Transcript A Synthetic Approach to Amphidinolide A: Application of

Total Synthesis of Rapamycin
HO
MeO
OMe
O
O
N
O
O
O
HO
MeO
O
O
HO
Isolation and Structure Determination:
Vézina, C.; Kudelski, A.; Sehgal, S. N. J.
Antibiotics 1975, 28, 721.
Swindells, D. C. N.; White, P. S.; Findlay, J. A.
Can. J. Chem. 1978, 56, 2491.
Findlay, J. A.; Radics, L. Can. J. Chem. 1981,
59, 49.
McAlpine, J. B.; Swanson, S. J.; Jackson, M.;
Whittern, D. N. J. Antibiotics 1991, 44, C-3.
Total Syntheses:
Nicolaou, K. C.; Chakraborty, T. K.; Piscopio, A. D.; Minowa, N.; Bertinato, P. J. Am. Chem. Soc.
1993, 115, 4419.
Hayward, C. M.; Yohannes, D.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115, 9345.
Romo, D.; Meyer, S. D.; Johnson, D. D.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 7906.
Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leazer, J. L., Jr.; Leahy, J. W.; Maleczka, R. E., Jr.
J. Am. Chem. Soc. 1995, 117, 5407-5408.
Immunomodulators
HO
HO
HO
rapamycin
FK-506
MeO
MeO
MeO
OMe
OMe
O
O
N
N
O
O
O
HO
HO
O
O
O
O
O
O
O
O
O
HO
HO
O
N
O
OH
O
O
MeO
MeO
O
O
HO
OMe
OMe
Me
O
Me
O
Me
H
N
N
N
N
O
H
OH O
O
Me
Me
Me
N
H
O
H
N
O
N
H
H
Me
O
N
O
N
N
O
O
N
cyclosporin A
Rapamycin’s Mechanism of Action
IL-2 Receptor
The Cell Cycle
Restriction
Point
?
G1
p70 S6 Kinase
S
G0
M
Cdc2 Kinase
G2
40S Ribosomal Protein S6
Schreiber, S.L.; Albers, M. W.; Brown, E. J. Acc. Chem. Res. 1993, 26, 412.
Chung, J.; Kuo, C. J.; Crabtree, G. R.; Blenis, J. Cell 1992, 69, 1227.
KCN's Retrosynthetic Analysis of Rapamycin
TIPSO
A
MeO
HO
O
MeO
OHC
34
O
OPMB
34
1
O
O
HO
8
O
O
HO
Boc
20
O
18
MeO
O
1
CO2H
N
22
N
OMe
OPMB
Xc
OMe
35
35
B
22
E
20
21
19
TIPSO
SnBu3
HO
HO
CO2H
8
Bu3Sn
19
C
10 OTIPS OMe
rapamycin
18 I
D
Synthesis of Oxazolidone A
OBn
OH
O
1. CSA, MeOH
2. TBSOTf
1. m-CPBA
2. NaH, BnBr, TBAI
O
3. H2, 10% Pd-C
4. Swern [O]
OTMS
then TMSCl
MeO
O
TBSO
Pd(OAc)2
OH
TBSO
CeCl3
THF/MeOH
MeO
MeO
TBSO
LiBH4
MeCN
MeO
LDA, THF,
-78 °C;
TBSO
OMe
NMe2
xylenes,
reflux
MeO
NMe2
4
3
1
O
TBSO
3
TBSO
[3,3]
1
6
OH
1. LiEt3BH
6
4
MeO
MeO
TBSO
O
NMe2
2. H2, 10% Pd-C
MeO
Synthesis of Oxazolidone A (continued)
SeCN
TBSO
O3,
MeOH/CH2Cl2,
-78 °C;
TBSO
OH
NO2
MeO
MeO
Bu3P, THF;
then 30%
H2O2
TBSO
MeO
then Me2S
CHO
mechanism?
O
O
1.
