3642 J . Org. Chem., Vol. 63, No. 11, 1998
Blaskovich et al.
(M+ - 57, 47); HRMS (EI, 70 eV) calcd for C25H27NO6 437.1838,
found 437.1833 (M+). Anal. Calcd for C25H27NO6: C, 68.64;
H, 6.23; N, 3.20. Found: C, 68.82; H, 6.51; N, 3.07.
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-1-a m in o-2-
(4-m e t h oxyb e n zyl)-2-oxoe t h yl]-4-m e t h yl-2,6,7-t r ioxa -
b icyclo[2.2.2]oct a n e, F m oc-L-â-a n isoleser in e(k et ) OBO
Ester 24a . Fmoc-L-â-anisoleserine OBO ester 15a (0.357 g,
0.690 mmol) was oxidized and purified under standard condi-
tions to give 0.288 g (81%) of colorless solid. Recrystallization
attempts (Et2O/hexane, EtOAc/hexane) were unsuccessful: mp
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-1-a m in o-2-
oxoh exyl]-4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]octan e, Fm oc-
L-â-bu tylser in e(ket) OBO Ester 21a. Fmoc-L-â-n-butylserine
OBO ester 12a (0.202 g, 0.432 mmol) was oxidized and purified
under standard conditions to give 0.201 g (100%) of colorless
solid. Recrystallization (Et2O/hexane) gave 0.160 g (80%) of
product: mp 92-94 °C; [R]20D ) -54.7 (c ) 1.63, EtOAc); TLC
(solvent A) Rf )0.66; 1H NMR (CDCl3, 200 MHz) δ 7.77-7.25
(m, 8H), 5.73 (d, J ) 8.9 Hz, 1H), 4.64 (d, J ) 9.0 Hz, 1H),
4.37-4.4 (m, 3H), 3.93 (s, 6H), 2.82 (dt, J ) 17.5, 7.5 Hz, 1H),
2.55 (dt, J ) 17.4, 7.1 Hz, 1H), 1.59 (quint, J ) 7.4 Hz, 2H),
1.27 (sext, J ) 7.3 Hz, 2H), 0.90 (t, J ) 7.2 Hz, 3H), 0.81 (s,
3H); 13C NMR (CDCl3, 50.3 MHz) δ 205.0, 155.9, 143.9, 143.8,
141.1, 127.5, 126.9, 125.2, 119.8, 106.9, 72.8, 67.1, 62.2, 47.0,
42.1, 30.6, 25.5, 22.1, 14.1, 13.8; IR (cast from CH2Cl2) 1722,
1512, 1047, 1022, 1005, 761, 741 cm-1; MS (EI, 70 eV) m/z
465 (M+, 6), 421 (M+ - 44, 2), 380 (M+ - 85, 8); HRMS (EI, 70
eV) calcd for C27H31NO6 465.2152, found 465.2145 (M+). Anal.
Calcd for C27H31NO6: C, 69.66; H, 6.73; N, 3.01. Found: C,
69.70; H, 6.53; N, 3.05.
93-96 °C; [R]20 ) -26.6 (c ) 0.94, EtOAc); TLC (solvent A)
D
1
Rf ) 0.45; H NMR (CDCl3, 200 MHz) δ 8.07 (d, J ) 8.9 Hz,
2H), 7.76-7.25 (m, 8H), 6.93 (d, J ) 8.9 Hz, 2H), 6.04 (d, J )
9.5 Hz, 1H), 5.59 (d, J ) 9.5 Hz, 1H), 4.36-4.19 (m, 3H), 3.88
(s, 6H), 3.85 (s, 3H), 0.75 (s, 1H); 13C NMR (CDCl3, 50.3 MHz)
δ 193.1, 163.7, 155.8, 143.8, 141.1, 131.9, 129.3, 127.5, 126.9,
125.2, 119.8, 113.4, 107.3, 72.8, 67.2, 56.9, 55.3, 47.0, 30.6, 14.1;
IR (cast from CH2Cl2) 1724, 1681, 1600, 1574, 1512, 1222,
1181, 1049, 1031, 1009, 910, 846, 761, 734 cm-1; MS (EI, 70
eV) m/z 515 (M+, 4), 471 (M+ - 44, 1); HRMS (EI, 70 eV) calcd
for C30H29NO7 515.1944, found 515.1940 (M+). Anal. Calcd
for C30H29NO7: C, 69.89; H, 5.68; N, 2.17. Found: C, 69.64;
H, 5.69; N, 2.39.
