Total Synthesis of Rapamycin
45
Total Synthesis of Rapamycin 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. O N HO M eO O O O O OMe HO O O HO M eO
description
Total Synthesis of Rapamycin. 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. - PowerPoint PPT Presentation
Transcript of Total Synthesis of Rapamycin
Total Synthesis of Rapamycin
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.
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
Immunomodulators
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
rapamycin FK-506
cyclosporin A
OH
O
HO
O
OMe
N
MeO
O
O
OMe
O
O
HOO
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
O
N
H
N
O
N
Me
NN
N
N
H O
NN
H O
NH
O
Me O Me O Me
O
O
NMe
O
MeO
H
Me
OH
H
Rapamycin’s Mechanism of Action
IL-2 Receptor
?
p70 S6 Kinase
The Cell Cycle
G0
G1
G2M
S
RestrictionPoint
40S Ribosomal Protein S6
Cdc2 Kinase
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
rapamycin
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
1
35
34
18
19
20
22
218
D
TIPSO
MeO
Xc
O 35
B
TIPSO
OHC
OMe
OPMB
OPMB
22
OMe
I
OTIPS
HO
CO2HHO8
10
18
19
1N CO2H
Boc
C
E
34
A
Bu3Sn
SnBu3
20
Synthesis of Oxazolidone A
MeO
TBSO
OOH OBn
O
1. m-CPBA
2. NaH, BnBr, TBAI
1. CSA, MeOH2. TBSOTf
3. H2, 10% Pd-C4. Swern [O]
LDA, THF, -78 °C;
then TMSCl
MeO
TBSO
OTMS
Pd(OAc)2
MeCN
MeO
TBSO
O
MeO
TBSO
OH
LiBH4
CeCl3THF/MeOH
NMe2
OMeMeO
xylenes,reflux
MeO
TBSOO
NMe2
MeO
TBSO
O
NMe2
[3,3]
MeO
TBSO
1. LiEt3BH
2. H2, 10% Pd-C
31
4
6
4
6
3
1
OH
Synthesis of Oxazolidone A (continued)
MeO
TBSO
MeO
TBSOSeCN
NO2
Bu3P, THF;then 30%
H2O2
mechanism?
O3,MeOH/CH2Cl2,
-78 °C;
then Me2S
OH
MeO CHO
TBSO
ON
O
(EtO)2P
O
O
LiCl, i-Pr2NEt
1.
2. Et3SiH, (Ph3P)3RhCl
TBSO
MeO
N
O
A
1. HF, MeCN
2. TIPSCl, imid.
O
O
TIPSO
MeO
N
O
O
O
KCN's Retrosynthetic Analysis of Rapamycin
rapamycin
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
1
35
34
18
19
20
22
218
D
TIPSO
MeO
Xc
O 35
B
TIPSO
OHC
OMe
OPMB
OPMB
22
OMe
I
OTIPS
HO
CO2HHO8
10
18
19
1N CO2H
Boc
C
E
34
A
Bu3Sn
SnBu3
20
Synthesis of Subunit B
OOH
XcTIPSO
MeOOMe
O Xc
OH OTIPS
Z-enolate
(+)-β-citronellene
1. m-CPBA
2. HClO4 H2O/THF
HOHO
1. NaIO4, H2O/THF
2. CrO3, H2SO4 acetone
CO2H
PivCl, Et3N;
then
N O
O
Li
Me Ph
N
O
O
O
Me Ph
Bu2BOTf, CH2Cl2, -78 °Cthen Et3N, -78 °C to 0 °C
then OHCOTIPS
OMe
then 30% H2O2
O
BO
Bu
Bu
N
O
Ph
Me
OTIPSO
MeO
ON
O
Xc =O
OH
XcTIPSO
MeOOMe
O Xc
OH OTIPS
Synthesis of Subunit B (continued)