N
TIPSO
TBSO
O
(EtO)2P
MeO
MeO
O
1. HF, MeCN
O
O
2. TIPSCl, imid.
LiCl, i-Pr2NEt
2. Et3SiH, (Ph3P)3RhCl
N
N
O
O
A
O
O
KCN's Retrosynthetic Analysis of Rapamycin
TIPSO
A
MeO
HO
O
MeO
OHC
34
O
OPMB
34
1
O
O
HO
8
O
O
HO
Boc
20
O
18
MeO
O
1
CO2H
N
22
N
OMe
OPMB
Xc
OMe
35
35
B
22
E
20
21
19
TIPSO
SnBu3
HO
HO
CO2H
8
Bu3Sn
19
C
10 OTIPS OMe
rapamycin
18 I
D
Synthesis of Subunit B
HO
HO
1. m-CPBA
CO2H
1. NaIO4, H2O/THF
2. HClO4
H2O/THF
2. CrO3, H2SO4
acetone
(+)--citronellene
Ph
O
O
O
Bu2BOTf, CH2Cl2, -78 °C
then Et3N, -78 °C to 0 °C
PivCl, Et3N;
N
then O
then
Me
O
Me
N
TIPSO
O
OHC
OMe
Ph
B
O
OTIPS
Li
N
O
Me
Bu
O
MeO
Z-enolate
then 30% H2O2
Ph
TIPSO
TIPSO
MeO
MeO
X
Xcc
OH
OH
OTIPS
OTIPS
OH
OH
O
O
O
Xc =
O
O
X
Xcc
OMe
OMe
N
O
Bu
Synthesis of Subunit B (continued)
OH
OMe
O
1. LiBH4
1. TBAF
2. anisaldehyde
dimethylacetal
2. TsCl
3. LiEt3BH
3. Dibal
4. Swern
OTIPS
OH
OTIPS
OMe
Xc
OMe
OPMB
OMe
OHC
OPMB
CrCl2/NiCl2, DMSO
OPMB
CHO
TBSO
OMe
I
TBSO
OPMB
OMe
1. TIPSOTf
2. HF•pyr.
3. Swern
OPMB
OHC
OPMB
TIPSO
B
OPMB
HO
KCN's Retrosynthetic Analysis of Rapamycin
TIPSO
A
MeO
HO
O
MeO
OHC
34
O
OPMB
34
1
O
O
HO
8
O
O
HO
Boc
20
O
18
MeO
O
1
CO2H
N
22
N
OMe
OPMB
Xc
OMe
35
35
B
22
E
20
21
19
TIPSO
SnBu3
HO
HO
CO2H
8
Bu3Sn
19
C
10 OTIPS OMe
rapamycin
18 I
D
Synthesis of Vinyliodide D
Me
Bu3SnH, THF
Me3Si
Me
Mo(allyl)Br(CO)2(MeCN)2
Me3Si
SnBu3
25 °C
Me3Si
1. LiI, LiAlH4, Et2O
O
Me
O
O
N
MeO
Me3Si
I
Me
Me
t-BuLi, Et2O, -78 °C
then:
Me
I2, CH2Cl2
Me3Si
O
2. NaH, MeI, DMF
OMe
O
O
O
O
Me
1. CSA, MeOH
2. CF3SO2Cl, Et3N
Me
I
Me
OPMB
Me3Si
Me
Me3Si
3. K2CO3, MeOH
O
OMe
t-BuLi, Et2O, -78 °C
then 2-thienylCu(CN)Li;
then epoxide
OMe
OH
OPMB
Synthesis of Vinyliodide D (continued)
OPMB
CHO
OTIPS OMe
OTIPS OMe
1. DDQ
I
1. HO
2. Swern [O]
I
HO
CO2Me
LDA, THF; then
aldehyde, THF/HMPA
CO2H
HO
OTIPS OMe
2. LiOH, THF/MeOH/H2O
I
D
KCN's Retrosynthetic Analysis of Rapamycin
TIPSO
A
MeO
HO
O
MeO
OHC
34
O
OPMB
34
1
O
O
HO
8
O
O
HO
Boc
20
O
18
MeO
O
1
CO2H
N
22
N
OMe
OPMB
Xc
OMe
35
35
B
22
E
20
21
19
TIPSO
SnBu3
HO
HO
CO2H
8
Bu3Sn
19
C
10 OTIPS OMe
rapamycin
18 I
D
The Union of A + B + E
TIPSO
TIPSO
MeO
Bu2BOTf, CH2Cl2, -78 °C
then Et3N, -78 °C to 0 °C
MeO
O
Me
Ph
35
O
OPMB
34
35
then
A
OMe
Xc
OMe
N
OH
OPMB
TIPSO
OPMB
O
OHC
34
A–B
OPMB
O
TIPSO
B
then 30% H2O2
TIPSO
1
N
MeO
1. LiBH4 (98%)
2. TsCl, Et3N,
DMAP (91%)
3. LiEt3BH (91%)
OMe
35
Boc
OPMB
34
OH
CO2H
OPMB
TIPSO
