C NMR (125 MHz,
mp¼118e120 ꢁC; ½a D24
ꢃ
þ16.9 (c 4.5, CH2Cl2); 1H NMR (500 MHz,
CDCl3):
d
(ppm) 7.37e7.25 (m, 20H), 5.97 (app. sex, J¼8.0 Hz, 1H),
5.13 (d, J¼17.0 Hz,1H), 5.05 (d, J¼10.0 Hz,1H), 4.17 (d, J¼11.0 Hz,1H),
4.00 (d, J¼11.0 Hz,1H), 3.69 (s,1H), 3.45 (s, 3H), 3.24 (d, J¼6.0 Hz,1H),
2.98 (m, 4H), 2.57 (d, J¼6.0 Hz, 1H), 2.36 (app. s, 1H); 13C NMR
CDCl3): d (ppm) 198.5, 168.2, 166.4, 142.4, 137.5, 129.8, 128.3, 127.9,
127.7, 127.6, 74.0, 73.3, 66.4, 63.0, 61.8, 58.9, 47.1, 32.9; IR (thin film)
[cmꢀ1]:
n
¼3060, 2925, 1754, 1723, 1638, 1493, 1449, 1339, 751, 735,
(125 MHz, CDCl3):
d
(ppm) 167.6, 142.8, 138.0, 132.9, 130.2, 128.3,
700; HRMS for C35H34N2O5Na [MþNa] calcd, 585.2366, found,
585.2377 (Error¼1.88 ppm).
128.0, 127.8, 127.7, 127.5, 118.9, 74.0, 73.2, 66.1, 63.6, 61.8, 61.3, 40.3,
33.1; IR (thin film) [cmꢀ1]:
1493, 1449, 730, 700; HRMS for C36H37N2O4 [MþH] calcd, 561.2748,
found, 561.2738 (Error¼ꢀ1.75 ppm). X-ray quality crystals were
obtained by slow evaporation of a CH2Cl2/hexanes mixture.
n
¼3062, 3032, 2931, 1751, 1640, 1599,
4.1.6. (2R,3R)-2-((Benzyloxy)methyl)-3-(2-hydroxyethyl)-N-me-
thoxy-N-methyl-4-oxo-1-tritylazetidine-3-carboxamide (7). To a so-
lution of aldehyde 6 (118 mg, 0.210 mmol, 1 equiv) in MeOH (2 mL)
at 0 ꢁC was added sodium borohydride (24 mg, 0.631 mmol,
3 equiv). The solution was stirred for 30 min and concentrated to
dryness. The residue was redissolved in CH2Cl2 (10 mL), washed
with sat NH4Cl (3ꢂ10 mL), brine (10 mL), dried (MgSO4), and
concentrated to afford the product 7 as a colorless solid (82 mg, 69%
4.1.3. (2R,3S)-3-Allyl-2-((benzyloxy)methyl)-N-methoxy-N-methyl-
4-oxo-1-tritylazetidine-3-carboxamide. Mp¼151e154
ꢁC;
½ ꢃ
a 2D4
þ27.4 (c 3.4, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d (ppm) 7.36e7.22
(m, 20H), 5.78 (ddt, J¼17.0, 10.0, 7.0 Hz, 1H), 5.06 (d, J¼17.5 Hz, 1H),
5.03 (d, J¼10.0 Hz, 1H), 4.54 (s, 1H), 4.10 (d, J¼11.0 Hz, 1H), 3.92 (d,
J¼11.0 Hz, 1H), 3.70 (s, 3H), 3.31e3.28 (m, 4H), 3.10e3.09 (m, 2H),
yield). mp¼80e83 ꢁC; ½a D24
ꢃ
þ50.4 (c 0.222, CH2Cl2); 1H NMR
(500 MHz, CDCl3):
d
(ppm) 7.37e7.26 (m, 20H), 4.13 (d, J¼11.0 Hz,
2.34 (dd, J¼4.5, 13.0 Hz, 1H); 13C NMR (125 MHz, CDCl3):
d
(ppm)
1H), 4.02 (br s, 1H), 3.95 (d, J¼11.0 Hz, 1H), 3.75e3.71 (m, 3H), 3.39
(s, 3H), 3.32 (d, J¼10.5 Hz, 1H), 2.61 (ddd, J¼2.0, 4.5, 14.0 Hz, 1H),
2.22 (d, J¼10.0 Hz, 1H), 2.12 (ddd, J¼4.0, 9.0, 13.5 Hz, 1H); 13C NMR
169.5, 166.2, 142.5, 137.5, 133.9, 130.0, 128.5, 128.2, 127.9, 127.8,
127.5, 117.9, 73.8, 73.3, 66.3, 64.8, 61.7, 61.2, 47.9, 32.3; IR (thin film)
[cmꢀ1]:
n
¼3064, 3032, 2932, 2862, 1755, 1642, 1493, 1444, 1345,
(125 MHz, CDCl3): d (ppm) 169.5, 169.4, 142.2, 137.7, 130.0, 128.3,
732, 700; HRMS for C36H37N2O4 [MþH] calcd, 561.2748, found,
128.1, 127.9, 127.7, 74.0, 73.2, 65.5, 64.3, 61.7, 61.2, 60.1, 39.1, 33.1; IR
561.2732 (Error¼ꢀ2.73 ppm).
