Total synthesis of (-)-kaitocephalin

Article abstract of DOI:10.1021/ol0515154

(Chemical Equation Presented) Total synthesis of the potent AMPA/KA receptor antagonist (-)-kaitocephalin (1) and its three diastereomers has been accomplished. The synthesis features strictly substrate-controlled operations to α-formylglutamate 3 startin

Full text of DOI:10.1021/ol0515154

Supporting information
Total Synthesis of (-)-Kaitocephalin
Masanori Kawasaki, Tetsuro Shinada,* Makoto Hamada, and Yasufumi Ohfune*
Graduate School of Science, Osaka City University
Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
1

index
P a r t 1. Gen er a l Met h ods
S3
P a r t 2. E xper im en t a l Det a ils
S4
P a r t 3. St er eoch em ica l Assign m en t of 8
S34
P a r t 4. St er eoch em ica l Assign m en t of (7S, 9S)-24a a n d (7S, 9R)-24b
S36
P a r t 5. Spect r a l Da t a
P a r t 6. H P LC P r ofiles
S40
S63
2

General Methods
All r ea gen t s a n d solven t s wer e pu r ch a sed fr om eit h er Aldr ich Ch em ica l Com pa n y, In c.,
Mer ck & Co., In c., N a ca la i Tesqu e Com pa n y, Lt d., P ept ide In st it u t e, Tok yo Ka sei
Kogyo Co., Lt d., or Wa k o P u r e Ch em ica l In du st r ies, Lt d., a n d u sed wit h ou t fu r t h er
pu r ifica t ion u n less ot h er wise in dica t ed. Dich lor om et h a n e (CH
ph osph or ic pen t a oxide (P ). Met h a n ol (MeOH ) wa s dist illed fr om m a gn esiu m
t u r n in g a n d iodin e. E t h a n ol (E t OH ) wa s dist illed fr om ca lciu m h ydr ide (Ca H ).
2
Cl
2
) wa s dist illed fr om
2
O
5
2
Melt in g poin t s wer e det er m in ed wit h a Ya n a co MP -21 m elt in g poin t a ppa r a t u s a n d
wer e u n cor r ect ed. Opt ica l r ot a t ion s wer e t a k en on J ASCO P -1030 pola r im et er wit h a
sodiu m la m p (D lin e). F TIR spect r a wa s m ea su r ed on a J ASCO F T/IR-420 in fr a ed
spect r oph ot om et er. 1 H N MR spect r a wer e r ecor ded on a n eit h er J E OL J N M-LA 300
(
300 MH z), J E OL J N M-LA 400 (400 MH z), or Br u k er AVAN CE 600 (600 MH z)
1
spect r om et er. Ch em ica l sh ift s of H N MR wer e r epor t ed in per t s per m illion (ppm , δ)
r ela t ive t o CH Cl
. 1 3 C N MR spect r a wer e r ecor ded on a n eit h er J E OL J N M-LA 300 (75 MH z) or
J E OL J N M-LA 400 (100 MH z) spect r om et er. Ch em ica l sh ift s of 1 3 C N MR wer e r epor t ed
3
(δ = 7.26) in CDCl
3
or H DO (δ = 4.80) in D
2
O, or C
6
D
5
H (δ = 7.15) in
C
6
D
6
in ppm (δ) r ela t ive t o CH Cl
3
(δ = 77.0) in CDCl
3
, CH
3
OH (δ = 49.0) in D
2
O, or C
6
5
D H (δ
=
128.0) in C . Low r esolu t ion m a ss spect r a (LRMS) a n d H igh r esolu t ion m a ss
6
D
6
spect r a (H RMS) wer e obt a in ed on a n J E OL J MS-AX500 for fa st a t om bom ba r dm en t
ion iza t ion (FAB), ch em ica l ion iza t ion (CI), or elect r on ion iza t ion (E I). E lem en t a l
a n a lysis wer e r ecor ded on a P er k in -E lm er 240C. All r ea ct ion s wer e m on it or ed by t h in
la yer ch r om a t ogr a ph y (TLC), wh ich wa s per for m ed wit h pr ecoa t ed pla t es (silica gel 60
F -254, 0.25 m m t h ick n ess, m a n u fa ct u r ed by Mer ck ). TLC visu a liza t ion wa s
a ccom pa n ied u sin g U V la m p (245 n m ) or a ch a r r in g solu t ion (et h a n oic p-a n isa ldeh yde,
et h a n oic ph osph om olybdic a cid, a qu eou s pot a ssiu m per m a n ga n a t e a n d bu t a n oic
n in h ydr in ). Da isogel IR-60 1002W (40/63 m m ) wa s u sed for fla sh colu m n
ch r om a t ogr a ph y on silica gel. Rever sed ph a se ch r om a t ogr a ph y wa s per for m ed on
Cosm osil○ 140C1 8 -P RE P.
R
3

(
2R)-1-tert-Butyl 2-(tert-butyldimethylsilyloxymethyl)-5-oxopyrrolidine-
,2-dicarboxylate methyl ester (6)
1
O
H N CO H
2
2
OH
cat. NaCN
Dowex 50W x4
MeOH, reflux
O
HO C
2
MeOH, reflux
H N CO Me
2
2
4
CO Me
CO Me
2
1) TBSCl, NEt , DMAP, CH Cl , rt
2
3
2
2
O
O
OH
OTBS
N
2) Boc O, NEt , DMAP, THF, rt
N
2
3
H
Boc
5
6
○
R
To a solu t ion of 4 (10.0 g, 56.6 m m ol) in MeOH (566 m L) wa s a dded Dowex 50W
x4 (124 g) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s h ea t ed t o r eflu x for 12
da ys, filt er ed, elu t ed wit h MeOH /N E t (9:1), a n d con cen t r a t ed u n der r edu ced
3
pr essu r e t o give δ-la ct on e in t er m edia t e. To a solu t ion of t h e δ-la ct on e in MeOH (566
m L) wa s a dded N a CN (555 m g, 11.3 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion
m ixt u r e wa s h ea t ed t o r eflu x for 18 h , filt er ed t h r ou gh a t h in silica gel pa d, a n d
con cen t r a t ed u n der r edu ced pr essu r e t o give 5. To a solu t ion of 5 in CH
2
Cl (283 m l)
2
wa s a dded TBSCl (10.2 g, 67.9 m m ol), N E t
m g, 5.66 m m ol) a t 0 oC. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e
u n der a r gon for 20 h , qu en ch ed wit h sa t . N a H CO , a n d ext r a ct ed wit h et h yl a cet a t e
x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s
3
(11.9 m L, 84.9 m m ol) a n d DMAP (691
3
(
MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. To a solu t ion of t h e
4
r esidu e in TH F (283 m L) wa s a dded Boc
4.0 m m ol) a n d DMAP (781 m g, 6.40 m m ol) a t 0 oC. Th e r ea ct ion m ixt u r e wa s
st ir r ed a t r oom t em per a t u r e u n der a r gon for 15 h , qu en ch ed wit h sa t . N H Cl, a n d
ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h
br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h
2
O (14.0 m L, 61.2 m m ol), N E t (9.00 m L,
3
6
4
4
h exa n e/E t OAc = 15:1 t h en 8:1) t o give 6 (12.3 g, 56%, 4 st eps) a s color less oil: [α]2 5
D
4

+
1
44.6 (c 1.10, CH Cl ); F TIR (n ea t ) 2955, 2932, 2889, 2857, 1794, 1747, 1725, 1472,
3
-
1
1
369, 1312, 1257 cm ; H N MR (400 MH z, CDCl ) δ 4.24 (d, J = 10.4 H z, 1H ), 3.96 (d,
3
J = 10.4 H z, 1H ), 3.71 (s, 3H ), 2.67 (ddd, J = 17.6, 10.2, 8.8 H z, 1H ), 2.47 (ddd, J =
1
1
1
7.6, 10.8, 3.9 H z, 1H ), 2.24 (ddd, J = 12.9, 10.2, 3.9 H z, 1H ), 2.10-2.01 (m , 1H ),
.46 (s, 9H ), 0.84 (s, 9H ), 0.03 (s, 3H ), 0.008 (s, 3H ); 1 3 C N MR (100 MH z, CDCl
) δ
74.2, 171.8, 149.2, 83.5, 68.9, 64.9, 52.3, 31.5, 27.9, 26.9, 25.7, 18.0, -5.67; H RMS
3
+
+
(
FAB) m /z (M+H ) ca lcd for [C1 8
H
3 3 N O Si+H ] 388.2155, fou n d 388.2153.
6
(
2R)-1-tert-Butyl 2-(hydroxymethyl)-5-oxopyrrolidine-1,2-dicarboxylate methyl
ester (6A)
CO Me
CO Me
2
TBAF, AcOH
THF, rt
2
O
O
OTBS
OH
N
N
Boc
Boc
6
6A
To a solu t ion of 6 (925 m g, 2.39 m m ol) in TH F (12 m L) wa s a dded AcOH (1.03 m L,
7.9 m m ol) a n d TBAF (1M solu t ion in TH F, 5.98 m L, 5.98 m m ol) a t 0 oC. Th e
1
r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon for 22 h , qu en ch ed
wit h sa t . N a H CO , a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic
3
la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d
4
con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n
ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 4:1 t h en 1:1) t o give 6A (607 m g,
o
9
3
3%) a s wh it e solids: m p. 116-117 C (dec); [α]2 5
D
+26.2 (c 0.65, CH Cl
3
); F TIR (n ea t )
) δ 4.19 (dd,
-
1
1
424, 2981, 2946, 1787, 1735, 1308, 1270 cm ; H N MR (400 MH z, CDCl
3
J = 11.5, 4.88 H z, 1H ), 3.82 (dd, J = 11.5, 8.8 H z, 1H ), 3.78 (s, 3H ), 2.75-2.80 (br m ,
1
1
8
H ), 2.50-2.70 (m , 2H ), 2.41 (ddd, J = 13.2, 9.76, 5.84 H z, 1H ), 2.13 (ddd, J = 13.2,
0.0, 8.04 H z, 1H ), 1.50 (s, 9H ); 1 3 C N MR (75 MH z, CDCl
) δ 173.9, 172.7, 149.6,
3
4.2, 68.6, 64.5, 52.6, 30.7, 27.9, 25.3; H RMS (FAB) m /z (M+H )+ ca lcd for
+
[
C
1 2
H
1 9 N O
6
+H ] 274.1290, fou n d 274.1287; An a l. Ca lcd for C1 2
H
1 9 N O : C, 52.74; H ,
6
5