E–A–B
DCC,
Hunig's base
CH2Cl2, -20 °C
(85%)
Elaboration of EAB
RO
RO
MeO
MeO
OMe
OMe
OR'
R = TIPS
R' = PMB
O
N
OR'
RO
1. OsO4,
NMO
2. Pb(OAc)4
O
Boc
OR'
75%
overall
EAB
O
N
RO
OR'
O
Boc
O
TIPSO
MeO
OMe
1. CHI3,
CrCl2 (94%)
OTES
2. DDQ (98%)
3. TESOTf; then
silica gel (94%)
O
N
OTES
TIPSO
O
H
I
TIPSO
The Introduction of D
MeO
OMe
OTES
O
OTES
DIC, HOBT
TIPSO
HO
N
CO2H
D
HO
O
H
OTIPS OMe
I
I
TIPSO
(95%)
MeO
OMe
OTES
O
N
HO
TIPSO
rapamycin
O
O
HO
OTES
I
18
MeO
introduce C-19—C-20,
adjust the oxidation
state of the "D"
fragment, and remove
the protective groups
I
21
OTIPS
EABD
The End Game – Tricarbonyl Formation
HO
TIPSO
MeO
MeO
OMe
OMe
O
OTES
O
N
HO
1. Swern
2. HF•pyr
I
18
MeO
OTIPS
O
TIPSO
O
O
HO
OTES
I
21
3. Swern
4. HF, MeCN
N
O
HO
O
O
O
HO
I
MeO
I
O
Note: the first HF step removes the TES groups and the second HF step removes the TIPS groups
The End Game – The “Stitching” Stille Reaction
HO
HO
MeO
MeO
OMe
O
O
SnBu3
20
O
O
O
HO
Bu3Sn
N
O
HO
I
MeO
O
I
O
HO
19
C
O
O
OMe
Pd(MeCN)2Cl2,
Hunigs base
DMF/THF, 0.01M,
25 °C (27%)
N
O
20
O
O
HO
MeO
19
O
rapamycin
Summary
•
Completed the first total synthesis of (-)-rapamycin.
– The longest linear sequence from an article of commerce consists of
thirty-seven steps.
– The longest linear sequence from our five sub-targets is
sixteen steps.
– Total steps: 102
•
Instructional applications of the Stille reaction, oxidation chemistry, chiral
auxiliaries, organosilicons, protective groups, etc.
Smith’s Retrosynthetic Analysis of
Rapamycin and Demethoxyrapamycin
TIPSO
HO
42
MeO
MeO
I
S
O
OMe
34
27
O
O
O
A
B
HO
N
1
N
S
CO2H
S
O
20
O
O
HO
O
S
PMBO
MeO
10
O
E
O
O
O
OBPS
O
OMe
C
Rapamycin
SnBu3
D
Smith, A. B., III; Condon, S. M.; McCauley, J. A.; Leahy, J. W.; Leazer, J. L., Jr.; Maleczka, R. E., Jr. Tetrahedron Lett. 1994, 35, 4907.
Smith, A. B., III; Maleczka, R. E., Jr.; Leazer, J. L., Jr.; Leahy, J. W.; McCauley, J. A.; Condon, S. M. Tetrahedron Lett. 1994, 35, 4911.
Synthesis of Iodide A
1) n-BuLi,
BF3·Et2O,
TIPSO
MeO
SO2Ph
O
TIPSO
OBPS
2) Na(Hg) (60%, 2 steps)
MeO
OBPS
Smith, A.B., III; Hale, K.J.;
Laakso, L.M.; Chen, K.; Riéra, A.
Tetrahedron Lett. 1989, 30, 6963.
OH
TIPSO
TIPSO
1) LiI, BF3·Et2O (75%)
1) MsCl, Et3N (90%)
2) NaH, HMPA (85%)*
MeO
2) PMBOC(NH)CCl3,
BF3·Et2O (75%)
MeO
I
O
A
PMBO
* Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik, S. Tetrahedron Lett. 1990, 31, 1669.
