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Total Synthesis and Stereochemical Assignment of (-)-Ushikulide A
Barry M. Trost, Brendan M. O’Boyle, Daniel HundJ. Am. Chem. Soc. 2009, 131, 15061-15074
Presented by Maria DeMuro, Justin Sears, and Kaylee WendelDecember 1, 2009
(-)-Ushikulide
• Exhibits potent immunosuppressant activity– Works against excessive growth of mouse
lymphocytes• Isolated from a culture broth of Streptomyces sp.
IUK-102– Sterochemically undefined member of oligomycin-
rutamycin family
Stereochemistry
• (-)-Ushikulide is a natural product with a large degree of sterochemical complexity.
• Impossible to randomly prepare diastereomers – 14 sterocenters : 214 stereoisomers = 16384 possibilities
• Knew structure was very similar to the natural product cytovaricin, for which a crystal structure has been determined– NMR comparisons showed that 8 stereocenters matched– Only 6 stereocenters remained
Synthetic Planning
Synthetic Planning• Objective-
– Make a full three-dimensional structure of a complex natural product• This provides information to explore the relationship between
chemical structure and function
• To make C-14, C-15 olefin, used less common sp3-sp2 Suzuki coupling and esterification
• Utilized alkenes and alkynes as orthogonal surrogates for hydroxyl and carbonyl functionalities
• New and highly regioselective gold catalyzed spiroketalization
• Use of (S,S) ProPhenol in enantio- and diastereoselective alkynlation and aldol reactions
Nuclear Overhauser effect
-Spectral Technique to determine coupling between hydrogens-Coupling determined by proximity, not bonding
-Irradiate one hydrogen-Can measure interactions between other nearby hydrogens
-In this example, NOE is used to confirm the trans stereochemistry of the diol-If cis, hydrogen would be pointing in the opposite direction and would not be close enough to couple with the irradiated hydrogen.
Preparing the Aldehyde Fragment1. Alkylation
S
S
OS
SBr
OMe
OMe n-BuLi, THF
then HCl, H2O
91% 13c
+
Mechanism
S
S
H
Li
S
S
Li
BrOMe
OMe
S
S
OMe
OMe
H+
S
S
OMe
OH
S
S
OMe
H2O
S
S
OMe
OHH
B-
S
S
OMe
OH
H+
S
S
O
OH
H
S
S
H
OH
B-
S
S
H
O
Preparing the Aldehyde Fragment
2. Crimmins Aldol Reaction
MeN S
O S
Ph
TiCl4, NMP, (-)-sparteine
CH2Cl2S
S
N S
O S
Ph
Me
OH
14 15c90%, single diasteromer
S
S
O13c
+
3. TBS Protection
TBSOTf, 2,6-lutidine
CH2Cl2S
S
N S
O S
Ph
Me
TBSO
S
S
N S
O S
Ph
Me
OH
15c
Preparing the Aldehyde Fragment4. DIBAL Reduction
Mechanism
S
S
N S
O S
Ph
Me
TBSODIBAL-H
CH2Cl2S
S O
Me
TBSO
87% over previous 2 steps16c
Preparing the Alkyne Fragment1. Noyori Asymmetric Hydrogentation
O
O O (R)-BINAP, [RuCl2(C6H6)]2
MeOH, H2, 1800 psiO
O OH
92%, 99% ee
Mechanism
Preparing the Alkyne Fragment2. PMB Protection
O
O OH PMBO(C=NH)CCl3 1 mol%
Cu(OTf)2, PhMe
85%
O
O OPMB
3. DIBAL Reduction
O
O OPMB DIBAL-H
CH2Cl282%
H
O OPMB
17
Preparing the Alkyne Fragment4. Crotylation
H
O OPMB
17then H2O2, NaOH, H2O
80%
OPMB(+) Ipc2-cis-crotyl, THF OH
19a
Mechanism
Preparing the Alkyne Fragment5. TBS protection
OPMBOH
19a
OPMBTBSO
19c
TBSCl, imidazole, DMF
87%
6. Hydroboration-iodination
OPMBTBSO
19c
9-BBN, THF
then NaOCH3 MeOH, I2
85%
OPMBTBSO
19d
I
7. Nucleophilic Substitution
OPMBTBSO
19d
I
TMS Acetylenen-BuLi, THF, DMPU
then KOH, MeOH
81%
OPMBTBSO
20
Completion of Spiroketal Fragment
Me
OHS
S
Me
Me
OPMB
OTBS
OBz
Me
Me
OPMB
OTBS
OPMB
O
Me
O
Me
OH
TBSO
I
47a16c 20
