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Totalsynthesisof(‐)‐NakadomarinA
Jakubec,P.;Cockfield,D.M.;Dixon,D.J.
J.Am.Soc.Chem.ASAP.
N
O
N
H
(-)-Nakadomarin A
Outline
o BiologicalacHvity
o Previoussynthesis
o Synthesisfromthepaper
• Retrosynthesis• Forwardsynthesis
BiologicalacHvity
N
O
N
H
(-)-Nakadomarin A1
Isolatedin1997fromaseaspongeAmphimedobyKobayashioffthecoastoftheKeramaIslands,Okinawa
onlyknownmemberofthemanzaminefamilytocontainafuranring
Limitedavailabilityfromnature:6mgisolatedfrom1kgofwetsponge
BioacHvityincludesanHcancer,anHfungalandanHbacterial
Kobayashi,J.;Watanabe,D.;Kawasaki,N.;Tsuda,M.J.Org.Chem.1997,62,9236‐9239.
Structure
N
O
N
H
(-)-Nakadomarin A1
Kobayashi,J.;Watanabe,D.;Kawasaki,N.;Tsuda,M.J.Org.Chem.1997,62,9236‐9239.
Structuralfeatures:
• Ringsystem:8/5/5/5//15/6
• 4stereogeniccenters,1quaternary
• Zalkene
PreviousSynthesis
N
O
N
H
(-)-Nakadomarin A1
CompletedSyntheses:(+)‐NakadomarinA:Nagata,NakagawaandNishida,JACS,2003,125,7484YoungandKerr,JACS,2007,129,1465
(‐)‐NakadomarinA:Ono,NakagawaandNishida,ACIE,2004,43,2020
PublishedApproaches:Furstner,JACS,1999,121,11108Magnus,TL,2002,43,947Tius,OL,2003,5,1171Williams,OL,2004,6,4539Funk,OL,2006,8,3833.
Nakagawa’ssynthesis(‐)‐NakadomarinA
Ono,K.;Nakagawa,M.;Nishida,A.Angew.Chem.Int.Ed.2004,43,2020.
ForwardSynthesis:
36longestlinearsteps
2.5mgofthetargetproduct.
Nakagawa’ssynthesis(+)‐NakadomarinA
Forwardsynthesis:37longestlinearsteps
Nagata,T.;Nakawaga,M.;Nishida,A.J.Am.Chem.Soc.2003,125,7484.
Kerr’ssynthesis
(+)‐NakadomarinA
Forwardsynthesis:
29longestlinearsteps
Young,I.S.;Kerr,M.A.J.Am.Soc.Chem.2007,129,1465.
RetrosyntheHcanalysis
Synthesisoffragment7
N
NN
N
SH
NaH, THF
HNO
OTs
N N
NNS
NH
O
N
NN
N
SNa
+THF, reflux, 12 h
96%
9 1011
N N
NNS
N
O
O
O
N N
NNS
N
OO
O
O
Br
NaH, TBAI(cat.)DMSO, 12 h, RT
71%
N N
NNS
N
O
O
O
OO
O
O
m-CPBA, CH2Cl2RT, 14 h
78%
HCl, THFRT, 2 h
98%
121314
N
O
MeOOC
7
Synthesisoffragment7
IntramolecularJulia‐Kocienski
N
O
MeOOC
7
N
O
N
O
MeOOC
N N
NNS
N
OO
O
O
Cs2CO3, DMF, THF, H2O
70 oC, 10 h
56%
LHMDS, THF
MeO OMe
O
-78 oC to 0 oC, 2.5 h
82%
14 15 7
ModifiedJuliaolefinaHon
N
S
S
RO
O
LDA
N
S
S
RO
O
Li
H
O
R'
R
R'
R
R'+
ModifiedJuliaolefinaHon
N
S
S
RO
O
LDA
N
S
S
RO
O
Li
H
O
R'
R
R'
R
R'+
ModifiedJuliaolefinaHon
N
S
S
RO
O
LDA
N
S
S
RO
O
Li
H
O
R'
R
R'
R
R'+
Py,PT,TBTprovidesevenhigherEselecHvitythanBTinintermolecularreacHons.
Julia‐KocienskiolefinaHon
Blakemore,P.R.;Cole,W.J.Kocienski,P.J.Synlef,2008,26.
IntramolecularJulia‐KocienskiolefinaHon
Aissa,C.J.Org.Chem.2006,71,360.