7
.01; N , 5.13. F ou n d: C, 52.83; H , 7.04; N , 5.05.
(
2R)-1-tert-Butyl 2-formyl-5-oxopyrrolidine-1,2-dicarboxylate methyl ester (3)
CO Me
CO Me
2
TEMPO, PhI(OAc)2
CH Cl , rt
2
O
O
OH
N
N
CHO
2
2
Boc
Boc
6A
3
To a solu t ion of 6A (6.4 g, 23.4 m m ol) in CH
2
Cl (60 m l) wa s a dded TE MP O (365 m g,
2
2
.34 m m ol) a n d P h I(OAc) (8.30 g, 25.8 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion
2
m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon for 26 h , filt er ed t h r ou gh
t h in silica gel pa d, elu t ed wit h et h yl a cet a t e, a n d con cen t r a t ed u n der r edu ced
pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h
h exa n e/E t OAc = 8:1 t h en 2:1) t o give 3 (6.2 g, 98%) a s color less oil: [α]2 9
+27.5 (c
D
0
1
2
1
.95, CH Cl
293, 1257, 1154 cm ; H N MR (300 MH z, CDCl
.53-2.61 (m , 2H ), 2.20-2.24 (m , 2H ), 1.45 (s, 9H ); 1 3 C N MR (75 MH z, CDCl
3
); F TIR (n ea t ) 3541, 1798, 1763, 1740, 1717, 1458, 1437, 1371, 1321,
-
1
1
3
) δ 9.98 (s, 1H ), 3.86 (s, 3H ),
3
) δ 193.6,
+
72.0, 169.7, 148.7, 84.8, 72.1, 53.2, 30.3, 27.7, 24.9; H RMS (FAB) m /z (M+H ) ca lcd
+
for [C1 2
H
1 7 N O
6
+H ] 272.1134, fou n d 272.1142.
6

(
2R)-1-tert-Butyl 2-((E)-2-(methoxycarbonyl)vinyl)-5-oxopyrrolidine-1,2-
dicarboxylate methyl ester (7)
CO Me
CO Me
2
2
Ph PCHCO Me
3 2
O
O
N
o
N
CHO
toluene, 80 C
Boc
Boc
CO Me
2
3
7
To a solu t ion of 3 (588 m g, 2.17 m m ol) in t olu en e (7 m L) wa s a dded P h
3
P CH CO
2
Me
o
(
1.09 g, 3.25 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t 80 C
u n der a r gon for 1.5 h a n d con cen t r a t ed u n der r edu ce pr essu r e. Th e r esidu e wa s
pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 8:1 t h en
3
1
1
=
3
2
1
:1) t o give 7 (695 m g, 98%, 2:1 m ixt u r e of r ot a m er s) a s color less oil: [α]2 5
D
+66.9 (c
.15, CH Cl ); F TIR (n ea t ) 2981, 2956, 1794, 1749, 1723, 1662, 1437, 1371, 1304,
3
-
1
1
258, 1155 cm ; H N MR (400 MH z, CDCl ) δ 7.43 (d, J = 15.9 H z, 1/3H ), 7.42 (d, J
3
15.9 H z, 2/3H ), 5.85 (d, J = 15.9 H z, 1/3H ), 5.84 (d, J = 15.9 H z, 2/3H ), 3.77 (s, 1H ),
.76 (s, 2H ), 3.73 (s, 1H ), 3.72 (s, 2H ), 2.42-2.60 (m , 2H ), 2.20-2.34 (m , 1H ),
.00-2.12 (m , 1H ), 1.39 (s, 3H ), 1.38 (s, 6H ); 1 3 C N MR (75 MH z, CDCl
70.6, 165.9, 148.4, 144.9, 119.9, 84.2, 68.4, 53.0, 51.8, 30.0, 29.9, 27.6; H RMS
) δ 172.7,
3
+
+
(
FAB) m /z (M+H ) ca lcd for [C1 5
H
2 1 N O +H ] 328.1396, fou n d 328.1398.
7
(
2R)-1-tert-Butyl 2-((1R,2S)-2-(methoxycarbonyl)-1,2-dihydroxyethyl)-5-oxopyrro-
lidine-1,2-dicarboxylate methyl ester (8)
CO Me
CO Me
2
2
OsO , DMAP
4
OH
O
O
N
o
N
THF, -78 C
Boc
Boc
CO Me
CO Me
2
2
OH
7
8
To a solu t ion of 7 (1.6 g, 4.89 m m ol) in TH F (49 m L) wa s a dded DMAP (1.43 g, 11.7
7

o
m m ol) a n d OsO
4
(1.5 g, 5.91 m m ol) a t -78 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t
o
-
78 C u n der a r gon for 19 h , qu en ch ed wit h N a H SO
3
(5.1 g, 49.0 m m ol) in wa t er (50
m L), st ir r ed a t r oom t em per a t u r e for 1 h , a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e
com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
4
,
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 5:1 t h en 1:1) t o give 8
(
1.73 g, 98%)a s wh it e solids: m p. 148-149 oC (dec); [α]2 2
F TIR (n ea t ) 3470, 1786, 1742, 1304, 1284, 1257, 1155 cm ; H N MR (400 MH z,
CDCl ) δ 4.70 (d, J = 5.4 H z, 1H ), 4.64 (d, J = 8.0 H z, 1H ), 4.10 (br d, J = 9.0 H z, 1H ),
.85 (s, 3H ), 3.79 (s, 3H ), 3.30, (br d, J = 5.9 H z, 1H ), 2.45-2.60 (m , 3H ), 2.10-2.20
m , 1H ), 1.52 (s, 9H ); 1 3 C N MR (100 MH z, CDCl
) δ 173.6, 173.4, 171.6, 151.4, 84.6,
2.2, 71.1, 70.2, 53.2, 52.8, 30.7, 27.9, 25.0; H RMS (FAB) m /z (M+H )+ ca lcd for
D
+31.9 (c 1.15, CH Cl );
3
-
1
1
3
3
(
3
7
+
[
C
1 5
H
2 3 N O
9
+H ] 362.1451, fou n d 362.1451; An a l. Ca lcd for C1 5
H
2 3 N O : C, 49.86; H ,
9
6
.42; N , 3.88. F ou n d: C, 49.89; H , 6.42; N , 3.81.
(
2R)-1-tert-Butyl 2-((4R,5S)-5-(methoxycarbonyl)-2-thioxo-1,3-dioxolan-4-yl)-
5
-oxopyrrolidine-1,2-dicarboxylate methyl ester (9)
CO Me
CO Me
2
2
TCDI
OH
CO Me
2
O
O
N
N
CH Cl , reflux
2
2
Boc
Boc
CO Me
O
O
2
OH
8
9
S
To a solu t ion of 8 (1.2 g, 3.32 m m ol) in CH
2
Cl (11 m L) wa s a dded TCDI (888 m g,
2
4
.98 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s h ea t ed t o r eflu x u n der
a r gon for 2 h a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 8:1 t h en 3:1) t o give 9
(
1.3 g, 99%) a s color less oil: [α]2 5
D
+78.7 (c 0.84, CH Cl
3
); F TIR (n ea t ) 1797, 1757,
-
1
1
1
715, 1311, 1281, 1151 cm ; H N MR (400 MH z, CDCl
3
) δ 5.88 (d, J = 6.1 H z, 1H ),
8

5
1
1
.29 (d, J = 6.1 H z, 1H ), 3.92 (s, 3H ), 3.80 (s, 3H ), 2.70-2.82 (m , 1H ), 2.63 (ddd, J =
7.8, 10.2, 5.1 H z, 1H ), 2.13-2.29 (m , 2H ), 1.52 (s, 9H ); 1 3 C N MR (100 MH z, CDCl
) δ
88.3, 171.5, 170.2, 165.8, 149.4, 85.4, 83.2, 80.1, 68.4, 53.8, 53.4, 30.1, 27.8, 22.9;
3
+
+
H RMS (FAB) m /z (M+H ) ca lcd for [C1 6
H
2 1 N O S+H ] 404.1015, fou n d 404.1012.
9
(
2R)-Methyl 2-((1S,2R)-2-(methoxycarbonyl)-2-azido-1-hydroxyethyl)-5-
oxopyrrolidine-2-carboxylate (11)
CO Me
CO Me
CO Me
2
2
2
TFA
NaN , PPTS
3
N
3
CO Me
CO Me
2
O
O
2
O
N
o
N
N
CH Cl , 0 C
DMF, rt
2
2
H
Boc
H
CO Me
2
O
O
O
O
HO
9
10
11
S
S
To a solu t ion of TFA (16 m L) in CH
2
Cl
2
(16 m L) wa s a dded a solu t ion of 9 (1.32 g,
o
o
3
.29 m m ol) in CH
2
Cl
2
(8 m L) a t 0 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t 0 C u n der
a r gon for 1.5 h a n d con cen t r a t ed u n der r edu ced pr essu r e t o give 10. To a solu t ion of
1
0 in DMF (17 m L) wa s a dded N a N
3
(647 m g, 9.96 m m ol) a n d P P TS (1.67 g, 6.64
o
m m ol) a t 0 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon
for 16 h , qu en ch ed wit h sa t . N a H CO
3
, a n d ext r a ct ed wit h et h yl a cet a t e (x4). Th e
com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
4
,
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 3:1, 1:1 t h en 1:9) t o
give 11 (846 m g, 89%) a s color less oil: [α]2 5
+56.3 (c 0.48, CH Cl
114, 1742, 1692, 1260 cm ; H N MR (300 MH z, CDCl ) δ 7.08 (br s, 1H ), 4.21 (d, J
7.9 H z, 1H ), 3.93 (d, J = 7.9 H z, 1H ), 3.82 (s, 3H ), 3.80 (s, 3H ), 2.26-2.45 (m , 4H );
); F TIR (n ea t ) 3333,
D
3
-
1
1
2
3
=
1
3
C N MR (75 MH z, CDCl ) δ 178.3, 172.5, 169.2, 73.9, 68.2, 62.4, 53.1, 53.0, 29.4,
3
+
+
2
5.8; H RMS (FAB) m /z (M+H ) ca lcd for [C1 0
H
1 4
N
4
O +H ] 287.0991, fou n d 287.0976.
6
9