(thin film) [cmꢀ1]:
752, 700; HRMS for C35H37N2O5 [MþH] calcd, 565.2697, found,
565.2707 (Error¼1.77 ppm).
n
¼3436, 3059, 2925,1749,1641,1493, 1445,1357,
4.1.4. (3S,4R)-3-Acetyl-3-allyl-4-(benzyloxymethyl)-1-tritylazetidin-
2-one (5). To a solution of allyl b-lactam 4 (612 mg, 1.09 mmol,
1 equiv) inTHF(11 mL)at ꢀ41 ꢁC was addedmethyllithium(asa 1.6M
4.1.7. (2R,3S)-2-((tert-Butyldimethylsilyloxy)methyl)-N-methoxy-N-
methyl-4-oxo-1-tritylazetidine-3-carboxamide (9). To a solution of
solution in ether, 1.87 mL, 2 equiv). The solution was stirred for
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W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
5
b
-lactam 815 (301 mg, 0.699 mmol, 1 equiv) in dimethylformamide
1449, 776, 755, 734, 701; HRMS for C35H44N2O4SiNa [MþNa] calcd,
607.2968, found, 607.2990 (Error¼3.62 ppm).
(1 mL) was added tert-butyldimethylsilyl chloride (158 mg,
1.05 mmol, 1.5 equiv) and imidazole (143 mg, 2.10 mmol, 3 equiv).
The solution was stirred overnight, after which TLC (50% EtOAc/
Hex) indicated complete consumption of starting material. The
solution was diluted with water (25 mL) and extracted with EtOAc
(3ꢂ25 mL). The combined organic layers were washed with water
(3ꢂ50 mL), brine (50 mL), dried (MgSO4), and concentrated. The
resulting residue was purified by flash chromatography (15% EtOAc/
Hex to 30% EtOAc/Hex) to obtain 328 mg (86% yield) of product 9 as
4.1.10. (2R,3R)-3-Allyl-2-(((tert-butyldiphenylsilyl)oxy)methyl)-N-
methoxy-N-methyl-4-oxo-1-tritylazetidine-3-carboxamide (12). To
a suspension of potassium hydride (367 mg, 3.21 mmol, 3 equiv)
and sodium iodide (16 mg, 0.11 mmol, 0.1 equiv) in THF at 0 ꢁC was
added the trans-
solution was stirred for 30 min, after which allyl bromide (185
b
-lactam 10 (715 mg, 1.07 mmol, 1 equiv). The
L,
m
2.14 mmol, 2 equiv) was added. The resulting solution was warmed
to room temperature and stirred overnight, after which TLC (30%
EtOAc/Hexanes) indicated consumption of starting material. The
reaction was quenched with sat. NH4Cl (1 mL) and the aqueous
phase extracted with EtOAc (3ꢂ1 mL). The combined organics were
washed with brine (5 mL), dried (MgSO4), and concentrated to
obtain the title compound 12 (621 mg, 82% yield) as a single di-
a colorless solid. mp¼82e84 ꢁC; ½a D23
ꢃ
þ10 (c 0.8, CH2Cl2); 1H NMR
(500 MHz, CDCl3): d (ppm) 7.34e7.29 (m, 15H), 4.56 (s, 1H), 4.28 (s,
1H), 3.80 (s, 3H), 3.25 (s, 3H), 3.13 (d, J¼11.5 Hz, 1H), 2.45 (d,
J¼11.5 Hz, 1H), 0.88 (s, 9H), ꢀ0.06 (s, 3H), ꢀ0.07 (s, 3H); 13C NMR
(125 MHz, CDCl3):
d (ppm) 167.9, 163.7, 142.2, 130.1, 127.9, 127.6,
74.1, 62.5, 60.7, 57.6, 51.1, 32.4, 25.9, 25.8, 18.4, ꢀ5.3, ꢀ5.7; IR (thin
film) [cmꢀ1]:
n¼3060, 3033, 2954, 2930, 2857, 1755, 1658, 1445,
astereomer. mp¼60e63 ꢁC; ½a D25
ꢃ
þ33.6 (c 3.65, CH2Cl2); 1H NMR
1348, 735, 701; HRMS for C32H40N2O4SiNa [MþNa] calcd, 567.2655,
found, 567.2681 (Error¼4.58 ppm).
(500 MHz, CDCl3): d (ppm) 7.46e7.32 (m, 10H), 7.17e7.13 (m, 15H),
6.06 (app. ddt, J¼7.0, 10.0, 17.0 Hz, 1H), 5.23 (d, J¼17.0 Hz, 1H), 5.09
(d, J¼10.0 Hz, 1H), 3.76 (dd, J¼3.5, 10.0 Hz,1H), 3.68 (app. t, J¼10 Hz,
1H), 3.41 (s, 3H), 3.20 (dd, J¼7.0, 14.0 Hz, 1H), 3.15 (s, 3H), 2.82 (dd,
J¼3.5, 10.0 Hz, 1H), 2.66 (dd, J¼7.0, 14.0 Hz, 1H), 0.94 (s, 9H); 13C
4.1.8. (2R,3S)-2-(((tert-Butyldiphenylsilyl)oxy)methyl)-N-methoxy-
N-methyl-4-oxo-1-tritylazetidine-3-carboxamide (10). To a solution
of
(1.5 mL) was added tert-butyldiphenylsilyl chloride (1.24
4.75 mmol, 3 equiv), imidazole (324 mg, 4.75 mmol, 3 equiv), and
triethylamine (662 L, 4.75 mmol, 3 equiv). The solution was stirred
b
-lactam 815 (682 mg, 1.58 mmol, 1 equiv) in dimethylformamide
NMR (125 MHz, CDCl3): d (ppm) 167.7, 167.0, 142.8, 135.9, 134.0,
mL,
133.6, 133.5, 129.7, 129.6, 127.8, 127.6, 127.4, 118.5, 73.7, 65.0, 62.3,
61.7, 60.8, 39.7, 32.9, 26.8, 19.2; IR (thin film) [cmꢀ1]:
2858, 1754, 1653, 736, 701; HRMS for C45H48N2O4SiNa [MþNa]
calcd, 731.3281, found, 731.3301 (Error¼2.73 ppm).