OMeO Xc
OH OTIPS
1. LiBH4
2. TsCl3. LiEt3BH OMe
OH OTIPS1. TBAF2. anisaldehyde dimethylacetal
3. Dibal4. Swern
CHO
OMe
OPMB
HO
OMe
OPMB
OPMBCrCl2/NiCl2, DMSO
I
OPMB
OHC
OMe
OPMB
TBSO
TBSO
1. TIPSOTf2. HF•pyr.
3. Swern TIPSO
OHC
OMe
OPMB
OPMB
B
KCN's Retrosynthetic Analysis of Rapamycin
rapamycin
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
1
35
34
18
19
20
22
218
D
TIPSO
MeO
Xc
O 35
B
TIPSO
OHC
OMe
OPMB
OPMB
22
OMe
I
OTIPS
HO
CO2HHO8
10
18
19
1N CO2H
Boc
C
E
34
A
Bu3Sn
SnBu3
20
Synthesis of Vinyliodide D
Bu3SnH, THF
Mo(allyl)Br(CO)2(MeCN)2
MeMe3Si Me3SiSnBu3
Me I2, CH2Cl2
25 °CMe3Si
I
Me
t-BuLi, Et2O, -78 °Cthen:
MeON
O
O
O
Me
Me3Si
Me
O O
O1. LiI, LiAlH4, Et2O
2. NaH, MeI, DMF
Me3Si
Me
OMe O
O
1. CSA, MeOH2. CF3SO2Cl, Et3N
3. K2CO3, MeOH
Me3Si
Me
OMeO
I OPMB
Me
t-BuLi, Et2O, -78 °Cthen 2-thienylCu(CN)Li;then epoxide
Me3Si
Me
OMe OH
Me
OPMB
Synthesis of Vinyliodide D (continued)
I
OMeOTIPS1. DDQ
2. Swern [O]
CHOOMe
I
OTIPS
OPMB
OMe
I
OTIPS
HO
CO2HHO1. HO CO2Me
LDA, THF; thenaldehyde, THF/HMPA
2. LiOH, THF/MeOH/H2O
D
KCN's Retrosynthetic Analysis of Rapamycin
rapamycin
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
1
35
34
18
19
20
22
218
D
TIPSO
MeO
Xc
O 35
B
TIPSO
OHC
OMe
OPMB
OPMB
22
OMe
I
OTIPS
HO
CO2HHO8
10
18
19
1N CO2H
Boc
C
E
34
A
Bu3Sn
SnBu3
20
The Union of A + B + E
B
TIPSO
OHC
OMe
OPMB
OPMB
TIPSO
MeO
N
O
O
35
34
A
Bu2BOTf, CH2Cl2, -78 °Cthen Et3N, -78 °C to 0 °C
then
then 30% H2O2
Me
PhO
35
34
TIPSOOH
OMe
TIPSO
OPMB
OPMB
MeO
Xc
O
A–B
1. LiBH4 (98%)
2. TsCl, Et3N, DMAP (91%)3. LiEt3BH (91%)
35
34
TIPSOOH
OMe
TIPSO
OPMB
OPMB
MeON CO2H
Boc
DCC,Hunig's base
CH2Cl2, -20 °C(85%)
1
E–A–B
Elaboration of EAB
Boc
N
ROO
O
OMe
RO
MeO
1. OsO4, NMO2. Pb(OAc)4
EAB
OR'
OR'
Boc
N
O
ROO
O
OMe
RO
MeO
OR'
OR'
75%overall
R = TIPSR' = PMB
1. CHI3, CrCl2 (94%)
2. DDQ (98%)3. TESOTf; then silica gel (94%)
TIPSOO
OMe
TIPSO
OTES
OTES
MeO
N O
H I
The Introduction of D
EABD
rapamycin
TIPSOO
OMe
TIPSO
OTES
OTES
MeO
N O
H I OMe
I
OTIPS
HO
CO2HHO
D
DIC, HOBT
(95%)
introduce C-19—C-20, adjust the oxidation
state of the "D" fragment, and remove the protective groups
OTIPS
N
I
I
TIPSO
MeO
O
O
HO
O
OMe
TIPSO
OTES
OTES
HO
MeO
18 21
The End Game – Tricarbonyl Formation
Note: the first HF step removes the TES groups and the second HF step removes the TIPS groups
OTIPS
N
I
I
TIPSO
MeO
O
O
HO
O
OMe
TIPSO
OTES
OTES
HO
MeO
18 21
O
N
I
I
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
1. Swern2. HF•pyr
3. Swern4. HF, MeCN
The End Game – The “Stitching” Stille Reaction
rapamycin
O
N
I
I
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
C
19
20
Pd(MeCN)2Cl2,Hunigs base
DMF/THF, 0.01M,25 °C (27%) O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
MeO
19
20
SnBu3
Bu3Sn
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 ofRapamycin and Demethoxyrapamycin
1
Rapamycin
3427
E
10
20
42
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.