(
(
2R)-Methyl 2-((1S,2R)-2-(methoxycarbonyl)-2-azido-1-
tert-butyldimethylsilyloxy)ethyl)-5-oxopyrrolidine-2-carboxylate (11A)
CO Me
CO
2
Me
2
TBSOTf, 2,6-lutidine
CH Cl , rt
N
N
3
3
O
O
N
N
H
2
2
H
CO Me
CO Me
2
2
HO
TBSO
11
11A
To a solu t ion of 11 (8.8 m g, 31 µm ol) in CH
2
Cl
2
o
(0.3 m L) wa s a dded TBSOTf (11 µL,
4
6 µm ol) a n d 2,6-lu t idin e (9 µL, 77 µm ol) a t 0 C. Th e r ea ct ion m ixt u r e wa s st ir r ed
a t r oom t em per a t u r e u n der a r gon for 4 h , qu en ch ed wit h sa t . N a H CO
ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h
br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h
h exa n e/E t OAc = 4:1 t h en 3:2) t o give 11A (11 m g, 89%) a s color less oil: [α]2 6
+35.9
c 1.00, CH Cl ); F TIR (n ea t ) 2955, 2929, 2857, 2115, 1745, 1705, 1269, 1217 cm ; H
3
, a n d
4
D
-
1
1
(
3
N MR (300 MH z, CDCl
3
) δ 6.04 (br d, J = 11.2 H z, 1H ), 4.41 (d, J = 5.1 H z, 1H ), 4.05
(
d, J = 5.1 H z, 1H ), 3.80 (s, 3H ), 3.77 (s, 3H ), 2.27-2.50 (m , 4H ), 0.85 (s, 9H ), 0.11 (s,
3
5
H ), 0.10 (s, 3H ); 1 3 C N MR (75 MH z, CDCl
3
) δ 176.7, 171.8, 167.8, 74.7, 68.7, 64.5,
+
3.0, 52.8, 29.4, 25.6, 24.9, 18.0, -4.53, -4.56; H RMS (FAB) m /z (M+H ) ca lcd for
+
[
C
1 6
H
2 8
N
4
O
6
Si+H ] 401.1856, fou n d 401.1851.
10

Spirolactam (12)
O
CO Me
2
N
Ph
P
3
3
NH
CO Me
O
N
O
THF, H O, rt
N
H
2
CO Me
2
H
TBSO
2
TBSO
11A
12
To a solu t ion of 11A (14 m g, 35 µm ol) in TH F -H
2
O (3:1) (0.4 m L) wa s a dded P P h
3
(
18 m g, 70 µm ol) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom
t em per a t u r e for 15 h a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s
pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 3:1, 1:1
t h en 1:5) t o give 12 (8.6 m g, 72%) a s color less oil: [α]2 0
-2.6 (c 1.01, CH Cl
); F TIR
D
3
-
1
(
n ea t ) 3245, 2956, 2929, 2858, 1728, 1691, 1462, 1437, 1363, 1254, 1223, 1156 cm ;
1
H N MR (400 MH z, CDCl
.93 (d, J = 7.1 H z, 1H ),3.80 (s, 3H ), 2.58-2.66 (m , 1H ), 2.30-2.51 (m , 2H ), 1.88-2.05
m , 1H ), 0.91 (s, 9H ), 0.09 (s, 3H ), 0.05 (s, 3H ); 1 3 C N MR (75 MH z, CDCl
) δ 178.1,
75.0, 171.5, 77.3, 67.3, 59.1, 52.8, 29.3, 25.5, 22.7, 17.8, -4.44, -5.46; H RMS (FAB)
3
) δ 7.19 (br s, 1H ), 6.51 (br s, 1H ), 4.41 (d, J = 7.1 H z, 1H ),
3
(
3
1
+
+
m /z (M+H ) ca lcd for [C1 5
H
2 6
N
2
O Si+H ] 343.1739, fou n d 343.1688.
5
(
1S,7aR)-Methyl 1-((R)-(methoxycarbonyl)azidomethyl)-hexahydro-3,3-
dimethyl-5-oxopyrrolo[1,2-c]oxazole-7a-carboxylate (11B)
CO Me
2
CO Me
2
N
3
2
, 2-Dimethoxypropane, CSA
N
O
3
O
N
N
toluene, reflux
H
O
CO Me
2
CO Me
2
HO
11
11B
To a solu t ion of 11 (496 m g, 1.73 m m ol) in t olu en e (8.6 m L) wa s a dded 2,
2
-dim et h oxypr opa n e (541 µL, 5.19 m m ol) a n d CSA (40 m g, 0.173 m m ol) a t r oom
11

t em per a t u r e. Th e r ea ct ion m ixt u r e wa s h ea t ed t o r eflu x u n der a r gon for 18 h ,
qu en ch ed wit h sa t . N a H CO , a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed
3
or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d
4
con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n
ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 8:1, 5:1, 3:1, 1:1 t h en 1:10) t o give
1
0
1B (169 m g, 30%) a s color less oil a n d r ecover y of 11 (248 m g, 50%): [α]2 5
D
-49.4 (c
-
1
1
.79, CH Cl
3
); F TIR (n ea t ) 2111, 1744, 1710, 1373, 1252, 1171 cm ; H N MR (300
MH z, CDCl
3
) δ 4.86 (d, J = 9.15 H z, 1H ), 3.85 (s, 3H ), 3.84 (s, 3H ), 3.82 (d, J = 9.15
H z, 1H ), 2.85 (ddd, J = 16.7, 11.5, 8.4 H z, 1H ), 2.53 (ddd, J = 16.5, 9.0, 0.9 H z, 1H ),
2
3
6
.34 (ddd, J = 13.2, 11.5, 8.9 H z, 1H ), 2.11 (ddd, J = 13.3, 8.4, 0.9 H z, 1H ), 1.71 (s ,
H ), 1.36 (s, 3H ); 1 3 C N MR (75 MH z, CDCl
) δ 173.0, 171.2, 168.2, 93.3, 76.7, 75.0,
3
1.3, 53.4, 52.9, 35.1, 26.9, 26.6, 26.1; H RMS (FAB) m /z (M+H )+ ca lcd for
+
[
C
1 3
H
1 8
N
4
O
6
+H ] 327.1304, fou n d 327.1304.
Cbz-amine (13)
1
) H , Pd-C
CO Me
2
CO Me
2
2
N
AcOEt, rt
NHCbz
3
O
O
N
N
2
) CbzOSu, DMAP
O
CO
2
Me
O
CO Me
2
CH Cl , rt
2
2
11B
13
To a solu t ion of 11B (48 m g, 0.147 m m ol) in et h yl a cet a t e (0.7 m L) wa s a dded P d-C
5 m g, 10 wt %) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom
(
t em per a t u r e u n der h ydr ogen for 2.5 h , filt er ed, a n d con cen t r a t ed u n der r edu ced
pr essu r e. To a solu t ion of t h e r esidu e in CH
2
Cl
2
(0.7 m L) wa s a dded CbzOSu (48 m g,
o
0
.191 m m ol) a n d DMAP (23 m g, 0.191 m m ol) a t 0 C. Th e r ea ct ion m ixt u r e wa s
st ir r ed a t r oom t em per a t u r e u n der a r gon for 21 h , qu en ch ed wit h sa t . N H
4
Cl, a n d
ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h
12

br in e, dr ied over a n h ydr ou s MgSO
pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h
h exa n e/E t OAc = 4:1 t h en 1:1) t o give 13 (57 m g, 89%) a s color less oil: [α]2 6
-33.1 (c
); F TIR (n ea t ) 3297, 2996, 2954, 1744, 1709, 1534, 1373, 1266, 1227,
4
, filt er ed, a n d con cen t r a t ed u n der r edu ced
D
0
1
5
2
1
.83, CH Cl
3
-
1
1
170 cm ; H N MR (300 MH z, CDCl ) δ 7.26-7.34 (m , 5H ), 5.45 (br d, J = 8.3 H z, 1H ),
3
.11 (s, 2H ), 4.56 (d, J = 10.1 H z, 1H ), 4.40-4.47 (br m , 1H ), 3.81 (s, 3H ), 3.76 (s, 3H ),
.78 (ddd, J = 16.5, 11.7, 8.0 H z, 1H ), 2.46-2.60 (br m , 1H ), 2.15-2.30 (br m , 1H ),
.95 (dd, J = 13.2, 8.0 H z, 1H ), 1.72 (s, 3H ), 1.34 (s, 3H ); 1 3 C N MR (75 MH z, CDCl
)
3
δ 173.6, 171.5, 170.7, 155.3, 135.7, 128.5, 128.4, 128.2, 93.4, 77.9, 75.2, 67.6, 54.7,
5
3.4, 52.6, 35.1, 27.1, 26.2, 25.9; H RMS (FAB) m /z (M+H )+ ca lcd for
+
[
C
2 1
H
2 6
N
2
O
8
+H ] 435.1767, fou n d 435.1769.
(
4R,5S)-3-Benzyl 5-((R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-
oxopyrrolidin-2-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester (15)
CO Me
CO Me
CO Me
2
2
2
NHCbz
TFA
CO
2
Me Boc O, DMAP
CO Me
2
O
O
2
O
N
N
N
CH Cl , rt
H
THF, rt
Boc
CO Me
2
2
2
O
O
NCbz
O
NCbz
13
14
15
To a solu t ion of 13 (18 m g, 0.042 m m ol) in CH
2
Cl (0.2 m L) wa s a dded TFA (0.2 m L)
2
o
a t 0 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon for 3 h
a n d con cen t r a t ed u n der r edu ced pr essu r e t o give 14. To a solu t ion of 14 in TH F (0.2
m L) wa s a dded Boc
t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon
for 15 h , qu en ch ed wit h sa t . N H Cl, a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e
2
O (14 µL, 62 µm ol) a n d DMAP (7.6 m g, 62 µm ol) a t r oom
4
com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
4
,
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
13

fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 10:1 t h en 3:1) t o give
5 (21 m g, 92%, 2:1 m ixt u r e of r ot a m er s) a s color less oil: [α]2 7
+46.6 (c 0.53,
CH Cl ); F TIR (n ea t ) 2981, 2946, 1795, 1752, 1717, 1408, 1352, 1308, 1298, 1258,
1
D
3
-
1
1
1
5
2
1
159 cm ; H N MR (300 MH z, CDCl ) δ 7.23-7.35 (m , 5H ), 5.15-5.22 (m , 1H ),
3
.04-5.11 (m , 1H ), 4.80-4.98 (m , 2H ), 3.80 (s, 1H ), 3.78 (s, 2H ), 3.70 (s, 1H ), 3.53 (s,
H ), 2.42-2.62 (m , 2H ), 2.10-2.25 (m , 1H ), 1.81-1.96 (m , 1H ), 1.73 (s, 2H ), 1.67 (s,
H ), 1.51 (s, 2H ), 1.49 (s, 6H ), 1.48 (s, 3H ), 1.45 (s, 1H ); 1 3 C N MR (75 MH z, CDCl
)
3
δ 173.3, 173.2, 170.6, 170.5, 170.47, 170.4, 152.5, 151.3, 149.6, 149.4, 136.1, 135.8,
1
6
2
28.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.7, 94.4, 93.8, 84.3, 84.2, 75.3, 74.9, 68.4,
8.3, 67.6, 66.8, 61.3, 60.6, 52.7, 52.5, 52.4, 30.9, 30.8, 27.8, 26.1, 25.1, 24.9, 24.0,
1.7, 21.4; H RMS (FAB) m /z (M+H )+ ca lcd for [C2 6
H
N O
1 0 +H -Boc]+ 435.1767,
3 4
2
fou n d 435.1775.
(
4R,5S)-3-Benzyl 4-methyl 5-((2R,5R)-1-(tert-butoxycarbonyl)-2-(methoxy-
carbonyl)-5-allylpyrrolidin-2-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate (20)
1
) LiBEt H
THF, -78 C
allylmagnesium bromide
7R
CO Me
3
CO Me
CO Me
2
2
2
o
CO Me CuBr Me S, BF Et O
CO Me
2
3
2
CO Me
2
2
2
O
AcO
N
N
N
o
o
H
Boc
2) Ac O, DMAP
Boc
THF, -78 C to 0 C
Boc
2
O
NCbz
O
NCbz
O
NCbz
CH Cl , rt
2
2
15
18
20
R : 7S = ca. 2:1
7
To a solu t ion of 15 (159 m g, 0.298 m m ol) in TH F (3 m L) wa s a dded LiBE t H (1 M
3
o
solu t ion in TH F, 446 µL, 0.446 m m ol) a t -78 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t
o
-
78 C u n der a r gon for 1 h , qu en ch ed wit h sa t . N a H CO
3
/ 30% H
2
2
O (1:1, 17 m L),
st ir r ed a t r oom t em per a t u r e for 2 h , a n d ext r a ct ed wit h diet h yl et h er (x3). Th e
com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. To a solu t ion of t h e r esidu e in
4
,
CH
2
Cl
2
(3 m L) wa s a dded Ac O (42 µL, 0.447 m m ol) a n d DMAP (55 m g, 0.447 m m ol)
2
14

a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der
a r gon for 1.5 h , qu en ch ed wit h sa t . N H Cl, a n d ext r a ct ed wit h diet h yl et h er (x3).
4
Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h sa t . N a H CO , dr ied over a n h ydr ou s
3
MgSO
pr essu r e t o give 18. To a solu t ion of Cu Br dim et h ylsu lfide com plex (245 m g, 1.19
m m ol) in TH F (1.5 m L) wa s a dded a llylm a gn esiu m br om ide (1M solu t ion in E t O,
4
, filt er ed t h r ou gh t h in silica gel pa d, a n d con cen t r a t ed u n der r edu ced
2
o
o
o
1
.2 m L, 1.20 m m ol) a t -40 C u n der a r gon , st ir r ed a t -40 C for 1 h , cooled t o -78 C,
o
a dded BF
3
･E t
2
O (321 µL, 1.20 m m ol), a n d st ir r ed a t -78 C for 0.5 h . To a m ixt u r e
o
wa s a dded a solu t ion of 18 in TH F (0.5 m L x3) a t -78 C. Th e r ea ct ion m ixt u r e wa s
o
o
st ir r ed a t -78 C for 1 h , wa r m ed t o 0 C for 2 h , qu en ch ed wit h a m ixt u r e of sa t .
N a H CO a n d 1N N H OH , a n d ext r a ct ed wit h diet h yl et h er (x3). Th e com bin ed
3
4
or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d
4
con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n
ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 10:1 t h en 6:1) t o give 20 (100 m g,
6
0%, a n in sepa r a ble m ixt u r e of dia st er eom er s (ca .2:1) a n d a m ixt u r e of r ot a m er s)
a s color less oil a n d r ecover y of 18 (13.5 m g, 8%).
0: F TIR (n ea t ) 2978, 2952, 1746, 1717, 1699, 1405, 1390, 1365, 1352, 1211 cm ;
-
1
2
1
Com plex H N MR spect r a wa s obser ved, beca u se of a m ixt u r e of dia st er eom er s a n d
r ot a m er s. See a ppen dix.; 1 3 C N MR (75 MH z, CDCl
) δ 172.4, 172.2, 171.0, 152.6,
51.6, 151.5, 136.4, 136.0, 135.5, 128.5, 128.3, 128.1, 127.9, 127.7, 127.6, 127.5,
3
1
1
6
2
16.9, 116.4, 93.7, 93.6, 93.2, 93.0, 80.6, 80.3, 80.27, 75.2, 74.5, 69.4, 69.1, 67.5,
7.4, 66.7, 66.6, 61.8, 61.1, 61.9, 58.9, 58.7, 52.3, 52.2, 52.1, 38.7, 38.4, 38.1, 37.1,
9.1, 28.6, 28.3, 27.6, 27.3, 26.9, 26.2, 25.1, 24.9, 24.0, 23.8; H RMS (FAB) m /z
+
+
(
M+H ) ca lcd for [C2 9
H
4 0
N
2
O +H ] 561.2812, fou n d 561.2811.
9
15

(
(
4R,5S)-3-Benzyl 5-((2R,5R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-(2-
tert-butyldimethylsilyloxymethyl)-2-hydroxyethyl)pyrrolidin-2-yl)-2,2-dimethyl
oxazolidine-3,4-dicarboxylate methyl ester (22ab)
7
R
CO Me
2
CO Me
1) cat.OsO , NMO
2
4
HO
CO Me
CO Me
2
2
t-BuOH, H O, rt
2
N
H
N
H
Boc
Boc
TBSO
O
NCbz
2) TBSCl, NEt
CH Cl , rt
3
, DMAP
O
NCbz
2
2
20
22ab
To a solu t ion of 20 (100 m g, 0.179 m m ol) in t -Bu OH -H
OsO
2
O (1.8 m L, 1:1) wa s a dded
o
4
(114 µL, 1g/25 m L in t -Bu OH ) a n d N MO (26 m g, 0.215 m m ol) a t 0 C. Th e
r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e for 4 h , qu en ch ed wit h KH SO
a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed
wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
3
a q,
4
pr essu r e. To a solu t ion of t h e r esidu e in CH
2
Cl (1.8 m L) wa s a dded TBSCl (32 m g,
2
0
.215 m m ol), t r iet h yla m in e (37 µL, 0.267 m m ol), a n d DMAP (2 m g, 17.9 µm ol) a t
r oom t em per a t u r e u n der a r gon for 14 h , qu en ch ed wit h sa t . N H Cl, a n d ext r a ct ed
wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied
over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e
r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc
10:1 t h en 6:1) t o give 22a b (78 m g, 62%, a n in sepa r a ble m ixt u r e of 4
dia st er eom er s a n d a m ixt u r e of r ot a m er s) a s color less oil: F TIR (n ea t ) 3476, 2953,
4
4
=
-
1
1
2
930, 2857, 1748, 1715, 1697, 1457, 1436, 1404, 1353, 1253, 1213 cm ; Com plex H
N MR spect r a wa s obser ved, beca u se of a m ixt u r e of dia st er eom er s a n d r ot a m er s.
See a ppen dix.; 1 3 C N MR (100 MH z, CDCl
) δ 172.4, 172.3, 172.0, 171.5, 170.9, 170.8,
70.6, 154.0, 153.7, 153.0, 152.5, 151.5, 151.4, 136.4, 136.2, 136.1, 135.9, 128.4,
3
1
1
8
6
5
28.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 93.8, 93.6, 93.5, 93.1, 93.0, 81.6, 81.1,
0.8, 80.4, 80.3, 76.5, 75.5, 75.1, 75.0, 74.6, 70.6, 70.0, 69.8, 69.6, 69.5, 69.1, 68.9,
7.8, 67.5, 67.4, 67.2, 66.7, 66.5, 66.4, 62.0, 61.8, 61.7, 61.3, 61.1, 61.0, 60.9, 57.7,
7.1, 56.9, 56.6, 56.5, 56.3, 55.9, 52.3, 52.1, 38.4, 38.0, 37.6, 37.1, 37.0, 31.1, 30.7,
16

3
2
0.2, 29.8, 29.6, 29.4, 29.2, 29.1, 28.7, 28.2, 28.1, 27.4, 26.2, 25.9, 25.8, 25.1, 25.0,
4.99, 24.8, 24.0, 23.9, 23.85, 23.83, 23.81, 23.7, 23.69, 23.65, 18.4, 18.19, 18.17,
-
5.24, -5.34, -5.44, -5.48; H RMS (FAB) m /z (M+H )+ ca lcd for [C3 5
H
5 6
N O
11 Si+H ]+
2
7
09.3731, fou n d 709.3717.
(
(
4R,5S)-3-Benzyl 5-((2R,5R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-(2-
tert-butyldimethylsilyloxymethyl)-2-azidoethyl)pyrrolidin-2-yl)-2,2-dimethyl
oxazolidine-3,4-dicarboxylate methyl ester (23ab)
CO Me
CO Me
2
HO
2
N3
CO Me DPPA, DEAD
CO Me
2
2
N
N
H
Ph P
H
3
Boc
Boc
TBSO
TBSO
O
NCbz
O
NCbz
THF, rt
22ab
23ab
To a solu t ion of 22a b (78 m g, 0.11 m m ol) in TH F (0.6 m L) wa s a dded DP PA (47 µL,
.22 m m ol), P P h (58 m g, 0.22 m m ol), a n d DE AD (35 µL, 0.22 m m ol) a t r oom
0
3
t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon
for 1 h a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by fla sh
colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 10:1 t h en 7:1) t o give 23a b
(
80 m g, 99%, a n in sepa r a ble m ixt u r e of 4 dia st er eom er s a n d a m ixt u r e of r ot a m er s)
a s color less oil: F TIR (n ea t ) 2953, 2857, 2108, 1746, 1716, 1698, 1457, 1404, 1390,
-
1
1
1
352, 1254, 1212, 1161 cm ; Com plex H N MR spect r a wa s obser ved, beca u se of a
m ixt u r e of dia st er eom er s a n d r ot a m er s. See a ppen dix.; 1 3 C N MR (100 MH z, CDCl
)
3
δ 172.4, 172.2, 171.9, 171.7, 170.9, 154.0, 153.5, 153.0, 152.5, 151.5, 151.4, 136.3,
1
9
6
5
36.0, 128.5, 128.3, 128.1, 128.0, 127.9, 127.7, 127.5, 93.7, 93.6, 93.5, 93.3, 93.1,
3.0, 80.83, 80.78, 75.7, 75.5, 75.1, 74.9, 74.5, 69.2, 69.0, 68.6, 67.4, 67.0, 66.96,
6.7, 66.6, 66.3, 65.9, 62.6, 62.4, 61.9, 61.7, 61.5, 61.4, 61.1, 60.9, 58.4, 57.7, 57.0,
6.7, 56.6, 56.5, 56.0, 52.4, 52.3, 52.2, 52.13, 52.11, 52.09, 35.6, 35.4, 35.1, 34.4,
17