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-1-a m in o-2-
c y c l o h e x y l -2 -o x o e t h y l ] -4 -m e t h y l -2 , 6 , 7 -t r i o x a -
bicyclo[2.2.2]octan e, Fm oc-L-â-cycloh exylser in e(ket) OBO
Ester 25a . Fmoc-L-â-cyclohexylserine OBO ester 16a (0.252
g, 0.511 mmol) was oxidized and purified under standard
conditions to give 0.185 g (74%) of colorless solid. Recrystal-
lization (Et2O/hexane) gave 0.145 g (58%) of product: mp
154.5-155.5 °C; [R]20D ) -47.3 (c ) 1.82, EtOAc); TLC (solvent
A) Rf ) 0.68; 1H NMR (CDCl3, 200 MHz) δ 7.77-7.25 (m, 8H),
5.75 (d, J ) 9.2 Hz, 1H), 4.80 (d, J ) 9.3 Hz, 1H), 4.36-4.4
(m, 3H), 3.93 (s, 6H), 2.83 (tt, J ) 11.1, 3.0 Hz, 1H), 2.07-
1.03 (br m, 10 H), 0.80 (s, 3H); 13C NMR (CDCl3, 50.3 MHz) δ
208.3, 155.7, 143.9, 143.8, 141.1, 127.5, 126.9, 125.2, 119.8,
107.1, 72.9, 67.1, 60.4, 49.9, 47.0, 30.6, 29.2, 26.9, 26.0, 25.7,
25.1, 14.2; IR (cast from CH2Cl2) 1720, 1048, 1025, 1005, 987,
760, 739 cm-1; MS (EI, 70 eV) m/z 491 (M+, 6), 475 (M+ - 16,
2), 380 (M+ - 111, 3); HRMS (EI, 70 eV) calcd for C29H33NO6
491.2308, found 491.2305 (M+). Anal. Calcd for C29H33NO6:
C, 70.86; H, 6.78; N, 2.85. Found: C, 71.00; H, 7.00; N, 2.93.
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-1-a m in o-2-
o x o -3-b u t e n y l]-4-m e t h y l-2,6,7-t r io x a b ic y c lo [2.2.2]-
octa n e, F m oc-L-â-vin ylser in e(k et) OBO Ester 22a . Fmoc-
L-â-vinylserine OBO ester 13a (0.185 g, 0.422 mmol) was
oxidized and purified under standard conditions to give 0.075
g (41%) of colorless solid, a portion of which was recrystallized
(Et2O/hexane) to give 0.027 g of product: mp 113-115 °C;
[R]20 ) -36.2 (c ) 0.83, EtOAc); TLC (solvent A) Rf ) 0.53;
D
1H NMR (CDCl3, 200 MHz) δ 7.77-7.25 (m, 8H), 6.69 (dd, J
) 17.3, 10.2 Hz, 1H), 6.37 (dd, J ) 17.3, 1.2 Hz, 1H), 5.81 (d,
J ) 9.0 Hz, 1H), 5.77 (dd J ) 10.2, 1.2 Hz, 1H), 4.88 (d, J )
9.1 Hz, 1H), 4.37-4.4 (m, 3H), 3.92 (s, 6H), 0.79 (s, 3H); 13C
NMR (CDCl3, 50.3 MHz) δ 193.7, 155.9, 143.8, 141.2, 134.4,
128.9, 127.5, 127.0, 125.2, 119.8, 107.1, 72.9, 67.2, 61.0, 47.0,
30.7, 14.4; IR (cast from CH2Cl2) 1725, 1706, 1612, 1047, 1008,
988, 761, 739 cm-1; MS (CI, CH4) m/z 436 (MH+, 100), 391
(MH+ - 45, 15), 380 (MH+ - 56, 18); HRMS (CI, CH4) calcd
for C25H26NO6 436.1760, found 436.1754 (MH+). Anal. Calcd
for C25H25NO6: C, 68.96; H, 5.80; N, 3.22. Found: C, 68.72;
H, 6.01; N, 3.21.