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
I
S
OBPS
N CO2HS
S
S O
O
MeO O
PMBO
TIPSO
MeO
OMeO
SnBu3
OO
C
BA
D
Synthesis of Iodide A
1) n-BuLi, BF3·Et2O,
2) Na(Hg) (60%, 2 steps)
1) MsCl, Et3N (90%)
2) NaH, HMPA (85%)*
* Shekhani, M. S.; Khan, K. M.; Mahmood, K.; Shah, P. M.; Malik, S. Tetrahedron Lett. 1990, 31, 1669.
1) LiI, BF3·Et2O (75%)
2) PMBOC(NH)CCl3, BF3·Et2O (75%)
Smith, A.B., III; Hale, K.J.; Laakso, L.M.; Chen, K.; Riéra, A.Tetrahedron Lett. 1989, 30, 6963.
MeOSO2Ph
TIPSO TIPSO
MeO
OBPS
OH
O
MeO
TIPSO
OBPS
O
I
PMBO
MeO
TIPSO
A
Synthesis of Dithiane B
2) Me2CuLi, Et2O
1) LHMDS, Tf2NPh
2) Swern [O]3) Al(Hg) (46%, 3 steps)
1) n-BuLi,
2) HS(CH2)3SH,
1) Swern [O] 1) TBAF, THF (94%)
2) TsCl, Et3N (95%)3) NaI, acetone (91%)4) PhSO2Na, DMF
20% HMPA/THF
(94%, 2 steps)(91%)
(75%)
(70%)
OBPSHO
S OBPS
S S
S SO2Ph
S
S
O
OHCO
S
O
S
O
O
O
O
B
BF3·Et2O
Synthesis of Dithiane C
1) BPSCl, imid. (88%)1) α-Chymotrypsin* (88%)
2) BH3·Me2S, (MeO)3B (90%) 2) DIBAL (92%)3) Swern [O] (88%)4) HS(CH2)3SH, BF3·Et2O (61%)
1) TBAF, THF (88%)2) Swern [O] (94%)
3) p-TsOH, MeOH, (CH3O)3CH (97%)
S
MeO2C
S
OBPS
CO2Me CO2MeHO
BPSO S
S
SS
MeO
MeO
* Mohr, P.; Waespe-Sarcevic, N.; Tamm, C.; Gawronska, K.; Gawronski, J .K. Helv. Chim. Acta. 1983, 66, 2501.
C
C
Retrosynthetic Analysis of Rapamycin
1
Rapamycin
3427
E
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20
42
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
I
S
OBPS
N CO2HS
S
S O
O
MeO O
PMBO
TIPSO
MeO
OMeO
SnBu3
OO
C
BA
D
Synthesis of the Ortho Ester Exploitation of Alternate Ortho Ester DiastereomerEmployed in Smith’s Latrunculin Synthetic Venture
O O
OO
Allyl alcohol
O
CSA (85%)
O
2) HPLC separation of diastereomers
O
DMP, TsOHO
(65%)
O
m-CPBA, CH2Cl2
NaHCO3 (70%)
Zibuck, R.; Liverton, N. J.; Smith, A. B., III J. Am. Chem. Soc. 1986, 108, 2451.
1)LDA, MeI
HOOH
(+)-Latrunculin B
(86%)
OH
OS
O
O
HN
O
H
Synthesis of the E and Z Eneynes
+1) "Bu3Sn"
2) H+
Bu3Sn
TMS
E
1) Bu3Sn(Bu)Cu(CN)Li2, -78 °C
2) NH4Cl / MeOH (65%, 2 steps)
1 : >50
Bu3Sn
TMS
Conditions Ratio (E : Z)
27 : 1
Z
1) Bu3Sn(Me)Cu(CN)Li2 -78 °C -30 °C
2) NH4Cl / MeOH (71%, 2 steps)
TMS
Mechanism of Olefin Isomerization
Bu3Sn
TMS
Z
Bu3Sn
TMS
E
Bu3Sn(R)Cu(CN)Li2
-78 °C to -30 °C
TMS
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.