3
2
1
7
4.3, 34.2, 33.0, 30.6, 30.3, 30.2, 29.9, 29.6, 29.3, 29.28, 29.25, 29.0, 28.9, 28.7, 28.2,
8.17, 27.34, 27.26, 26.2, 25.71, 25.7, 25.2, 25.0, 24.8, 24.2, 24.0, 23.7, 18.14, 18.11,
8.09, -5.59, -5.61, -5.64; H RMS (FAB) m /z (M+H )+ ca lcd for [C3 5
34.3796, fou n d 734.3804.
H
N O
1 0 Si+H ]+
5 5
5
(
(
4R,5S)-3-Benzyl 5-((2R,5R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-(2-
tert-butyldimethylsilyloxymethyl)-2-(4-(benzyloxy)-3,5-dichlorobenzamido)ethyl)
pyrrolidin-2-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester (24ab)
H
CO Me
1) Me P,
CO Me
2
N3
2
3
Ar
N
CO Me
CO Me
2
THF-H O, rt
2
2
N
N
H
H
O
Boc
Boc
Cl
OBn
Cl
TBSO
2) ArCO H
TBSO
O
NCbz
2
O
NCbz
BOP, DIPEA
Ar =
CH Cl , rt
2
2
23ab
24ab
To a solu t ion of 23a b (80 m g, 0.11 m m ol) in TH F -H
2
O (0.5 m L, 3:1) wa s a dded P Me
3
(
1M solu t ion in TH F, 545 µL, 0.545 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion
m ixt u r e wa s st ir r ed a t r oom t em per a t u r e for 1 h a n d con cen t r a t ed u n der r edu ced
pr essu r e. To a solu t ion of t h e r esidu e in CH
,5-dich lor oben zoic a cid (39 m g, 0.13 m m ol), BOP r ea gen t (58 m g, 0.13 m m ol) a n d
DIP E A（28 µL, 0.16 m m ol) a t 0 oC. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom
t em per a t u r e u n der a r gon for 14 h , qu en ch ed wit h sa t . N H Cl, a n d ext r a ct ed wit h
et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over
a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e
wa s pu r ified by pr epa r a t ive TLC (developed wit h h exa n e/E t OAc = 3:1) t o give 24a b
51 m g, 48%, a n in sepa r a ble m ixt u r e of dia st er eom er s a n d a m ixt u r e of r ot a m er s)
a s color less oil a n d (7S, 9S)-24a (29 m g, 27%) a s color less oil.
2
Cl
2
(0.5 m L) wa s a dded 4-ben zyloxy-
3
4
4
(
2
1
4a b: F TIR (n ea t ) 3323, 2952, 2929, 2857, 1746, 1717, 1700, 1668, 1541, 1470, 1457,
-
1
1
405, 1351, 1259, 1212 cm ; Com plex H N MR spect r a wa s obser ved, beca u se of a
18

m ixt u r e of dia st er eom er s a n d r ot a m er s. See a ppen dix.; 1 3 C N MR (100 MH z, CDCl
δ 171.7, 171.6, 171.5, 170.8, 170.7, 170.5, 170.4, 164.4, 164.2, 153.4, 153.2, 153.1,
)
3
1
1
1
9
6
6
5
3
2
1
52.9, 152.73, 152.71, 152.66, 152.63, 152.55, 151.51, 151.47, 151.4, 136.2, 136.1,
35.94, 135.91, 132.0, 131.99, 131.7, 131.65, 131.61, 130.2, 129.9, 129.7, 128.49,
28.47, 128.43, 128.38, 128.32, 128.2, 128.1, 127.9, 127.8, 127.6, 127.5, 93.84, 93.80,
3.7, 93.35, 93.33, 93.2, 81.83, 81.81, 81.76, 81.68, 80.6, 76.0, 75.3, 74.9, 69.4, 68.8,
8.73, 68.70, 68.5, 67.5, 67.4, 67.35, 66.7, 66.5, 64.5, 64.1, 62.24, 62.22, 62.0, 61.9,
1.3, 61.2, 61.0, 60.9, 57.04, 57.0, 56.9, 55.63, 55.59, 55.3, 52.4, 52.3, 52.26, 52.2,
2.16, 52.12, 51.0, 50.9, 50.8, 50.7, 50.6, 37.1, 36.7, 36.5, 36.4, 36.1, 31.34, 31.30,
1.2, 30.9, 30.8, 30.6, 29.6, 29.4, 29.0, 28.96, 28.8, 28.32, 28.26, 26.2, 26.1, 25.8,
5.73, 25.70, 25.6, 25.3, 25.22, 25.20, 25.0, 24.99, 24.96, 24.89, 24.2, 23.8, 18.14,
8.07, -5.37, -5.40, -5.49, -5.51; H RMS (FAB) m /z (M+H )+ ca lcd for
+
[
C
4 9
H
6 5
N
3
O
1 2 Cl
2
Si+H ] 986.3793, fou n d 986.3799.
Desilylation of 24ab
H
H
H
CO Me
CO Me
CO Me
2
Ar
N
2
Ar
N
2
Ar
N
CO Me TBAF, AcOH
CO Me
CO Me
2
2
2
H
N
H
N
+
H
N
O
O
O
Boc
THF, rt
Boc
Boc
TBSO
HO
HO
O
NCbz
O
NCbz
O
NCbz
24ab
(7R, 9S)-25a
(7R, 9R)-25b
To a solu t ion of 24a b (51 m g, 51.8 µm ol) in TH F (0.3 m L) wa s a dded AcOH (3 µL,
o
5
1.8 µm ol) a n d TBAF (1M solu t ion in TH F, 207 µL, 207 µm ol) a t 0 C. Th e r ea ct ion
m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon for 0.5 h , qu en ch ed wit h sa t .
N a H CO , a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e
3
wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der
4
r edu ced pr essu r e. Th e r esidu e wa s pu r ified by pr epa r a t ive TLC (developed wit h
h exa n e/E t OAc = 1:1) t o give (7R, 9S)-25a (25 m g, 55%, a n in sepa r a ble m ixt u r e of
19

dia st er eom er s a n d a m ixt u r e of r ot a m er s) a s color less oil a n d (7R, 9R)-25b (17 m g,
8%, a m ixt u r e of r ot a m er s) a s color less oil.
4R,5S)-3-Benzyl5-((2R,5R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-((S)-
-(hydroxylmethyl)-2-(4-(benzyloxy)-3,5-dichlorobenzamido)ethyl)pyrrolidin-2-yl)
3
(
2
-
2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester ((7R, 9S)-25a): F TIR
(
n ea t ) 3322, 2976, 2951, 1746, 1717, 1699, 1669, 1550, 1456, 1406, 1352, 1268, 1214
-
1
1
cm ; Com plex H N MR spect r a wa s obser ved, beca u se of a m ixt u r e of dia st er eom er s
a n d r ot a m er s. See a ppen dix.; 1 3 C N MR (100 MH z, CDCl
) δ 171.9, 171.6, 171.3,
71.2, 170.7, 170.6, 170.5, 170.4, 165.3, 165.1, 154.24, 154.21, 153.50, 153.49, 153.1,
3
1
1
1
1
7
6
2
53.0, 152.7, 152.5, 151.5, 151.4, 136.2, 136.1, 135.9, 135.8, 131.5, 131.3, 129.87,
29.85, 128.6, 128.54, 128.49, 128.44, 128.39, 128.37, 128.20, 128.18, 128.03, 128.0,
27.8, 127.79, 93.9, 93.7, 93.5, 93.2, 82.3, 82.28, 82.26, 82.22, 82.19, 76.5, 75.8, 75.1,
5.0, 68.94, 68.90, 68.86, 68.81, 67.7, 67.6, 66.83, 66.80, 64.4, 64.3, 64.2, 62.0, 61.9,
1.3, 61.2, 56.13, 56.10, 55.85, 55.77, 53.6, 36.9, 35.7, 35.6, 31.4, 31.0, 30.9, 29.9,
9.8, 28.9, 28.7, 28.33, 28.26, 26.3, 26.2, 25.4, 25.2, 25.0, 24.97, 24.4, 23.9; H RMS
+
+
(
FAB) m /z (M+H ) ca lcd for [C4 3
H
5 1
N
3
O
1 2 Cl +H ] 872.2928, fou n d 872.2924.
2
(
4R,5S)-3-Benzyl 5-((2R,5R)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-((R)-
-(hydroxylmethyl)-2-(4-(benzyloxy)-3,5-dichlorobenzamido)ethyl)pyrrolidin-2-yl)
2
-
2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester ((7R, 9R)-25b): [α]2 2
D
+
1
7.5 (c 0.83, CH Cl
3
); F TIR (n ea t ) 3339, 2976, 2951, 1746, 1717, 1703, 1669, 1548,
-
1
1
456, 1405, 1352, 1270, 1213 cm ; Com plex H N MR spect r a wa s obser ved, beca u se
) δ 172.0, 171.8,
70.7, 170.4, 165.9, 165.7, 153.6, 153.5, 153.0, 152.95, 152.7, 151.5, 136.2, 136.0,
of a m ixt u r e of r ot a m er s. See a ppen dix.; 1 3 C N MR (100 MH z, CDCl
3
1
1
1
6
3
35.9, 130.84, 130.83, 129.8, 129.7, 128.6, 128.5, 128.47, 128.4, 128.37, 128.2, 128.0,
27.8, 127.5, 94.1, 93.6, 82.2, 82.16, 76.5, 75.9, 75.1, 69.1, 69.0, 67.7, 67.0, 66.9,
6.8, 61.9, 61.2, 57.4, 57.3, 52.5, 52.48, 52.38, 52.29, 52.25, 52.1, 36.1, 35.8, 31.4,
1.0, 30.2, 29.9, 29.7, 28.5, 28.4, 28.34, 28.30, 26.2, 25.04, 25.0, 23.9; H RMS (FAB)
+
+
m /z (M+H ) ca lcd for [C4 3
H
5 1
N
3
O
1 2 Cl +H ] 872.2928, fou n d 872.2915.
2
20