n
¼3071, 2933,
m
for 10 h at 60 ꢁC, after which TLC (50% EtOAc/Hex) indicated
complete consumption of starting material. The solution was di-
luted with water (15 mL) and extracted with CH2Cl2 (3ꢂ15 mL). The
combined organic layers were washed with water (3ꢂ30 mL), brine
(5 mL), dried (MgSO4), and concentrated. The resulting residue was
purified by flash chromatography (10% EtOAc/Hex to 30% EtOAc/
Hex) to obtain 1.065 g (100% yield) of product 10 as a colorless solid.
4.1.11. (1R,5R)-1-Allyl-6-trityl-3-oxa-6-azabicyclo[3.2.0]heptane-
2,7-dione (13). To a solution of b-lactam 12 (101 mg, 0.14 mmol,
1 equiv) in THF (0.57 mL) was added TBAF (1 M solution in THF,
0.43 mL, 3 equiv). The resulting solution was refluxed for 16 h. The
solution was quenched with sat. aq. NH4Cl (5 mL) and extracted
with EtOAc (3ꢂ5 mL). The combined organic layers were washed
with brine (10 mL), dried over MgSO4, and concentrated. Flash
chromatography (15% EtOAc/Hex to 50% EtOAc/Hex) afforded the
title compound 13 (35 mg, 60% yield) as a colorless solid.
mp¼74e77 ꢁC; ½a 2D5
ꢃ
þ34.8 (c 3.0, CH2Cl2); 1H NMR (500 MHz,
CDCl3): d (ppm) 7.54e7.24 (m, 25H), 4.73 (s, 1H), 4.32 (s,1H), 3.78 (s,
3H), 3.25 (s, 3H), 3.07 (d, J¼12.0 Hz, 1H), 2.81 (dd, J¼4.0, 12.0 Hz,
1H), 1.07 (s, 9H); 13C NMR (125 MHz, CDCl3):
(ppm) 167.7, 163.8,
142.3, 135.8, 135.7, 132.9, 132.7, 130.1, 129.9, 128.0, 127.8, 127.6, 74.2,
62.7, 61.8, 57.6, 51.4, 32.5, 27.1, 19.4; IR (thin film) [cmꢀ1]:
¼3057,
2932, 2858, 1755, 1657, 1445, 1428, 1347, 739, 701; HRMS for
d
Mp¼158e160 ꢁC; ½a D24
ꢃ
þ105.5 (c 1.83, CH2Cl2); 1H NMR (500 MHz,
n
CDCl3): d (ppm) 7.35e7.34 (m, 9H), 7.14e7.12 (m, 6H), 5.82 (ddt,
J¼10.0, 17.0, 7.5 Hz, 1H), 5.26 (dd, J¼1.0, 17.0 Hz, 1H), 5.20 (dd, J¼1.0,
10.0 Hz, 1H), 4.45 (d, J¼4.5 Hz, 1H), 3.74 (dd, J¼4.5, 11.5 Hz, 1H), 3.25
(d, J¼11.5 Hz,1H), 2.80 (d, J¼7.5 Hz, 2H); 13C NMR (125 MHz, CDCl3):
C
42H45N2O4Si [MþH] calcd, 669.3143, found, 669.3163
(Error¼3.01 ppm).
d
(ppm) 171.4,162.6,141.7,131.5,129.7,128.5,128.3,120.4, 74.8, 68.6,
4.1.9. (2R,3R)-3-Allyl-2-((tert-butyldimethylsilyloxy)methyl)-N-me-
62.8, 58.4; IR (thin film) [cmꢀ1]:
n
¼3060, 2928, 2856, 1787, 1751,
thoxy-N-methyl-4-oxo-1-tritylazetidine-3-carboxamide
a suspension of KH (147 mg, 1.10 mmol, 2 equiv) and NaI (8 mg,
0.055 mmol, 0.1 equiv) in THF (5 mL) at 0 ꢁC was added trans-
lactam 9 (300 mg, 0.551 mmol,1 equiv). The solution was stirred for
1 h, after which allyl bromide (52 L, 0.606 mmol, 1.1 equiv) was
(11). To
1598, 1492, 1445, 741, 700; HRMS for C27H24NO3 [MþH] calcd,
410.1756, found, 410.1764 (Error¼1.95 ppm).