Bu3Sn
TMS
Bu3Sn
TMS
Cu(CN)(R)Li2
Cu(CN)(R)Li2
H+
H+
Stereochemistry of Eneyne Addition to Aldehyde
1.1 : 1 α : β
6 : 1 α : β
O
O
O
OH
TMS
O
O
O
OH
n-BuLi, THF, - 78 °C (65%)
TMS
n-BuLi, THF, - 78 °C (73%)
EZ
O O
CHO
O
Bu3Sn
TMSBu3Sn
TMS
Synthesis of Dienylstannane D
1mp 96 °C
O
O
O
OMe
SnBu3
O
O
O
OH
TMS
O
O
O
OH
TMS1) MeI, DMSO; KOH (75%)2
2) n-Bu3SnH, AIBN, toluene, 90 °C (50%)
1) aq. KOH, DMSO, MeI (83%)1
2) n-Bu3SnH, AIBN, toluene, 90 °C (55%)
2Formation of the alkoxidein the absence of MeIresults in furan formation.
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.
O
O
O
OMe
O
O
O
O
D
Retrosynthetic Analysis of Rapamycin
1
Rapamycin
3427
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42
O
N
HO
MeO
O
O
O
O
OMe
HO
O
O
HO
I
S
OBPS
N CO2HS
S
S O
O
MeO O
PMBO
TIPSO
MeO
OMeO
SnBu3
OO
C
BA
D
Construction of a C27-C42 Aldehyde
S
S
CHO
TBSO
MeOH, p-TsOH(MeO)3CH (93%) S
S TBSO
OMe
OMe
t-BuLi, 10% HMPA/THF-78 °C (91%)
CF3CO2H, acetonereflux (70%)
B'
PMBO
TIPSO
MeO I
AB
TIPSO
MeO
PMBO
OMe
S S TBSO
OMe
TIPSO
MeO
PMBO
CHO
S S TBSO
A
Construction of the C22-C42 Subunit
TIPSO
MeO
PMBO
CHO
S S TBSOOBPS
SS
t-BuLi, 10% HMPA/THF, -78 °C (69%)
1.2 : 1 (S):(R) Mixture
TIPSO
MeO
PMBO S S TBSO
OBPS
SS
OH
TBSO
CHOS
S
5 : 1 Mixture(S) : (R)
SS
OBPS
Li
SS
OBPS
TBSOS
S
OH
Synthesis of Demethoxyrapamycin:Construction of Advanced ABC Intermediate
1) TsOH, acetone (75%)
2) CBr4, HMPT, THF (94%)3) n-BuLi, THF (90%)
ABC
1) t-BuLi, 10% HMPA/THF, -78 °C
(68%, 2 steps)2)
3) TBSOTf, 2,6-lutidine, -78 °C (84%)
SS
MeO
TBSOS S
TIPSO
MeO
PMBO
SS
MeO
MeOMeO
S S
TIPSO
MeO
PMBOO
SS
TBSOS S
TIPSO
MeO
PMBO
MeO
Retrosynthetic Analysis of Rapamycinand Demethoxyrapamycin:
Introduction of the Tricarbonyl Segment
1
ABC
3427
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O
N
HO
MeO
O
O
O
O
R
HO
O
O
HO
N CO2H
O
MeO
OMeO
SnBu3
OO
Rapamycin (R = OMe)Demethoxyrapamycin (R = H)
SS
TBSOS S
TIPSO
MeO
PMBO
R
D
Tricarbonyl Formation I
TBSOO
O TBSO OMe
TMS
OHC
TBSO OMe
TMS
O O
O OH
N CO2H
O
TBSO OMe
TMS
N
O OO OH
1)
2) HOAc, H2O,THF (86%)3) TBSCl, imid. (97%)
1) DIBAL (98%)2) Swern [O] (80%)
2) Allylbromide, K2CO3
DMF (98%)
2 equiv. LHMDS, THF -78 °C (80%)
E
1) NaH, MeI, 15-crown-5 (80%)
TMS
Tricarbonyl Formation II
N
OAllyl
O
O
OTBS OMe
OH
TMS
N
OH
O
O
O OMeTBSO
O
N
OAllyl
O
O
O OMe
* Batchelor, M. J.; Gillespie, R. J.; Golec, J. M. C.; Hedgecock, C. J. R. Tetrahedron Lett. 1993, 34, 167.