Protected kaitocephalin ((7R, 9S)-26)
H
H
1
) cat.TEMPO, cat.KBr, NaOCl
CO Me
CO Me
2
Ar
N
2
Ar
N
o
CO Me
acetone-NaHCO aq, 0 C
CO Me
2
3
2
N
N
H
H
O
O
Boc
Boc
HO
2) TMSCHN , AcOEt
CO Me
O
NCbz
2
2
O
NCbz
(
7R, 9S)-25a
(7R, 9S)-26
To a solu t ion of (7R, 9S)-25a (25 m g, 28.7 µm ol) in a cet on e-5% N a H CO
3
a q (0.3 m L,
o
2
:1) wa s a dded TE MP O (ca .1 m g), KBr (ca .1 m g), a n d N a OCl solu t ion (70 µL) a t 0 C.
o
Th e r ea ct ion m ixt u r e wa s st ir r ed a t 0 C for 1 h , a cidified wit h sa t . KH SO
4
t o pH 3,
a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed
wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
pr essu r e. To a solu t ion of t h e r esidu e in et h yl a cet a t e wa s a dded a solu t ion of
t r im et h ylsilyl)dia zom et h a n e (2.0 M in E t O) a n d con cen t r a t ed u n der r edu ced
4
(
2
pr essu r e. Th e r esidu e wa s pu r ified by pr epa r a t ive TLC (developed wit h h exa n e/
E t OAc = 2:1) t o give (7R, 9S)-26 (18 m g, 72%, a n in sepa r a ble m ixt u r e of
dia st er eom er s a t C7 posit ion ) a s color less oil: F TIR (n ea t ) 3314, 2983, 2951, 1748,
-
1
1
1
716, 1700, 1668, 1551, 1456, 1407, 1352, 1269, 1211 cm ; Com plex H N MR
spect r a wa s obser ved, beca u se of a m ixt u r e of dia st er eom er s a n d r ot a m er s. See
a ppen dix.; 1 3 C N MR (100 MH z, CDCl
) δ 171.8, 171.5, 171.47, 171.45, 171.2, 171.15,
70.8, 170.6, 170.4, 164.23, 164.17, 153.5, 153.0, 152.96, 152.7, 151.5, 151.4, 136.2,
3
1
1
1
7
5
3
2
9
36.2, 136.0, 135.9, 130.9, 130.8, 129.8, 128.6, 128.5, 128.48, 128.42, 128.40, 128.3,
28.2, 128.1, 128.0, 127.9, 94.0, 93.9, 93.5, 93.3, 82.6, 82.5, 82.4, 82.37, 76.4, 75.8,
5.3, 75.1, 74.7, 68.9, 68.8, 68.5, 67.7, 66.9, 66.8, 62.0, 61.9, 61.3, 61.2, 55.25, 55.20,
2.6, 52.5, 52.48, 52.46, 52.38, 52.33, 52.3, 52.2, 51.9, 51.8, 37.9, 36.7, 31.8, 31.3,
1.0, 30.5, 29.7, 29.0, 28.8, 28.4, 28.3, 26.2, 26.1, 25.4, 25.04, 25.0, 24.96, 24.3,
3.9; H RMS (FAB) m /z (M+H )+ ca lcd for [C4 4
00.2900.
H
N
O
1 3 Cl
+H ]+ 900.2877, fou n d
5 1
3
2
21

Protected (9R)-isomer of kaitocephalin ((7R, 9R)-26)
H
H
1
) cat.TEMPO, cat.KBr, NaOCl
CO Me
CO Me
2
Ar
N
2
Ar
N
o
CO Me
acetone-NaHCO aq, 0 C
CO Me
2
3
2
N
N
H
H
O
O
Boc
Boc
HO
2) TMSCHN , AcOEt
CO Me
O
NCbz
2
2
O
NCbz
(
7R, 9R)-25b
(7R, 9R)-26
To a solu t ion of (7R, 9R)-25b (17 m g, 19.5 µm ol) in a cet on e-5% N a H CO
3
a q (0.2 m L,
o
2
:1) wa s a dded TE MP O (ca .1 m g), KBr (ca .1 m g), a n d N a OCl solu t ion (48 µL) a t 0 C.
o
Th e r ea ct ion m ixt u r e wa s st ir r ed a t 0 C for 1 h , a cidified wit h sa t . KH SO
4
t o pH 3,
a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed
wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
pr essu r e. To a solu t ion of t h e r esidu e in et h yl a cet a t e wa s a dded a solu t ion of
t r im et h ylsilyl)dia zom et h a n e (2.0 M in E t O) a n d con cen t r a t ed u n der r edu ced
4
(
2
pr essu r e. Th e r esidu e wa s pu r ified by pr epa r a t ive TLC (developed wit h h exa n e/
E t OAc = 2:1) t o give (7R, 9R)-26 (14 m g, 82%, a m ixt u r e of r ot a m er s) a s color less
oil: [α]2 2
669, 1541, 1457, 1405, 1352, 1270, 1214 cm ; Com plex H N MR spect r a wa s
obser ved, beca u se of a m ixt u r e of r ot a m er s. See a ppen dix.; 1 3 C N MR (100 MH z,
+10.1 (c 1.04, CH Cl ); F TIR (n ea t ) 3322, 2983, 2952, 1746, 1717, 1700,
D
3
-
1
1
1
CDCl
3
) δ 172.6, 172.1, 172.0, 171.9, 171.7, 170.7, 170.4, 165.0, 164.9, 164.59, 164.56,
1
1
1
6
5
3
53.64, 153.61, 153.1, 152.9, 152.87, 152.7, 151.5, 136.5, 136.2, 135.95, 135.90,
35.8, 130.63, 130.59, 130.0, 129.9, 129.8, 128.6, 128.5, 128.48, 128.4, 128.3, 128.1,
28.0, 127.93, 127.85, 127.5, 94.1, 93.9, 93.6, 82.4, 82.37, 81.4, 76.5, 75.9, 75.1, 74.8,
9.86, 69.83, 69.0, 68.9, 67.9, 67.7, 67.53, 67.51, 66.8, 66.6, 61.9, 61.2, 61.1, 57.3,
7.26, 57.0, 53.0, 52.6, 52.5, 52.45, 52.42, 52.3, 52.1, 37.8, 37.0, 31.4, 31.0, 30.8,
0.75, 30.0, 29.7, 28.4, 28.2, 26.2, 25.1, 25.0, 23.9, 23.8; H RMS (FAB) m /z (M+H )+
+
ca lcd for [C4 4
H
5 1
N
3
O
1 3 Cl
2
+H ] 900.2877, fou n d 900.2883.
22

Kaitocephalin (1)
Cl
H
CO Me
Ar
N
2
HO
Cl
CO Me
H
2
AlCl3
Me S, rt
CO H
N
N
2
O
H
Boc
NH2
CO Me
2
2
O
NCbz
N
H
2
O
H
CO H
HO
CO H
2
(
7R, 9S)-26
1
To a solu t ion of (7R, 9S)-26 (10 m g, 11.1 µm ol) in dim et h ylsu lfide (0.1 m L) wa s
a dded AlCl (41 m g, 0.311 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s
3
st ir r ed a t r oom t em per a t u r e for 18 h , qu en ch ed wit h H
2
O, a n d con cen t r a t ed u n der
r edu ced pr essu r e. Th e r esidu e wa s pu r ified by H P LC (Sen syu P a k , P E GASIL-ODS
φ 4.6 x 250 m m , elu t ion wit h 5% MeOH -20m M diet h yla m in e-CO
2
bu ffer pH 7, 1
m L/m in .) t o give cr u de k a it oceph a lin . Th e cr u de k a it oceph a lin wa s pu r ified by
○
R
Dowex
50W x4 (elu t ion wit h 1N N H
4
OH ) a n d H P LC (Sen syu P a k , P E GASIL-ODS
bu ffer pH 7, 1
φ 4.6 x 250 m m , elu t ion wit h 2% MeOH -20m M diet h yla m in e-CO
2
m L/m in .) t o give k a it oceph a lin (1) (1.8 m g, 29%) a s a wh it e powder a lon g wit h a
t r a ce a m ou n t of (7S, 9R)-isom er of 1.
Ka it oceph a lin : [α]2 4
-29.0 (c 0.30, H
O), lit . [α]2 4
-30.9 (c 0.7, H
O); F TIR (n ea t )
O) δ 7.67
D
2
D
1
2
-
1
3
379, 3247, 1635, 1589, 1473, 1389, 1354, 1315 cm ; H N MR (600 MH z, D
2
(
s, 2H ), 4.44 (s, 1H ), 4.37 (dd, J = 8.2, 5.5 H z, 1H ), 4.19 (s, 1H ), 3.69-3.75 (m , 1H ),
2
1
.45 (dt , J = 14.4, 5.9 H z, 1H ), 2.31 (ddd, J = 13.5, 6.5, 2.4 H z, 1H ), 2.12-2.15 (m ,
-
H ), 2.01-2.10 (m , 2H ), 1.60-1.67 (m , 1H ); H RMS (FAB) m /z (M-H ) ca lcd for
-
[
C
1 8
H
2 1
N
3
O
9
Cl
2
-H ] 492.0577, fou n d 492.0581.
23