Synthesis of Dithiane B
1) Swern [O]
HO
OBPS
S
2) HS(CH2)3SH,
BF3·Et2O
OBPS
1) TBAF, THF (94%)
S
2) TsCl, Et3N (95%)
3) NaI, acetone (91%)
4) PhSO2Na, DMF
(91%)
S
(94%, 2 steps)
SO2Ph
S
OHC
O
1) n-BuLi,
O
O
S
O
2) Swern [O]
3) Al(Hg) (46%, 3 steps)
S
O
1) LHMDS, Tf2NPh
20% HMPA/THF
(75%)
S
O
2) Me2CuLi, Et2O
(70%)
O
S
B
Synthesis of Dithiane C
1) -Chymotrypsin* (88%)
MeO2C
CO2Me
2) BH3·Me2S, (MeO)3B (90%)
1) BPSCl, imid. (88%)
HO
CO2Me
2) DIBAL (92%)
3) Swern [O] (88%)
4) HS(CH2)3SH,
BF3·Et2O (61%)
S
S
S
BPSO
S
C
1) TBAF, THF (88%)
2) Swern [O] (94%)
3) p-TsOH, MeOH,
(CH3O)3CH (97%)
S
OBPS
C
* Mohr, P.; Waespe-Sarcevic, N.; Tamm, C.; Gawronska, K.;
Gawronski, J.K. Helv. Chim. Acta. 1983, 66, 2501.
S
MeO
MeO
Retrosynthetic Analysis of Rapamycin
TIPSO
HO
42
MeO
MeO
I
S
O
OMe
34
27
O
O
O
A
B
HO
N
1
N
O
S
PMBO
S
CO2H
S
O
20
O
O
HO
O
MeO
10
E
O
O
Rapamycin
O
OBPS
O
OMe
C
SnBu3
D
Synthesis of the Ortho Ester
Exploitation of Alternate Ortho Ester Diastereomer
Employed in Smith’s Latrunculin Synthetic Venture
O
O
O
OH
H
HN
S
O
O
O
m-CPBA, CH2Cl2
Allyl alcohol
DMP, TsOH
(65%)
(+)-Latrunculin B
O
NaHCO3 (70%)
HO
O
OH
1)
LDA, MeI
(86%)
O
O
CSA (85%)
2) HPLC separation
of diastereomers
O
O
O
Zibuck, R.; Liverton, N. J.; Smith, A. B., III J. Am. Chem. Soc. 1986, 108, 2451.
Synthesis of the E and Z Eneynes
TMS
1) "Bu3Sn"
TMS
Bu3Sn
+
+
2) H
TMS
E
Conditions
Z
Ratio (E : Z)
1) Bu3Sn(Bu)Cu(CN)Li2, -78 °C
2) NH4Cl / MeOH (65%, 2 steps)
1) Bu3Sn(Me)Cu(CN)Li2
-78 °C
-30 °C
2) NH4Cl / MeOH (71%, 2 steps)
Bu3Sn
27 : 1
1 : >50
Mechanism of Olefin Isomerization
Cu(CN)(R)Li2
Bu3Sn(R)Cu(CN)Li2
Bu3Sn
TMS
H+
Bu3Sn
TMS
TMS
E
-78 °C to -30 °C
TMS
TMS
H+
Bu3Sn
Bu3Sn
Cu(CN)(R)Li2
Z
Corey, E. J.; Katzenellenbogen, J. A. J. Am. Chem. Soc. 1969, 91, 1851.
Piers, E.; Chong, J. M.; Morton, H. E. Tetrahedron Lett. 1981, 22, 4905.
Stereochemistry of Eneyne Addition to Aldehyde
O
O
O
CHO
n-BuLi, THF, - 78 °C (65%)
n-BuLi, THF, - 78 °C (73%)
TMS
Bu3Sn
Bu3Sn
TMS
E
Z
TMS
O
1.1 : 1
:
O
O
O
OH
O
O
TMS
OH
6:1
:
Synthesis of Dienylstannane D
O
1) aq. KOH, DMSO,
MeI (83%)1
O
O
OH
2) n-Bu3SnH, AIBN,
toluene, 90 °C (55%)
O
TMS
O
O
OMe
SnBu3
TMS
O
1) MeI, DMSO;
KOH (75%)2
D
O
O
OH
2) n-Bu3SnH, AIBN,
toluene, 90 °C (50%)
2
O
O
O
1
OMe
mp 96 °C
Formation of the alkoxide
in the absence of MeI
results in furan formation.
O
O
O
O
For examples see:
Bonnet, P. H.; Bohlmann, F. Chem. Ber. 1971, 104, 1616.
Marshal, J. A.; DuBay, W. J. J. Org. Chem. 1993, 58, 3435.