b
-
4.1.12. (3S,4R)-3-Acetyl-3-allyl-4-(((tert-butyldiphenylsilyl)oxy)
m
methyl)-1-tritylazetidin-2-one (14). To a solution of allyl b-lactam
added. The reaction mixture was allowed to stir overnight while
warming to room temperature. The solution was quenched with
sat. NH4Cl (10 mL) and the aqueous layer extracted with dichloro-
methane (2ꢂ10 mL). The combined organic layers were washed
with brine (5 mL), dried (MgSO4), concentrated, and the residue
purified by flash chromatography (gradient, 30% EtOAc/hexane to
70% EtOAc/hexane) to afford the title compound as a colorless solid
(70 mg, 22% yield), along with the fused lactone/lactam 13 (22 mg,
10% yield) as a colorless solid. Analytical data for 11: mp¼69e72 ꢁC;
12 (50 mg, 70.5
m
mol, 1 equiv) in THF (1 mL) at ꢀ41 ꢁC was added
methyllithium (as a 1.6 M solution in ether, 0.26 mL, 6 equiv). The
solution was stirred for 30 min, after which TLC (30% EtOAc/hex-
ane) showed complete consumption of starting material. The so-
lution was quenched with methanol, warmed to room temperature,
and concentrated. The residue was partitioned between CH2Cl2
(5 mL) and sat. aq. NH4Cl (5 mL) and the aqueous layer extracted
with CH2Cl2 (2ꢂ5 mL). The combined organic layers were washed
with brine (5 mL), dried (MgSO4) and concentrated to obtain the
product 14 (42 mg, 89% yield) as a colorless solid. mp¼63e67 ꢁC;
½
a 2D5
ꢃ
þ30.6 (c 5.8, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d (ppm) 7.29
(app. s, 15H), 6.03 (ddt, J¼10.0, 17.0, 7.0 Hz, 1H), 5.16 (dd, J¼2.0,
17.0 Hz, 1H), 5.05 (dd, J¼2.0, 10.0 Hz, 1H), 3.70 (dd, J¼3.0, 6.5 Hz,
1H), 3.50 (s, 3H), 3.20 (s, 4H), 3.07 (dd, J¼7.0, 14.0 Hz,1H), 3.03 (app.
s, 1H), 2.68 (dd, J¼7.0, 14.0 Hz, 1H), 0.79 (s, 9H), ꢀ0.16 (s, 6H); 13C
½
a 2D6
ꢃ
þ11.8 (c 3.35, CH2Cl2); 1H NMR (500 MHz, CDCl3):
d (ppm)
7.47e7.45 (m, 5H), 7.41e7.34 (m, 5H), 7.21e7.12 (m, 15H), 5.90 (ddt,
J¼10.0, 17.0, 7.0 Hz, 1H), 5.20 (dd, J¼1.0, 17.0 Hz, 1H), 5.12 (d,
J¼10.0 Hz, 1H), 3.78 (dd, J¼7.8, 3.7 Hz, 1H), 3.41 (dd, J¼10.8, 7.9 Hz,
1H), 2.97 (dd, J¼10.9, 3.7 Hz, 1H), 2.83 (dd, J¼7.1, 14.0 Hz, 1H), 2.74
(dd, J¼7.2, 14.0 Hz, 1H), 2.36 (s, 3H), 0.99 (d, J¼9.5 Hz, 9H).; 13C NMR
NMR (125 MHz, CDCl3):
d (ppm) 167.6, 143.1, 133.6, 130.1, 127.9,
127.6, 118.4, 73.8, 65.5, 61.9, 60.9, 60.1, 40.5, 33.1, 26.0, 18.3, ꢀ5.2,
ꢀ5.5; IR (thin film) [cmꢀ1]:
n
¼3060, 2930, 1754, 1653, 1599, 1493,
(125 MHz, CDCl3): d (ppm) 204.8, 168.2, 142.5, 135.8, 132.8, 129.89,
Please cite this article in press as: Hewitt, W. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.054

6
W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
129.74, 127.89, 127.76, 127.5, 119.4, 74.6, 67.0, 63.5, 61.3, 37.6, 30.3,
27.1, 19.3; IR (thin film) [cmꢀ1]:
1590, 1491, 1449, 822, 741, 701; HRMS for C44H45NO3SiNa [MþNa]
calcd, 686.3061, found, 686.3063 (Error¼0.27 ppm).
TLC (30% EtOAc/Hex) indicated complete consumption of starting
material. The solution was diluted in water (25 mL) and extracted
with EtOAc (3ꢂ50 mL) and the combined organics washed with
water (3ꢂ75 mL), brine (75 mL), dried (MgSO4), and concentrated
to afford 2.60 g of product 20 (92% yield) as a thick oil and was used
without further purification. An analytically pure sample was ob-
tained by flash chromatography (25% EtOAc/Hex to 50% EtOAc/Hex)
as a mixture of keto and enol tautomers (approx. 2.5:1 ratio; 1H
NMR data shown with major isomer H-count in whole integers and
n
¼3070, 2926, 2855, 1755, 1712,
4.1.13. (1S,5R)-1-Allyl-2-hydroxy-2-methyl-6-trityl-3-oxa-6-
azabicyclo[3.2.0]heptan-7-one (15). To a solution of lactam 14
(401 mg, 0.60 mmol, 1 equiv) in THF (2.2 mL) was added TBAF (1 M
solution in THF, 1.8 mL, 3 equiv) and acetic acid (0.26 mL,
4.53 mmol, 7.5 equiv). The solution was stirred at reflux for 4 h,
after which TLC (30% EtOAc/hexane) showed consumption of
starting material. The solution was quenched with sat. aq. NaHCO3
(10 mL) and extracted with EtOAc (3ꢂ10 mL). The combined or-
ganic layers were washed with brine (15 mL), dried over MgSO4,
and concentrated. The residue was purified by silica gel chroma-
tography (25% EtOAc/Hex to 50% EtOAc/Hex) to afford the title
minor isomer H-count as decimals). ½a D26
ꢃ
þ7.3 (c 3, CH2Cl2); 1H
NMR (500 MHz, CDCl3): d (ppm) 7.52e7.49 (m, 2.4H), 7.47e7.44 (m,
6H), 7.28e7.13 (m, 12.6H), 5.05 (s, 0.4H), 3.80e3.61 (m, 3.8H), 3.60
(s, 1.2H), 3.54 (s, 3H), 3.46e3.41 (m, 2H), 3.34e3.28 (m, 0.4H),
3.27e3.23 (m, 1H), 3.13 (s, 1.2H), 3.12 (s, 3H), 3.07 (s, 0.4H),
3.04e3.01 (m, 0.4H), 1.90e1.82 (m, 1.4H), 1.67e1.60 (m, 1H),
1.53e1.46 (m, 0.4H), 0.85 (s, 9H), 0.82 (s, 3.6H), 0.05 (s, 3H), 0.03 (s,
compound 15 (177 mg, 69% yield) as
a
colorless solid.