(
9R)-isomer of kaitocephalin (Deprotection of (7R, 9R)-26)
Cl
H
CO Me
Ar
N
2
HO
Cl
CO Me
H
2
AlCl3
CO H
N
N
2
O
H
Boc
NH2
Me S, rt
CO Me
2
2
O
NCbz
N
H
O
H
CO H
2
HO
CO H
2
(
7R, 9R)-26
(9R)-isomer of 1
To a solu t ion of (7R, 9R)-26 (12 m g, 13.3 µm ol) in dim et h ylsu lfide (0.2 m L) wa s
a dded AlCl (50 m g, 0.372 m m ol) a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s
3
st ir r ed a t r oom t em per a t u r e for 21 h , qu en ch ed wit h H
2
O, a n d con cen t r a t ed u n der
r edu ced pr essu r e. Th e r esidu e wa s pu r ified by H P LC (Sen syu P a k , P E GASIL-ODS
φ 4.6 x 250 m m , elu t ion wit h 5% MeOH -20m M diet h yla m in e-CO
2
bu ffer pH 7, 1
m L/m in .) t o give cr u de (9R)-k a it oceph a lin . Th e cr u de (9R)-k a it oceph a lin wa s
○
pu r ified by Dowex R 50W x4 (elu t ion wit h 1N N H
OH ) a n d H P LC (Sen syu P a k ,
4
P E GASIL-ODS φ 4.6 x 250 m m , elu t ion wit h 5% MeOH -20m M diet h yla m in e-CO
2
bu ffer pH 7, 1 m L/m in .) t o give (9R)-isom er of 1(2.0 m g, 27%) a s a wh it e powder.
(
9R)-isom er of 1: [α]2 4
D
-27.8 (c 0.85, H O); F TIR (n ea t ) 3388, 3063, 2989, 2729,
2
-
1
1
2
4
1
510, 1635, 1590, 1473, 1397, 1348 cm ; H N MR (600 MH z, D O) δ 7.68 (s, 2H ),
2
.44 (s, 1H ), 4.35 (dd, J = 9.9, 4.1 H z, 1H ), 4.19 (s, 1H ), 3.66 (t t , J = 10.3, 5.6 H z,
H ), 2.30-2.35 (m , 2H ), 2.17-2.26 (m , 2H ), 2.00-2.06 (m , 1H ), 1.61-1.69 (m , 1H );
-
-
H RMS (FAB) m /z (M-H ) ca lcd for [C1 8
H
2 1
N
3
O
9
Cl -H ] 492.0577, fou n d 492.0570.
2
24

(
4R,5S)-3-Benzyl 5-((2R,5S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-
allylpyrrolidin-2-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester (19)
1
) LiBEt H
THF, -78 C
allyltrimethylsilane
BF Et
CH Cl , -78 C
CO Me
3
CO Me
CO Me
2
2
2
o
CO Me
CO Me
3
O
2
CO Me
2
2
2
O
AcO
N
N
N
o
H
Boc
2) Ac O, DMAP
Boc
2
2
Boc
2
O
NCbz
O
NCbz
O
NCbz
CH Cl , rt
2
2
15
18
19
To a solu t ion of 15 (212 m g, 0.397 m m ol) in TH F (2 m L) wa s a dded LiBE t
3
H (1 M
o
solu t ion in TH F, 596 µL, 0.596 m m ol) a t -78 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t
o
-
78 C u n der a r gon for 1 h , qu en ch ed wit h sa t . N a H CO
3
/ 30% H
2
2
O (1:1, 19 m L),
st ir r ed a t r oom t em per a t u r e for 2 h , a n d ext r a ct ed wit h diet h yl et h er (x3). Th e
com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. To a solu t ion of t h e r esidu e in
4
,
CH
a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der
a r gon for 1.5 h , qu en ch ed wit h sa t . N H Cl, a n d ext r a ct ed wit h diet h yl et h er (x3).
2
Cl
2
(2 m L) wa s a dded Ac O (56 µL, 0.596 m m ol) a n d DMAP (73 m g, 0.596 m m ol)
2
4
Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h sa t . N a H CO
3
, dr ied over a n h ydr ou s
MgSO , filt er ed t h r ou gh t h in silica gel pa d, a n d con cen t r a t ed u n der r edu ced
4
pr essu r e t o give 18. To a solu t ion of 18 in CH
sila n e (315 µL, 1.99 m m ol) a n d BF ･E t
O (129 µL, 0.475 m m ol) a t -78 oC. Th e
r ea ct ion m ixt u r e wa s st ir r ed a t -78 oC u n der a r gon for 1 h , qu en ch ed wit h sa t .
N a H CO , a n d ext r a ct ed wit h diet h yl et h er (x3). Th e com bin ed or ga n ic la yer s wer e
2
Cl (2 m L) wa s a dded a llylt r im et h yl-
2
3
2
3
wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
r edu ced pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y
elu t ion wit h h exa n e/E t OAc = 10:1 t h en 6:1) t o give 19 (189 m g, 85%, 3 st eps, a
m ixt u r e of r ot a m er s) a s color less oil: [α]2 5
+28.3 (c 0.86, CH Cl ); F TIR (n ea t ) 2977,
949, 1746, 1713, 1698, 1390, 1351, 1211 cm ; H N MR (400 MH z, CDCl ) δ
4
, filt er ed, a n d con cen t r a t ed u n der
(
D
3
-
1
1
2
7
4
3
.26-7.35 (m , 5H ), 5.60-5.80 (br m , 1H ), 5.11-5.28 (m , 2H ), 4.80-5.05 (m , 4H ),
.05-4.20 (m , 1/3H ), 3.90-4.05 (m , 2/3H ), 3.75 (br s, 1H ), 3.73 (s, 2H ), 3.69 (s, 1H ),
25

3
1
1
8
3
.53 (s, 2H ), 2.25-2.50 (m , 2H ), 2.05-2.20 (m , 2H ), 1.78 (s, 2H ), 1.60-1.75 (m , 3H ),
.41 (br s, 9H ), 1.45-1.57 (m , 3H ); 1 3 C N MR (75 MH z, CDCl
) δ 172.1, 171.2, 153.6,
3
52.6, 151.5, 136.4, 136.0, 128.5, 128.4, 128.1, 127.9, 127.6, 116.4, 93.6, 93.1, 80.6,
0.3, 75.6, 74.5, 74.0, 69.1, 68.7, 67.4, 66.6, 62.0, 61.4, 61.1, 58.7, 52.3, 52.2, 52.1,
8.7, 38.1, 28.6, 28.2, 27.6, 27.3, 26.9, 26.2, 25.1, 24.0; H RMS (FAB) m /z (M+H )+
+
ca lcd for [C2 9
H
4 0
N
2
O
9
+H ] 561.2734, fou n d 561.2806.
(
4R,5S)-3-Benzyl 5-((2R,5S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-
5
-(2-(tert-butyldimethylsilyloxymethyl)-2-hydroxyethyl)pyrrolidin-2-yl)-2,2-
dimethyloxazolidine-3,4-dicarboxylate methyl ester ((7S)-22ab)
CO Me
1) cat.OsO , NMO
CO Me
2
2
4
HO
CO Me
CO Me
2
2
t-BuOH, H O, rt
2
N
H
N
H
Boc
Boc
TBSO
O
NCbz
2) TBSOTf, 2, 6-lutidine
O
NCbz
o
CH Cl , -78 C
2
2
1
9
(7S)-22ab
To a solu t ion of 19 (260 m g, 0.464 m m ol) in t -Bu OH -H
OsO
2
O (2.5 m L, 1:1) wa s a dded
o
4
(296 µL, 1g/25 m L in t -Bu OH ) a n d N MO (67 m g, 0.557 m m ol) a t 0 C. Th e
r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e for 2 h , qu en ch ed wit h KH SO
a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed
wit h br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
3
a q,
4
pr essu r e. To a solu t ion of t h e r esidu e in CH
2
Cl
2
(2.5 m L) wa s a dded TBSOTf (116 µL,
o
0
.422 m m ol) a n d 2,6-lu t idin e (70 µL, 0.603 m m ol) a t -78 C u n der a r gon for 15 m in .,
qu en ch ed wit h E t OH a n d sa t . N H Cl, a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e
4
com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO ,
4
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 10:1, 8:1 t h en 1:1) t o
give (7S)-22a b (214 m g, 65%, 2:1 in sepa r a ble m ixt u r e of dia st er eom er s a n d a
26

m ixt u r e of r ot a m er s) a s color less oil a n d r ecover y of diol (63 m g, 23%, 2:1
in sepa r a ble m ixt u r e of dia st er eom er s a n d a m ixt u r e of r ot a m er s).
(
7S)-22a b: F TIR (n ea t ) 3460, 2953, 2857, 1747, 1717, 1683, 1403, 1353, 1253, 1212
-
1
1
cm ; H N MR (300 MH z, CDCl
3
) δ 7.25-7.35 (m , 5H ), 5.10-5.30 (m , 5/3H ), 4.85-5.05
(
m , 7/3H ), 4.10-4.41 (m , 1H ), 3.50-3.76 (m , 9H ), 2.10-2.50 (m , 2H ), 1.39-1.76 (m ,
1
9H ), 0.89 (s, 6H ), 0.87 (s, 3H ), 0.06 (s, 4H ), 0.04 (s, 2H ); 1 3 C N MR (75 MH z, CDCl
)
3
δ 171.6, 170.9, 154.0, 152.6, 151.4, 136.3, 136.1, 136.0, 128.6, 128.4, 128.1, 127.9,
1
6
5
2
27.8, 127.6, 93.7, 93.6, 93.2, 93.0, 81.2, 80.9, 80.6, 75.6, 75.0, 74.7, 70.1, 69.9, 69.0,
7.9, 67.6, 67.4, 66.8, 66.6, 62.0, 61.4, 61.1, 56.7, 56.5, 56.0, 52.4, 52.22, 52.20,
2.17, 52.16, 52.12, 38.5, 29.5, 28.9, 28.8, 28.2, 27.4, 26.2, 26.0, 25.8, 25.2, 25.1,
+
5.0, 24.1, 24.0, 18.5, 18.2, -5.17, -5.27, -5.36, -5.42; H RMS (FAB) m /z (M+H ) ca lcd
+
for [C3 5
H
5 6
N
2
O
11 Si+H ] 709.3653, fou n d 709.3702.
(
(
4R,5S)-3-Benzyl 5-((2R,5S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-
2-(tert-butyldimethylsilyloxymethyl)-2-azidoethyl)pyrrolidin-2-yl)-2,2-
dimethyloxazolidine-3,4-dicarboxylate methyl ester ((7S)-23ab)
CO Me
CO Me
2
HO
2
N3
CO Me DPPA, DEAD
CO Me
2
2
N
N
H
Ph P
H
3
Boc
Boc
TBSO
TBSO
O
NCbz
O
NCbz
THF, rt
(
7S)-22ab
(7S)-23ab
To a solu t ion of (7S)-22a b (233 m g, 0.329 m m ol) in TH F (2 m L) wa s a dded DP PA
212 µL, 0.987 m m ol), P P h (258 m g, 0.987 m m ol), a n d DE AD (156 µL, 0.987 m m ol)
(
3
a t r oom t em per a t u r e. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der
a r gon for 1 h a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 10:1 t h en 8:1) t o give
(
7S)-23a b (234 m g, 97%, a n in sepa r a ble m ixt u r e of dia st er eom er s a n d a m ixt u r e of
27