2) (Ph3P)4Pd, Ph3P HOAc, THF (80%)
HO
O
1) Dess-Martin [O] (84%)*
2) HF, CH3CN, H2O (77%)
1) TBSOTf, Et3N (79%)
Pipecolinyl Acylation
MeO
TIPSO
PMBO TBSO
S
S
DCC, DMAP, CH2Cl2
ABC
(81%)
S S
ABCDE
DE
1) DDQ, aq. CH2Cl2 (95%)
2) MeI, CaCO3, 4:1:1 CH3CN/THF/H2O (64%)
MeO
TIPSO
HO TBSO
MeO
TIPSO
O TBSO
N
O
O
TBSOO MeO
ON
O
O
TBSOO MeO
O
OH
O
O
O
O
Proposed Endgame: Bis-Hydrostannylation
MeO
TIPSO
O TBSO
ABCDE
N
O
O
TBSOO MeO
O(14%)
MeO
TIPSO
O TBSO
N
O
O
TBSOO MeO
O
SnBu3
Bu3Sn
O
O
O
O
Bu3SnH, AIBN
Attempted Macrocyclizations
MeO
TIPSO
O TBSO
N
O
O
TBSOO MeO
O
SnBu3
Bu3Sn
O
O
I2
CDCl3
1) Pd(II)
2) HF•pyr, pyr
1) Pd(0)
2) HF•pyr, pyr
O
N
HO
MeO
O
O
O
O
HO
O
O
HO
MeO
MeO
TIPSO
O TBSO
N
O
O
TBSOO MeO
O
I
Bu3Sn
O
O
Preparation of ABC vinylstannane & DE vinyl iodide
TBSO
TIPSO
MeO
HO HO TBSO
TIPSO
MeO
Bu3Sn
Bu3SnH, AIBNPhH, 80 °C
(37%)
or
(Ph3P)2PdCl2,Bu3SnH
THF, 0 °C(90%)
O
O
O
O
N
OMe
O
O
O OMeTBSO
O
SnBu3
N
OH
O
O
O OMeTBSO
O
I
1) I2, CH2Cl2 (96%)
2) LiI, pyr 120 °C (50%)
Proposed Endgame Strategy for the Total Synthesis of Rapamycin
and Demethoxyrapamycin
1
Rapamycin (R = OMe)Demethoxyrapamycin (R = H)
3427
10 17
42
O
N
HO
MeO
O
O
O
O
R
HO
O
O
HO
MeO
O
N
TBSO
MeO
OH
CO2H
O
O
R
TIPSO
O
O
TBSO
MeO
I
Bu3Sn
Macrocyclization
N
OH
O
O
O
HF/MeCN
OMe
DCC, DMAP, DMAP•HCl,CH2Cl2, (59%)
*Hettrick, C. M.; Scott, W. J. J. Am. Chem. Soc. 1991, 113, 4903.
[(2-furfuryl)3P]2PdCl2*i-Pr2NEt, THF-DMF
(16%)
TBSO
O
demethoxyrapamycin
I
HO TBSO
TIPSO
MeO
Bu3Sn
O
O
O TBSO
TIPSO
MeO
Bu3Sn
N
O
O
OTBSO
MeO
I
O
O
O
O
N
TBSO
MeO
O
O
O
O
TIPSO
O
O
TBSO
MeO
Demethoxyrapamycin
N
OH
O
O
O
1) TBAF/HOAc/THF 0 °C (53%)
2) HF•pyr, pyr, THF, 0 °C
OMe
1) EDAC•HCl, DMAP,DMAP•HCl,
CH2Cl2 (48 %)
2) [(2-furfuryl)3P]2PdCl2i-Pr2NEt, THF-DMF
(65%)
TESO
O
demethoxyrapamycin
I
HO TBSO
TIPSO
MeO
Bu3Sn
O
O
O
N
HO
MeO
O
O
O
O
HO
O
O
HO
MeO
O
N
TBSO
MeO
O
O
O
O
TIPSO
O
O
TESO
MeO
Rapamycin
N
OH
O
O
O
1) TBAF/HOAc/THF 0 °C, 3h, (90%)
2) HF•pyr, pyr, THF 0 °C (71%)
OMe
1) EDAC•HCl, DMAP,DMAP•HCl,
CH2Cl2 (48 %)
2) [(2-furfuryl)3P]2PdCl2i-Pr2NEt, THF-DMF
(67%)
TESO
O
rapamycin
I
HO TBSO
TIPSO
MeO
Bu3Sn
O
O
O
N
HO
MeO
O
O
O
O
HO
O
O
HO
MeO
O
N
TBSO
MeO
O
O
O
O
TIPSO
O
O
TESO
MeO
OMe
OMe
OMe
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.