3H), 0.01 (s, 2.4H); 13C NMR (125 MHz, CDCl3):
d (ppm) 207.4, 178.3,
mp¼174e177 ꢁC; ½a D24
ꢃ
þ66.7 (c 2.0, CH2Cl2); 1H NMR (500 MHz,
171.7, 168.2, 146.9, 146.4, 129.2, 128.0, 127.8, 126.7, 126.4, 87.4, 71.5,
61.4, 61.3, 60.7, 60.0, 59.8, 55.1, 44.2, 37.1, 36.2, 32.0, 26.0, 25.9, 18.3,
CDCl3):
d (ppm) 7.29 (app. s, 9H), 7.16 (app. s, 6H), 6.03 (app. dp,
J¼7.5, 9.7 Hz, 1H), 5.25 (d, J¼16.9 Hz, 1H), 5.15 (d, J¼9.7 Hz, 1H), 4.11
(d, J¼2.0 Hz, 1H), 3.47 (dd, J¼10.7, 2.0 Hz, 1H), 2.75 (d, J¼10.7 Hz,
1H), 2.66e2.57 (m, 2H), 2.09 (s,1H),1.59 (s, 3H); 13C NMR (125 MHz,
ꢀ5.4; IR (thin film) [cmꢀ1]:
¼3435, 2954, 2856, 2102, 1633, 1471,
n
1447, 1254; HRMS for C33H44N2O4NaSi [MþNa] calcd, 583.2963,
found, 583.2978 (Error¼2.6 ppm).
CDCl3):
74.4, 67.8, 65.4, 63.2, 30.8, 23.5; IR (thin film) [cmꢀ1]:
2984, 2935, 1730, 1642, 1598, 1493, 1445, 737, 701; HRMS for
28H27NO3 calcd, 426.2064, found, 426.2072
[MþH]
(Error¼2.02 ppm).
d
(ppm) 168.1, 142.7, 134.3, 130.1, 127.9, 127.7, 118.9, 102.5,
n
¼3411, 3060,
4.1.16. (S)-6-((tert-Butyldimethylsilyl)oxy)-2-diazo-N-methoxy-N-
methyl-3-oxo-4-(tritylamino)hexanamide (21). To a solution of
b-
C
ketoamide 20 (6.3 g, 11.2 mmol) in acetonitrile (140 mL) was added
methanesulfonyl azide (1.5 mL, 16.9 mmol, 1.5 equiv) and 1,8-
diazabicyclo[2.2.0]undec-1-ene (DBU, 2.2 mL, 14.6 mmol,
1.3 equiv). The mixture was stirred at room temperature under
nitrogen for 4 h, concentrated and filtered over a plug of silica
(elution with hexanes/EtOAc 3:1). The clear solution was again
concentrated and the remaining solid was crystallized from CH2Cl2/
hexanes to obtain 6.4 g (97% yield) of 21 as a colorless solid.
4.1.14. 2-((3S)-2-Hydroxy-3-(tritylamino)tetrahydrofuran-2-yl)-N-
methoxy-N-methylacetamide (19). Hexamethyldisilazane (14.0 mL,
67.0 mmol, 2.3 equiv) was dissolved in dry THF (50 mL) and cooled
to 0 ꢁC. A solution of n-BuLi (2.5 M solution in hexanes, 25.6 mL,
64.1 mmol, 2.2 equiv) was added and the mixture was stirred for
15 min at 0 ꢁC. The solution was cooled to ꢀ78 ꢁC and N-methoxy-
N-methylacetamide (6.5 mL, 61.2 mmol, 2.1 equiv) was added
dropwise. The mixture was stirred for 45 min at ꢀ78 ꢁC and N,N-
dimethylpropyleneurea (DMPU, 50 mL) was added. After stirring
for an additional 15 min, a solution of lactone 18 (10.0 g, 29.1 mmol,
1 equiv) in THF (50 mL) was added, resulting in a deeply red so-
lution. The cooling bath was replaced by an ice bath and the solu-
tion was allowed to warm to 0 ꢁC and stirred for 2 h. The reaction
was quenched with a saturated aqueous solution of NH4Cl,
extracted with EtOAc, washed with brine, dried (MgSO4) and con-
centrated. The resulting residue was dissolved in a minimal amount
of CH2Cl2 and applied to a silica plug. The plug was first washed
with 10% EtOAc/Hex. The product was then eluted with EtOAc, and
the EtOAc was concentrated to obtain the title compound 19 as
a colorless solid and was employed in the next reaction without
mp¼124 ꢁC (decomposition); ½a 2D5
ꢃ
ꢀ28.0 (c 3.8, CH2Cl2); 1H NMR
(500 MHz, CDCl3):
d (ppm) 7.50e7.52 (m, 6H), 7.20e7.23 (m, 6H),
7.13e7.16 (m, 3H), 4.64e4.71 (m, 1H), 3.85 (app. t, J¼7.4 Hz, 2H),
3.61 (s, 3H), 3.48 (d, J¼10.6 Hz, 1H), 3.12 (s, 3H), 1.98e2.05 (m, 1H),
1.83e1.90 (m, 1H), 0.90 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR
(125 MHz, CDCl3):
71.2, 61.2, 60.3, 56.7, 38.0, 33.7, 26.0, 18.4, ꢀ5.2; IR (thin film)
[cmꢀ1]:
d (ppm) 196.1, 162.3, 146.6, 129.2, 127.8, 126.4,
n
¼3310, 3057, 2953, 2929, 2114, 1641, 1362, 1187, 1091;
HRMS for C33H43N4O4Si [MþH] calcd, 587.3048, found, 587.3069
(Error¼3.6 ppm).