r ot a m er s) a s color less oil: F TIR (n ea t ) 2953, 2931, 2857, 2106, 1746, 1716, 1701,
-
1
1
1
457, 1436, 1404, 1392, 1352, 1253, 1212, 1180 cm ; Com plex H N MR spect r a wa s
obser ved, beca u se of a m ixt u r e of dia st er eom er s a n d r ot a m er s. See a ppen dix.; 1 3
C
N MR (75 MH z, CDCl ) δ 172.0, 171.1, 171.0, 152.6, 151.5, 136.3, 128.5, 128.4, 128.2,
3
1
6
2
27.9, 127.8, 127.6, 93.7, 93.6, 93.5, 93.0, 81.0, 80.99, 80.97, 80.92, 80.86, 67.5, 66.7,
6.3, 62.0, 61.5, 61.3, 61.1, 56.1, 52.4, 52.2, 52.1, 35.5, 35.2, 34.4, 43.3, 28.4, 28.2,
+
5.3, 25.1, 25.0, 24.2, 24.0, 18.2, -5.53, -5.59; H RMS (FAB) m /z (M+H ) ca lcd for
+
[
C
3 5
H
5 5
N
5
O
1 0 Si+H ] 734.3796, fou n d 734.3817.
Reduction of (7S)-23ab followed by acylation of the resulting amines
(7S, 9S)-24a and (7S, 9R)-24b)
(
1
) Me P,
THF-H O, rt
H
H
CO Me
3
N3
TBSO
2
CO Me
CO Me
2
Ar
N
2
Ar
N
CO Me
2
2
CO Me
CO Me
2
2
H
N
N
N
O
H
+
O
H
Boc
2) ArCO H
2
Boc
Boc
O
NCbz
TBSO
TBSO
O
NCbz
O
NCbz
BOP, DIPEA
CH Cl , rt
2
2
(7S)-23ab
(7S, 9S)-24a
(7S, 9R)-24b
Cl
OBn
Cl
Ar =
To a solu t ion of (7S)-23a b (205 m g, 0.280 m m ol) in TH F -H O (2.8 m L, 3:1) wa s
2
a dded P Me
3
(1M solu t ion in TH F, 1.40 m L, 1.40 m m ol) a t r oom t em per a t u r e. Th e
r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e for 1.5 h a n d con cen t r a t ed u n der
r edu ced pr essu r e. To a solu t ion of t h e r esidu e in CH
2
Cl
2
(2.8 m L) wa s a dded
4
0
-ben zyloxy- 3,5-dich lor oben zoic a cid (100 m g, 0.336 m m ol), BOP r ea gen t (149 m g,
o
.336 m m ol) a n d DIP E A（73 µL, 0.420 m m ol) a t 0 C. Th e r ea ct ion m ixt u r e wa s
Cl, a n d
ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h
br in e, dr ied over a n h ydr ou s MgSO , filt er ed, a n d con cen t r a t ed u n der r edu ced
pr essu r e. Th e r esidu e wa s pu r ified by fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h
st ir r ed a t r oom t em per a t u r e u n der a r gon for 15 h , qu en ch ed wit h sa t . N H
4
4
28

h exa n e/E t OAc = 8:1, 6:1 t h en 5:1) t o give less pola r isom er (7S, 9R)-24b (75 m g,
7%) a s color less oil a n d (elu t ion wit h h exa n e/E t OAc = 5:1) t o give m or e pola r
isom er (7S, 9S)-24a (165 m g, 60%) a s color less oil.
4R,5S)-3-Benzyl 5-((2R,5S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-((S)-
-(tert-butyldimethylsilyloxymethyl)-2-(4-(benzyloxy)-3,5-dichlorobenzamido)
ethyl)pyrrolidin-2-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester
(7S, 9S)-24a): [α]2 0
+12.3 (c 0.53, CH Cl ); F TIR (n ea t ) 3335, 2953, 1748, 1716,
697, 1670, 1540, 1470, 1457, 1405, 1354, 1257 cm ; Com plex H N MR spect r a wa s
2
(
2
(
D
3
-
1
1
1
1
3
obser ved, beca u se of a m ixt u r e of r ot a m er s. See a ppen dix.; C N MR (75 MH z,
CDCl
3
) δ 171.9, 171.5, 171.4, 171.2, 170.9, 170.7, 164.5, 164.1, 153.3, 153.2, 152.8,
1
1
9
6
3
2
52.7, 152.6, 151.5, 151.4, 136.3, 136.26, 136.1, 136.0, 135.95, 135.7, 131.8, 130.1,
29.7, 128.6, 128.5, 128.45, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.63, 127.61,
3.8, 93.6, 93.3, 81.53, 81.50, 80.5, 75.3, 75.1, 75.0, 74.7, 74.6, 69.0, 68.3, 67.6, 66.8,
6.7, 66.6, 65.37, 65.35, 64.3, 62.0, 61.3, 61.1, 56.6, 52.4, 52.3, 52.2, 50.8, 49.1, 37.1,
6.2, 29.6, 29.5, 29.4, 29.1, 29.0, 28.3, 28.2, 27.4, 26.2, 25.8, 25.3, 25.1, 25.0, 24.2,
4.13, 24.12, 18.2, 18.1, -5.34, -5.44; H RMS (FAB) m /z (M+H )+ ca lcd for
+
[
C
4 9
H
6 5
N
3
O
1 2 Cl
2
Si+H ] 986.3793, fou n d 986.3800.
(
4R,5S)-3-Benzyl 5-((2R,5S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-((R)-
-(tert-butyldimethylsilyloxymethyl)-2-(4-(benzyloxy)-3,5-dichlorobenzamido)
ethyl)pyrrolidin-2-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester
(7S, 9R)-24b): [α]2 1
+42.2 (c 1.35, CH Cl ); F TIR (n ea t ) 3314, 2952, 2929, 1749,
716, 1700, 1667, 1541, 1457, 1406, 1351, 1258 cm ; Com plex H N MR spect r a wa s
obser ved, beca u se of a m ixt u r e of r ot a m er s. See a ppen dix.; 1 3 C N MR (75 MH z,
CDCl ) δ 171.6, 170.9, 164.2, 153.2, 152.6, 151.4, 136.2, 136.0, 132.1, 132.0, 129.7,
28.6, 128.51, 128.47, 128.40, 128.2, 128.03, 128.02, 127.8, 75.4, 75.0, 74.8, 68.5,
2
(
D
3
-
1
1
1
3
1
6
2
7.6, 66.8, 62.3, 62.1, 61.4, 55.3, 52.4, 52.3, 52.23, 52.20, 51.0, 36.5, 30.9, 30.8, 30.7,
9.7, 29.1, 29.0, 28.9, 28.3, 26.2, 25.9, 25.3, 25.1, 24.2, 18.2, -5.31, -5.44; H RMS
+
+
(
FAB) m /z (M+H ) ca lcd for [C4 9
H
6 5
N
3
O
1 2 Cl Si+H ] 986.3793, fou n d 986.3776.
2
29

(
4R,5S)-3-Benzyl 5-((2R,5S)-1-(tert-butoxycarbonyl)-2-(methoxycarbonyl)-5-((S)-
2
2
-(methoxycarbonyl)-2-(4-(benzyloxy)-3,5-dichlorobenzamido)ethyl)pyrrolidin-
-yl)-2,2-dimethyloxazolidine-3,4-dicarboxylate methyl ester ((7S, 9S)-26)
H
H
CO Me
1) TBAF, AcOH, THF, rt
CO Me
2
Ar
N
2
Ar
N
CO Me
CO Me
2
2
N
2) cat.TEMPO, cat.KBr, NaOCl
N
H
H
O
O
Boc
Boc
o
TBSO
acetone-NaHCO aq, 0 C
CO Me
O
NCbz
3
2
O
NCbz
3
) CH N2
2
(7S, 9S)-24a
(7S, 9S)-26
To a solu t ion of (7S, 9S)-24a (165 m g, 0.168 m m ol) in TH F (0.8 m L) wa s a dded
AcOH (9.6 µL, 0.168 m m ol) a n d TBAF (1M solu t ion in TH F, 670 µL, 0.67 m m ol) a t 0
oC. Th e r ea ct ion m ixt u r e wa s st ir r ed a t r oom t em per a t u r e u n der a r gon for 0.5 h ,
qu en ch ed wit h sa t . N a H CO , a n d ext r a ct ed wit h et h yl a cet a t e (x3). Th e com bin ed
3
or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
4
, filt er ed, a n d
con cen t r a t ed u n der r edu ced pr essu r e. To a solu t ion of t h e r esidu e in a cet on e-5%
N a H CO
3
a q (1.7 m L, 2:1) wa s a dded TE MP O (3 m g, 16.8 µm ol), KBr (2 m g, 16.8
o
µm ol), a n d N a OCl solu t ion (412 µL) a t 0 C. Th e r ea ct ion m ixt u r e wa s st ir r ed a t 0
oC for 0.5 h , a cidified wit h sa t . KH SO
t o pH 3, a n d ext r a ct ed wit h et h yl a cet a t e (x3).
4
Th e com bin ed or ga n ic la yer s wer e wa sh ed wit h br in e, dr ied over a n h ydr ou s MgSO
4
,
filt er ed, a n d con cen t r a t ed u n der r edu ced pr essu r e. To a solu t ion of dia zom et h a n e in
o
diet yl et h er wa s a dded a solu t ion of t h e r esidu e in et h yl a cet a t e a t 0 C, st ir r ed a t 0
oC for 0.5 h , a n d con cen t r a t ed u n der r edu ced pr essu r e. Th e r esidu e wa s pu r ified by
fla sh colu m n ch r om a t ogr a ph y (elu t ion wit h h exa n e/E t OAc = 6:1 t h en 2:1) t o give
(
7S, 9S)-26 (118 m g, 78%, a m ixt u r e of r ot a m er s) a s color less oil: [α]2 0
CH Cl ); F TIR (n ea t ) 3335, 2983, 2952, 1746, 1716, 1697, 1669, 1548, 1454, 1405,
352, 1270 cm ; Com plex H N MR spect r a wa s obser ved, beca u se of a m ixt u r e of
r ot a m er s. See a ppen dix.; 1 3 C N MR (75 MH z, CDCl
) δ 172.2, 172.1, 171.3, 171.2,
70.9, 170.7, 165.0, 164.7, 153.7, 153.6, 152.9, 152.89, 152.6, 151.4, 136.1, 135.9,
D
+27.9 (c 1.21,
3
-
1
1
1
3
1
1
9
35.87, 130.9, 130.6, 130.0, 129.8, 128.6, 128.5, 128.47, 128.4, 128.3, 128.1, 127.9,
3.9, 93.4, 82.2, 82.1, 81.2, 75.2, 75.1, 74.6, 69.54, 69.53, 68.3, 67.7, 66.9, 62.0, 61.3,
30