1-[N-(9-Flu or en ylm eth yloxycar bon yl)-(1S,2S)-1-am in o-
2-h yd r oxyb u t a n ol]-4-m et h yl-2,6,7-t r ioxa b icyclo[2.2.2]-
octa n e, F m oc-(2S,3S)-â-eth ylser in e OBO Ester , 27a . Ke-
tone 19a (0.101 g, 0.231 mmol) was reduced with LiBH4 to
give 0.079 g of crude product with a 93:7 erythro:threo ratio.
Purification gave 0.044 g (45%) of colorless solid. Recrystal-
lization (EtOAc/hexane) gave 0.037 g (38%) of crystals, with a
1-[N-(9-F lu or en ylm eth yloxyca r bon yl)-(1S)-1-a m in o-2-
o x o -4-p e n t e n y l]-4-m e t h y l-2,6,7-t r io x a b ic y c lo [2.2.2]-
octa n e, F m oc-L-â-a llylser in e(k et) OBO Ester 23a . Fmoc-
L-â-allylserine OBO ester 14a (0.426 g, 0.944 mmol) was
oxidized and purified under standard conditions to give 0.222
g (52%) of the desired product, 0.072 g (17%) of a product where
the alkene has isomerized into conjugation with the ketone,
and 0.035 g (8%) of recovered starting alcohol. A portion of
>99.5:<0.5 erythro:threo ratio: mp 151.5-152 °C; [R]20
)
D
-41.0 (c ) 1.28, EtOAc); TLC (solvent A) Rf ) 0.39 (erythro);
1H NMR (CDCl3, 200 MHz) major isomer ) erythro (>99.5%),
minor ) threo (<0.5%) δ 7.78-7.25 (m, 8H), 5.05 (d, J ) 10.2
Hz, 1H), 4.44-4.21 (m, 3H), 3.93 (s, 6H), 3.88 (dd, J ) 10.0,
7.4 Hz, 1H), 3.78-3.64 (m, 1H), 3.46 (s, 1H), 1.72-1.53 (m,
1H), 1.53-1.32 (m, 1H), 0.97 (t, J ) 7.4 Hz, 3H), 0.82 (s, 3H);
13C NMR (CDCl3, 50.3 MHz) δ 156.4, 144.1, 143.8, 141.2, 127.5,
126.9, 125.0, 119.9, 108.9, 72.6, 72.5, 66.7, 57.6, 47.2, 30.5, 26.0,
14.2, 9.7; IR (cast from CH2Cl2) 1720, 1045, 1002, 761, 736
cm-1; MS (EI, 70 eV) m/z 439 (M+, 3), 410 (M+ - 29, 11), 381
(M+ - 58, 100); HRMS (EI, 70 eV) calcd for C25H29NO6
439.1995, found 439.1990 (M+). Anal. Calcd for C25H29NO6:
C, 68.32; H, 6.65; N, 3.19. Found: C, 68.50; H, 6.83; N, 3.21.