4.1.17. (2S,3S)-2-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-N-methoxy-
N-methyl-4-oxo-1-tritylazetidine-3-carboxamide (22). Method A: A
degassed solution of
a-diazo-b-ketoamide 21 (5.7 g, 9.7 mmol,
1 equiv) in dry toluene (1 L), was cooled to 0 ꢁC and irradiated with
a medium pressure mercury vapor lamp for 4.5 h. DBU (7.2 mL,
48.5 mmol, 5 equiv) was added and the mixture was stirred at room
temperature overnight, concentrated and filtered over a plug of
silica (elution with EtOAc/hexanes 1:1). After removal of the sol-
vents the remaining oil was redissolved in EtOAc, washed with
saturated aqueous NH4Cl, water and brine and dried over MgSO4.
Concentration afforded 22 as a white foam (5.0 g, 92% yield), which
was used for the next step without further purification. Analytical
data were obtained from the crystalline solid after purification by
flash chromatography on silica gel (elution with hexanes/EtOAc 2:1,
1:1).
purification. mp¼60e64 ꢁC; ½a D25
ꢃ
ꢀ12.5 (c 53, CH2Cl2); 1H NMR
(500 MHz, CDCl3):
d
(ppm) 7.57 (d, J¼7.5 Hz, 6H), 7.26 (app. t,
J¼7.5 Hz, 6H), 7.18 (t, J¼7.5 Hz, 3H), 3.81 (app. dt, J¼3.5, 9.0 Hz, 1H),
3.66 (s, 3H), 3.48 (app. q, J¼8.0 Hz, 1H), 3.20 (s, 3H), 2.96 (dd, J¼8.0,
8.5 Hz, 1H), 2.70 (d, J¼15.5 Hz, 1H), 2.56 (d, J¼15.5 Hz, 1H), 2.39 (br-
s, 1H), 1.35 (app. quin, J¼9.0 Hz, 1H), 1.22 (m, 1H); 13C NMR
(125 MHz, CDCl3):
d (ppm) 173.2, 147.1, 129.0, 128.0, 126.5, 102.8,
70.5, 64.9, 61.6, 60.2, 36.7, 31.9, 31.2; IR (thin film) [cmꢀ1]:
3057, 2939, 2891, 1632, 1596, 1489, 1448, 1389, 771, 736, 709; HRMS
for
n¼3347,
C
27H31N2O4 [MþH] calcd, 447.2278, found, 447.2263
(Error¼ꢀ3.34 ppm).
Method B: To a degassed solution of
a-diazo-b-ketoamide 21
4.1.15. (S)-6-((tert-Butyldimethylsilyl)oxy)-N-methoxy-N-methyl-3-
oxo-4-(tritylamino)hexanamide (20). To a solution of the above
lactol 19 (2.384 g, 5.01 mmol, 1 equiv) in freshly distilled dime-
thylformamide (5 mL) was added tert-butyldimethylsilyl chloride
(1.133 g, 7.52 mmol, 1.5 equiv) and imidazole (682 mg, 10.0 mmol,
3 equiv). The resulting solution was stirred overnight, after which
(2.46 g, 4.19 mmol, 1 equiv) in dry toluene (1 L) was added DBU
(3.1 mL, 21.0 mmol, 5 equiv). The resulting solution was refluxed
under N2 for 1 h. After cooling to room temperature, the solution
was washed with aq. 5% citric acid (3ꢂ100 mL), brine (50 mL), dried
over MgSO4, and concentrated to afford the title compound (2.09 g,
89% yield) as a colorless solid, which was used for the next step
Please cite this article in press as: Hewitt, W. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.054

W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
7
without further purification. mp¼92e94 ꢁC; ½a D26
ꢃ
þ2.0 (c 2.6,
126.6, 73.2, 61.6, 54.5, 53.9, 41.8, 37.8, 31.7; IR (thin film) [cmꢀ1]:
CH2Cl2); 1H NMR (500 MHz, CDCl3):
d
(ppm) 7.26e7.34 (m, 15H),
n
¼3424, 3061, 2929, 1754, 1657, 1652, 1543, 1494, 1446, 735, 700;
4.39 (br d, J¼10.6 Hz, 1H), 4.35 (br s, 1H), 3.82 (s, 3H), 3.42e3.46 (m,
1H), 3.33e3.38 (m, 1H), 3.26 (s, 3H), 1.43e1.50 (m, 1H), 0.97e1.02
(m, 1H), 0.82 (s, 9H), ꢀ0.06 (s, 3H), ꢀ0.07 (s, 3H); 13C NMR
HRMS for C34H33N3O4Na [MþH] calcd, 548.2544, found, 548.2555
(Error¼1.08 ppm).