Synthesisoffragment7
IntramolecularJulia‐Kocienski
N
O
N
O
MeOOC
N N
NNS
N
OO
O
O
CsCO3, DMF, THF, H2O
70 oC, 10 h
56%
LHMDS, THF
MeO OMe
O
-78 oC to 0 oC, 2.5 h
82%
14 15 7
N
O
MeOOC
7
FirstexampleofIntramolecularJulia‐Kocienskiincomplexnaturalproductsynthesis
Synthesisoffragment8
O
P
OMe
O
OMe O
OAc
OAc
OHO
OOO
O2N
NaH, BuLi, THF, 0 oC, 1 h
Br
OOAc
OAc
,
THF, RT, 2 h
42%
HCl, EtOH
65 oC, 24 h
69%
(COCl)2
DMSO,
NEt3,
CH2Cl2
- 78 oC to RT
0.5 h
86%
MeNO2, KOH, EtOH
0 oC, 2 h
then MsCl, NEt3- 15 oC to RT 15 min
88%
16 17
18
198
Synthesisoffragment8O
P
OMe
O
OMe O
OAc
OAcNaH, BuLi, THF, 0 oC, 1 h
Br
OOAc
OAc
,
THF, RT, 2 h
42%
16 17
Grieco,P.A.;pogonowski,C.S.J.Am.Chem.Soc.1973,95,3071.
O
P
OMe
O
OMe
NaH, THF
n-BuLi O
P
OMe
O
OMe
Br O
P
OMe
O
OMe
OOAc
OAc
WHE
Synthesisoffragment8
O
P
OMe
O
OMe O
OAc
OAc
OHO
OOO
O2N
NaH, BuLi, THF, 0 oC, 1 h
Br
OOAc
OAc
,
THF, RT, 2 h
42%
HCl, EtOH
65 oC, 24 h
69%
(COCl)2
DMSO,
NEt3,
CH2Cl2
- 78 oC to RT
0.5 h
86%
MeNO2, KOH, EtOH
0 oC, 2 h
then MsCl, NEt3- 15 oC to RT 15 min
88%
16 17
18
198
Synthesisoffragment8
O
OAc
OAc
OHO
HCl, EtOH
65 oC, 24 h
69%17 18
O
OH
acid hydrolysis
HOO
HO
HO
O
HO
H2OH
AcO
H
H
Synthesisoffragment8
O
P
OMe
O
OMe O
OAc
OAc
OHO
OOO
O2N
NaH, BuLi, THF, 0 oC, 1 h
Br
OOAc
OAc
,
THF, RT, 2 h
42%
HCl, EtOH
65 oC, 24 h
69%
(COCl)2
DMSO,
NEt3,
CH2Cl2
- 78 oC to RT
0.5 h
86%
MeNO2, KOH, EtOH
0 oC, 2 h
then MsCl, NEt3- 15 oC to RT 15 min
88%
16 17
18
198
Forwardsynthesis
O
O2N
8
N
O
MeOOC
7
+
NH
HN
HN ON
F3C CF3
20
(15 mol%)
Toluene, 30 oC, 8 days
dr: 91:9
57%
N
MeOOC
O
O2N
O
4
N
O
O
N
O
NO2H2N
H H
O
MeOH, reflux, 3 h
68% 3
Nitro‐Mannich/LactamizaHoncascade
Nitro‐Mannich/LactamizaHoncascade
N
MeOOC
O
O2N
O
4
N
O
O
N
O
NO2H2N
H H
O
MeOH, reflux, 3 h
68% 3
H2N
H H
O
N
+
N
MeOOC
O
NH
O
NO2
nitro-Mannich Lactamization
Forwardsynthesis
N
O
O
N
O
NO2 AIBN, Bu3SnHToluene, reflux, 4 h
3
70%
N
O
O
N
O
21
R NO2
R H
Bu3Sn-H
Bu3Sn-NO2
Forwardsynthesis
N
O
O
N
ON
O
O
N
N
O
N
H
(-)-Nakadomarin A1
21
LiAlH4, toluene, - 20 oC, 1 h
then HCOOH, RT, 14 h
86%22
N
O
N
H
2
DIBAL, toluene, - 20 oC, 1 h
then HCl, 90 oC, 24 h
41%
Grubb's 1st generation catalyst(+)-CSA, CH2Cl2, reflux, 3.5 h62%
62:37 Z/E
SelecHvereducHonoflactam
RCM
Forwardsynthesis
DIBAL, toluene, - 20 oC, 1 h
N
O
O
N
22
N
O
N
H
2
then HCl, 90 oC, 24 h
ReducHon/iminiumionformaHon/diastereoselecHveC‐CbondformingcyalizaHon
N
O
N
HO
N
O
N
H
F-C alkylation like bond formation
Forwardsynthesis
N
O
O
N
ON
O
O
N
N
O
N
H
(-)-Nakadomarin A1
21
LiAlH4, toluene, - 20 oC, 1 h
then HCOOH, RT, 14 h
86%22
N
O
N
H
2
DIBAL, toluene, - 20 oC, 1 h
then HCl, 90 oC, 24 h
41%
Grubb's 1st generation catalyst(+)-CSA, CH2Cl2, reflux, 3.5 h62%
62:37 Z/E
SelecHvereducHonoflactam
RCM
ThefirstexampleofE/ZselecHvitybeingreversedwithandwithoutacid
Thankyou!
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