Retrosynthetic Analysis of Rapamycin
TIPSO
HO
42
MeO
MeO
I
S
O
OMe
34
27
O
O
O
A
B
HO
N
1
N
O
S
PMBO
S
CO2H
S
O
20
O
O
HO
O
MeO
10
E
O
O
Rapamycin
O
OBPS
O
OMe
C
SnBu3
D
Construction of a C27-C42 Aldehyde
S
CHO
S
MeOH, p-TsOH
(MeO)3CH (93%)
OMe
S
OMe
S
TBSO
t-BuLi, 10% HMPA/THF
-78 °C (91%)
TIPSO
TBSO
MeO
B'
I
A
TIPSO
PMBO
TIPSO
MeO
OMe
CF3CO2H, acetone
reflux (70%)
MeO
CHO
OMe
PMBO
S S
TBSO
PMBO
S S
AB
TBSO
Construction of the C22-C42 Subunit
TIPSO
S
S
t-BuLi, 10% HMPA/THF, -78 °C (69%)
OH
MeO
S
S
TIPSO
PMBO
S S
TBSO
MeO
CHO
OBPS
PMBO
SS
TBSO
1.2 : 1 (S):(R) Mixture
OBPS
Li
S
S
OH
S
S
S
CHO
S
OBPS
S
TBSO
S
TBSO
5 : 1 Mixture
(S) : (R)
OBPS
Synthesis of Demethoxyrapamycin:
Construction of Advanced ABC Intermediate
TIPSO
S
S
1) t-BuLi, 10% HMPA/THF, -78 °C
2) TIPSO
(68%, 2 steps)
MeO
S
S
MeO
MeO
S S
PMBO
TBSO
MeO
PMBO
MeO
O
S S
ABC
MeO
3) TBSOTf, 2,6-lutidine, -78 °C (84%)
TIPSO
MeO
MeO
S
1) TsOH, acetone (75%)
2) CBr4, HMPT, THF (94%)
3) n-BuLi, THF (90%)
S
PMBO
S S
TBSO
Retrosynthetic Analysis of Rapamycin
and Demethoxyrapamycin:
Introduction of the Tricarbonyl Segment
TIPSO
HO
42
R
MeO
MeO
R
34
27
S
S
O
PMBO
O
O
N
ABC
O
O
E
MeO
HO
CO2H
O
O
10
O
TBSO
HO
1
N
S S
17
O
O
O
OMe
SnBu3
Rapamycin (R = OMe)
Demethoxyrapamycin (R = H)
D
Tricarbonyl Formation I
O
1) NaH, MeI, 15-crown-5
(80%)
O
O
OH
O
TBSO
OMe
TBSO
O
2) HOAc, H 2O,THF (86%)
3) TBSCl, imid. (97%)
TMS
TMS
1)
1) DIBAL (98%)
2) Swern [O] (80%)
TBSO
CO2H
O
OMe
E
2 equiv. LHMDS, THF
-78 °C (80%)
OHC
TMS
O
N
O
O
OH
TBSO
2) Allylbromide, K2CO3
DMF (98%)
OMe
N
TMS
Tricarbonyl Formation II
OAllyl
N
OAllyl
O
N
1) Dess-Martin [O] (84%)*
2) HF, CH3CN, H2O (77%)
O
O
O
O
OH
HO
O
OTBS OMe
OMe
TMS
OH
N
O
1) TBSOTf, Et3N (79%)
2) (Ph3P)4Pd, Ph3P
HOAc, THF (80%)
O
O
TBSO
O
OMe
* Batchelor, M. J.; Gillespie, R. J.; Golec, J. M. C.; Hedgecock, C. J. R. Tetrahedron Lett. 1993, 34, 167.