(125 MHz, CDCl3):
d
(ppm) 167.6, 163.9, 142.4, 129.9, 128.0, 127.6,
4.1.21. (1R,5S)-2-Benzyl-N-methoxy-N-methyl-3,7-dioxo-6-trityl-
74.0, 62.6, 60.3, 56.3, 35.6, 32.3, 25.9, 18.3, ꢀ5.6, ꢀ5.7; IR (thin film)
2,6-diazabicyclo[3.2.0]heptane-1-carboxamide (16). General Pro-
cedure: A solution of the above secondary amide (55 mg,
[cmꢀ1]:
n
¼3059, 2953, 2928, 2856,1752,1657,1445,1101; HRMS for
C
33H43N2O4Si [MþH] calcd, 559.2987, found, 559.2982
0.10 mmol) in THF (1 mL) was cooled to ꢀ78 ꢁC. A freshly prepared
solution of LHMDS (0.17 mL, 1 M Solution in THF, 2.2 equiv) was
added and the solution was stirred at ꢀ78 ꢁC for 1 h. An oxidant
(0.2 mmol, 2 equiv) was then added. The solution was warmed to
0 ꢁC and allowed to stir for an additional 2 h before being quenched
with aq. sat. NaHCO3 (2 mL) and aq. sat. Na2S2O3 (2 mL). After
stirring for 5 min, the aqueous layer was extracted with EtOAc
(3ꢂ5 mL). The combined organic layers were washed with aq. sat.
NH4Cl (3ꢂ10 mL), Brine (10 mL), and dried over MgSO4. The crude
residue was then purified by flash chromatography (30% EtOAc/Hex
to 100% EtOAc) to afford the desired product 16 as a colorless solid.
(Error¼ꢀ0.8 ppm).
4.1.18. (2S,3S)-2-(2-Hydroxyethyl)-N-methoxy-N-methyl-4-oxo-1-
tritylazetidine-3-carboxamide (17). TBAF (1 M in THF, 10.8 mL,
1.5 equiv) was added to a solution of lactam 22 (4.0 g, 7.2 mmol,
1 equiv) in THF (4 mL) at room temperature. The mixture was
stirred for 2 h and concentrated under a stream of nitrogen. The
residue was dissolved in EtOAc, washed with saturated aqueous
NH4Cl, water and brine, dried (Na2SO4) and concentrated. Purifi-
cation by flash chromatography on silica gel (elution with EtOAc/
hexanes 6:1 to 8:1) yielded the product 17 as a white foam (2.9 g,
mp¼80 ꢁC (decomposition); ½a 2D5
ꢃ
þ60.0 (c 0.72, CH2Cl2); 1H NMR
91%). mp¼113e115 ꢁC; ½a D25
ꢃ
þ13.6 (c 3.3, CH2Cl2); 1H NMR
(500 MHz, CDCl3):
d
(ppm) 7.46e7.02 (m, 20H), 4.71 (d, J¼14.5 Hz,
(500 MHz, CDCl3):
d
(ppm) 7.27e7.34 (m, 15H), 4.40 (br d,
1H), 4.62 (d, J¼14.5 Hz, 1H), 4.44 (d, J¼6.5 Hz, 1H) 3.40 (s, 3H), 3.02
J¼10.5 Hz, 1H), 4.28 (br s, 1H), 3.81 (s, 3H), 3.39e3.50 (m, 2H), 3.27
(s, 3H), 2.16 (dd, J¼6.5, 18.5 Hz, 1H), 1.72 (d, J¼18.5 Hz, 1H); 13C NMR
(s, 3H), 1.47e1.54 (m, 1H), 1.36 (br s, 1H), 0.96e1.03 (m, 1H); 13C
(125 MHz, CDCl3):
d (ppm) 173.8, 163.2, 142.0, 136.1, 129.9, 129.8,
NMR (125 MHz, CDCl3):
d
(ppm) 167.6, 163.5, 142.3, 128.9, 128,1,
128.8, 128.3, 128.1, 127.8, 74.4, 61.3, 56.1, 46.8, 44.8, 34.7, 32.7; IR
127.6, 74.1, 62.6, 59.7, 56.5, 55.9, 35.4, 32.4; IR (thin film) [cmꢀ1]:
(thin film) [cmꢀ1]:
n¼3061, 3027, 2934,1765, 1702,1662,1494,1445,
n
¼3466, 3058, 2941, 1747, 1651, 1492, 1445; HRMS for C27H29N2O4
755, 733, 700; HRMS for C34H32N3O4 [MþH] calcd, 546.2387, found,
546.2408 (Error¼3.89 ppm).
[MþH] calcd, 445.2122, found, 445.2116 (Error¼ꢀ1.4 ppm).
4.1.19. 2-((2S,3S)-3-(Methoxy(methyl)carbamoyl)-4-oxo-1-
tritylazetidin-2-yl)acetic acid (23). To a biphasic solution of alcohol
17 (748 mg, 1.683 mmol, 1 equiv) in CCl4/CH3CN/H2O (11.2 mL,
2:2:3) was added NaIO4 (1.080 g, 5.049 mmol, 3 equiv) and RuCl3-
xH2O (10 mg, 0.034 mmol, 0.02 equiv) and the resulting solution
was stirred vigorously overnight at room temp. The resulting
brownish suspension was quenched with brine/sat. Na2S2O3 (1:1,
50 mL) and extracted with CH2Cl2 (3ꢂ50 mL). The combined or-
ganics were dried (MgSO4) and concentrated to obtain 680 mg
(90%) of a slightly brownish solid, which was recrystallized from
Acknowledgements
We thank the University of California, Santa Cruz and the
Deutsche Forschungsgemeinschaft (M.E.) for generous financial
support. Purchase of the 600 MHz NMR used in these studies was
supported by funds from the National Institutes of Health
(S10RR019918) and National Science Foundation (CHE-0342912).