product was recrystallized (Et2O/hexane): mp 55-58 °C; [R]20
D
) 55.6 (c ) 1.04, EtOAc); TLC (solvent A) Rf ) 0.53; 1H NMR
(CDCl3, 200 MHz) δ 7.77-7.25 (m, 8H), 6.05-5.85 (m, 1H),
5.72 (d, J ) 8.9 Hz, 1H), 5.19 (dd, J ) 9.6, 1.3 Hz, 1H), 5.14
(dd, J ) 17.1, 1.4 Hz, 1H), 4.70 (d, J ) 8.9 Hz, 1H), 4.37-4.4
(m, 3H), 3.93 (s, 6H), 3.57 (dd, J ) 17.7, 6.6 Hz, 1H), 3.37 (dd,
J ) 17.6, 7.0 Hz, 1H), 0.81 (s, 3H); 13C NMR (CDCl3, 50.3 MHz)
δ 202.6, 155.9, 143.8, 143.8, 141.1, 130.1, 127.5, 127.0, 125.1,
119.8, 118.8, 106.9, 72.9, 67.2, 62.0, 47.0, 46.8, 30.6, 14.2; IR
(cast from CH2Cl2) 1721, 1641, 1642, 1047, 1007, 761, 742 cm-1
;
Dep r otection of 27a : (2S,3S)-â-Eth ylser in e, 49. Fmoc-
L-â-ethylserine OBO ester 27a (0.0359 g, 0.082 mmol) was
deprotected to give 0.0127 g (>100%) of product 49 after ion
exchange chromatography. 1H NMR integration of the R-CH
proton indicated a 94:6 erythro (2S,3S):threo (2S,3R) ratio.
Recrystallization (H2O/acetone) gave 0.0095 g (87%) of colorless
crystals, also with a 94:6 erythro (2S,3S):threo (2S,3R) ratio
MS (EI, 70 eV) m/z 449 (M+, 45), 405 (M+ - 44, 15), 380 (M+
- 69, 64); HRMS (EI, 70 eV) calcd for C26H27NO6 449.1838,
found 449.1831 (M+). Anal. Calcd for C26H27NO6: C, 69.48;
H, 6.07; N, 3.12. Found: C, 69.57; H, 6.09; N, 3.05.
Isom er ized Oxid a t ion P r od u ct : 1-[N-(9-F lu or en yl-
m eth yloxyca r bon yl)-(E)-(1S)-1-a m in o-2-oxo-4-p en ten yl]-
4-m eth yl-2,6,7-tr ioxabicyclo[2.2.2]octan e. 1H NMR (CDCl3,
200 MHz): δ 7.77-7.26 (m, 8H), 7.01 (dq, J ) 15.5, 6.9 Hz,
1H), 6.43 (dd, J ) 15.6, 1.5 Hz, 1H), 5.82 (d, J ) 9.2 Hz, 1H),
4.83 (d, J ) 9.1 Hz, 1H), 4.37-4.4 (m, 3H), 3.92 (s, 6H), 1.92
(dd, J ) 6.9, 1.3 Hz, 3H), 0.80 (s, 3H); 13C NMR (CDCl3, 50.3
MHz): δ 193.1, 155.9, 144.1, 143.8, 141.1, 130.0, 127.5, 126.9,
126.0, 119.8, 107.2, 72.8, 67.1, 60.7, 47.0, 30.6, 18.4, 14.4.
1
as determined by H NMR. Derivatization followed by analy-
sis by HPLC indicated a 95:5 ratio of erythro (2S,3S):threo
(2S,3R), with 94.0% ee (conditions as for threo isomer 10a ).
49: mp 215-216 °C (dec); TLC (solvent C) Rf ) 0.58; 1H NMR
(D2O, 200 MHz) major isomer ) erythro (94%), minor ) threo
(6%) δ 3.88 (dt, J ) 3.7, 6.6 Hz, 1H), 3.72 (d, J ) 3.7 Hz, 0.94H),
3.53 (d, J ) 4.4 Hz, 0.06H), 1.41 (quintet, J ) 7.2 Hz, 2H),