Pipecolinyl Acylation
TIPSO
TIPSO
MeO
1) DDQ, aq. CH2Cl2 (95%)
S
S
PMBO
S S
MeO
O
2) MeI, CaCO3, 4:1:1
CH3CN/THF/H2O (64%)
TBSO
HO
O
TBSO
ABC
TIPSO
MeO
O
DCC, DMAP, CH2Cl2
O
O
TBSO
OH
(81%)
O
O
O
N
O
N
O
O
TBSO
O
MeO
DE
TBSO
O
MeO
ABCDE
Proposed Endgame: Bis-Hydrostannylation
TIPSO
TIPSO
MeO
MeO
O
O
N
O
TBSO
O
O
Bu3SnH, AIBN
(14%)
O
N
O
O
O
O
O
TBSO
Bu3Sn
O
TBSO
O
MeO
ABCDE
TBSO
O
MeO
SnBu3
Attempted Macrocyclizations
TIPSO
HO
MeO
MeO
O
O
N
O
O
TBSO
O
1) Pd(II)
2) HF•pyr, pyr
O
O
N
O
Bu3Sn
O
O
TBSO
O
O
MeO
HO
O MeO
O
SnBu3
TIPSO
MeO
O
O
N
I2
TBSO
O
O
CDCl3
O
1) Pd(0)
Bu3Sn
2) HF•pyr, pyr
O
TBSO
O
MeO
I
HO
Preparation of ABC vinylstannane & DE vinyl iodide
TIPSO
TIPSO
MeO
O
HO
Bu3SnH, AIBN
PhH, 80 °C
(37%)
O
or
TBSO
O
MeO
HO
O
TBSO
(Ph3P)2PdCl2,
Bu3SnH
THF, 0 °C
(90%)
Bu3Sn
OH
OMe
N
1) I2, CH2Cl2
(96%)
O
O
O
TBSO
O
OMe
2) LiI, pyr
120 °C
(50%)
SnBu3
N
O
O
O
TBSO
O
OMe
I
Proposed Endgame Strategy
for the Total Synthesis of Rapamycin
and Demethoxyrapamycin
TIPSO
HO
42
MeO
MeO
R
R
O
O
34
27
O
O
OH
HO
O
TBSO
1
N
O
CO2H
O
O
HO
MeO
O
10
Bu3Sn
N
I
O
17
O
TBSO
Rapamycin (R = OMe)
Demethoxyrapamycin (R = H)
MeO
O
Macrocyclization
TIPSO
TIPSO
MeO
O
HO
OH
O
MeO
O
TBSO
O
N
O
Bu3Sn
O
O
O
DCC, DMAP, DMAP•HCl,
CH2Cl2, (59%)
TBSO
OMe
TBSO
O
N
O
O
O
Bu3Sn
TBSO
O
MeO
I
I
TIPSO
MeO
O
[(2-furfuryl)3P]2PdCl2*
i-Pr2NEt, THF-DMF
O
N
(16%)
O
TBSO
HF/MeCN
O
O
O
TBSO
MeO
O
*Hettrick, C. M.; Scott, W. J. J. Am. Chem. Soc. 1991, 113, 4903.
demethoxyrapamycin
Demethoxyrapamycin
TIPSO
TIPSO
MeO
O
MeO
HO
OH
N
O
O
O
O
Bu3Sn
O
N
1) EDAC•HCl, DMAP,
DMAP•HCl,
CH2Cl2 (48 %)
O
TESO
O
TBSO
OMe
I
O
O
O
TESO
2) [(2-furfuryl)3P]2PdCl2
i-Pr2NEt, THF-DMF
(65%)
MeO
O
HO
MeO
O
1) TBAF/HOAc/THF
0 °C (53%)
O
N
2) HF•pyr, pyr,
THF, 0 °C
O
HO
O
O
O
HO
MeO
O
demethoxyrapamycin
O
TBSO
Rapamycin
TIPSO
TIPSO
OMe
MeO
O
HO
OH
N
O
MeO
OMe
TBSO
O
O
O
Bu3Sn
O
TESO
O
N
1) EDAC•HCl, DMAP,
DMAP•HCl,
CH2Cl2 (48 %)
O
OMe
I
O
O
O
TESO
2) [(2-furfuryl)3P]2PdCl2
i-Pr2NEt, THF-DMF
(67%)
MeO
O
HO
MeO
OMe
O
1) TBAF/HOAc/THF
0 °C, 3h, (90%)
O
N
2) HF•pyr, pyr, THF
0 °C (71%)
O
O
O
O
HO
MeO
O
rapamycin
HO
O
TBSO
Summary
•
Developed a highly convergent and efficient total synthesis of
(-)-rapamycin.
– The longest linear sequence from an article of commerce
consists of thirty-three steps.
– The longest linear sequence from our five sub-targets is
fourteen steps.
– After the coupling of the C(1)-C(20) fragment to the C(22)C(42) fragment only three steps are required to complete
the synthesis.
•
Completed the first total synthesis of demethoxyrapamycin.
– The synthesis serves as a structure proof.
– The synthesis establishes our unified synthetic approach
as being amenable to the preparation of analogs.