The single crystal X-ray diffraction data for compound 4 was
recorded on an instrument supported by the National Science
Foundation, Major Research Instrumentation (MRI) Program under
Grant No. CHE-0521569.
EtOAc. mp¼82 ꢁC (decomposition); ½a 2D5
ꢃ
þ27.5 (c 0.79, CH2Cl2); 1H
NMR (500 MHz, DMSO-d6):
d (ppm) 12.24 (br s, 1H), 7.39e7.34 (m,
9H), 7.19 (d, J¼7.0 Hz, 6H), 4.41 (s, 1H), 4.22 (app. dt, J¼3.0, 11.0 Hz,
Supplementary data
1H), 3.70 (s, 3H), 3.20 (s, 3H), 2,46 (dd, J¼10.5, 16.5 Hz, 1H), 1.31 (dd,
J¼3.5, 17.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6):
d (ppm) 171.3,
Copies of 1H NMR and 13C NMR spectra for all new compounds,
along with an ORTEP depiction of 4, are provided. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2014.05.054.
166.8,163.1,141.7,129.4,127.9,127.6, 73.3, 61.7, 54.9, 53.0, 36.0, 31.8;
IR (thin film) [cmꢀ1]:
n
¼3143, 3059, 2973, 2940, 1750, 1737, 1655,
1492, 1446, 736, 701; HRMS for C27H27N2O5 [MþH] calcd, 459.1914,
found, 459.1944 (Error¼6.4 ppm).
References and notes
4.1.20. (2S,3S)-2-(2-(Benzylamino)-2-oxoethyl)-N-methoxy-N-
methyl-4-oxo-1-tritylazetidine-3-carboxamide (24). To a solution of
acid 23 (250 mg, 0.545 mmol,1 equiv) in CH2Cl2 (5.5 mL, 0.1 M) was
added 1,10-carbonyldiimidazole (97 mg, 0.60 mmol, 1.1 equiv). The
resulting solution was stirred for 15 min, after, which benzylamine
(117 mg, 1.090 mmol, 2 equiv) was added and the solution was
allowed to stir at room temperature overnight. The reaction mix-
ture was diluted to 10 mL with CH2Cl2, washed with sat. NH4Cl
(3ꢂ10 mL), brine (10 mL) and dried (MgSO4). Concentration affor-
ded the desired compound 24 (294 mg, 98% yield) as a colorless
solid, which was recrystallized from EtOAc. mp¼91 ꢁC (de-
€
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ꢁ
~
ꢁ
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composition); ½a D25
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þ16.6 (c 1.2, CH2Cl2); 1H NMR (500 MHz,
b-Amino
DMSO-d6):
d
(ppm) 8.19 (app. t, J¼5.5 Hz, 1H), 7.39e7.13 (m, 20H),
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b-Amino Acids and
4.34e4.33 (m, 2H), 4.17 (dd, J¼6.0, 15.0 Hz, 1H), 4.09 (dd, J¼6.0,
15.5 Hz, 1H), 3.62 (s, 3H), 3.18 (s, 3H), 2.35 (dd, J¼11.5, 15.0 Hz, 1H),
b
b
1.45 (dd, J¼3.0,14.0 Hz,1H); 13C NMR (125 MHz, DMSO-d6):
d (ppm)
b
168.4, 166.5, 162.8, 141.6, 139.0, 129.2, 128.1, 127.8, 127.4, 127.0,
Please cite this article in press as: Hewitt, W. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.054

8
W.M. Hewitt et al. / Tetrahedron xxx (2014) 1e8
b-Amino Acid Residues to 19. An ORTEP depiction of 4 is provided in Supplementary data.
11. (a) Gelman, M. A.; Gellman, S. H. Using Constrained
Control
Escalante, J.; Sebesta, R.,
Corresponding Peptides: Synthesis, Secondary Structure, and Biological Activity,
in Ref. 8b, Chapter 23.
b
-Peptide Shape and Function, in Ref. 8b, Chapter 22. (b) Campo, M. A.;
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2194e2197 and references therein.
ꢂ
b
2-Amino Acids with Proteinogenic Side Chains and
ꢂ
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2004, 60, 7455e7506.
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W. J. J. Am. Chem. Soc. 2010, 132, 11379e11385.
26. Bruker-AXS APEX-II, 2.1.4, Madison, WI, 2007.
27. SHELXTL Crystal Structure Determination Package; Bruker Analytical X-ray
Systems: Madison, WI, 1995e1999.
16. For a recent discussion of Weinreb amide
a-alkylation reactions and their
challenges, see: Davies, S. G.; Fletcher, A. M.; Thomson, J. E. Chem. Commun.
2013, 8586e8598 and references therein.
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28. Crystallographic data for structure 4 have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication No. CCDC 996120.
Copies of the data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge CB2 1EZ, UK (fax: þ44-(0)1223e336033 or email:
deposit@ccdc.cam.ac.uk).
18. CCDC number.
Please cite this article in press as: Hewitt, W. M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.054