CHO
Me
OTBSS
S
Me
Me
OPMB
OTBS
Li
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
+
16c 28d
28c
20n-BuLi
Low Selectivity of Alkynation
•Syn to anti (desired) ratios were poor•In presence of LiBr and molecular sieves, showed moderate Felkin-Ahn selectivity (6:1 syn:anti)•Chelation controlled product was not feasible under a variety of conditions
2 Possible Solutions:•Addition to Weinreb amide, then diastereoselective Noyori reduction•Converge both epimers to anti product
Convergence of Epimers
• 28d and 28c were very easy to separate via column chromatagrophy, so Trost et al. decided to try the convergent pathway
• This involves addition of –Bz alcohol protecting group to 28d with inversion of stereochemistry, and addition to 28e with retention of stereochemistry
CHO
Me
OTBSS
S
Me
Me
OPMB
OTBS
Li
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
BzOHPPh3, DEAD
EtO2C
N
N
CO2Et
BzClPyridine
Me
OTBSS
S
Me
Me
OPMB
OTBS
OBz
+
16c 28d
28e
28c
Bz =Ph
O
Inversion of syn epimer: Mitsunobu Reaction
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
28d
Me
OTBSS
S
Me
Me
OPMB
OTBS
OBz
Ph3PN N
CO2Et
EtO2C
N N
CO2Et
EtO2C
PPh3
O
O
H
N NH
CO2Et
EtO2C
PPh3
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
N NH
CO2Et
EtO2C
PPh3
O
HR
N NH
CO2Et
EtO2C
PPh3
O
R
H+
HN N
H
CO2Et
EtO2C
PPh3
O
R
Me
OTBSS
S
Me
Me
OPMB
OTBS
OPPh3
O
O
Me
OTBSS
S
Me
Me
OPMB
OTBS
OBz
O PPh3
28c
Retention of Stereochemistry
Me
OTBSS
S
Me
Me
OPMB
OTBS
OH
Ph Cl
O`
Me
OTBSS
S
Me
Me
OPMB
OTBS
HO
O
Cl
Ph
Me
OTBSS
S
Me
Me
OPMB
OTBS
O
O
Ph
ROH
H
Cl
Me
OTBSS
S
Me
Me
OPMB
OTBS
O
O
Ph
ROH2 Cl-
H+ Transfer
28e
28c
Attempted Spiroketalization
Me
OHS
S
Me
Me
OPMB
OTBS
OBz
29c
Pd(CH3CN)2Cl2CH3CN, THFref lux OPMB
O
Me
O
Me
OBz
S
S
41
X
Me
OTBSS
S
Me
Me
OPMB
OTBS
OBz
28c
HCl, H2OMe
OHS
S
Me
Me
OPMB
OTBS
OBz
29c
First, deprotection:
Pd Catalyzed spiroketalization—utter failure:
AuCl Catalyzed Spiroketalization
• After attempts with Pd and Pt, decided to move on to gold• With gold, observed complete conversion, but wrong
spiroketal (42)• Optimized conditions—changing solvent and Bronsted Acid
affected product ratios• Found PPTS was best Bronsted Acid additive and THF best
solvent:
Me
OHS
S
Me
Me
OPMB
OTBS
OBz
29c
AuCl 10 mol %PPTS 10 mol %THF, 50 C
PPTS:
N H SO
OPMB
O
Me
O
Me
OBz
S
S
+OPMB
O
Me
O
S
S
41 42
Spiroketalization Mechanism
Me
OH
Me
Me
OPMB
OH
O
O
Ph
BnO Au
Me
OH O
O
Ph
BnO
Au
O
Me
OPMB
Me
H
H
Me
OH O
O
Ph
BnO
Au
O
Me
Me
OPMB
Me
OH O
BnO
Au
O
Me
Me
OPMB
Ph
O
+2HMe
OH O
BnO
H
O
Me
Me
OPMB
Ph
O
H
-Au
OPMB
O
Me
O
Me
OBz
OBn
33
33
Me
OH
BnO
H
O
Me
Me
PMBO
+HMe
OH
BnO
H
H
O
Me
OPMB
Me
OPMB
O
Me
O
BnO
Me
31b- Desired
32
+2H-Au-BzOH
Final Modifications to Spiroketal
OPMB
O
Me
O
Me
OBz
S
S
41
MeI, NaHCO3
MeCN, H2O
OPMB
O
Me
O
Me
OBz
45
O
OPMB
O
Me
O
Me
OH
TBSO
I
47a
OMs
44
OPMB
O
Me
O
Me
OBz
45O
Synthesis of Mesylate 44
CHO
(S,S) ProPhenol
Me2Znmethyl propiolate
O
MeO
OH
CO2Me
LiOH, H2O, CuCl, MeCNOH
MsCl, Et3N, CH2Cl2OMs
(S,S) ProPhenolOH
Me
NN
PhPh
OHHO Ph
Ph
Isovaleraldehyde 43 44b 44
Addition of Mesylate to Spiroketal
• Occurs via Marshall propargylation• 44 undergoes oxidative addition with
palladium(0)• Then transmetallation with zinc• Zinc reagent undergoes nucleophilic addition to
aldehyde
OPMB
O
Me
O
Me
OBzOMs
44
+
10 mol % Pd(OAc)2ZnEt2, PPh3, THF
OPMB
O
Me
O
Me
OBz
HO
O45
46a
Part I: Formation of Allenyl ZincPd(OAc)2
Pd(PPh3)2
Reductive EliminationOMSH
R
Pd
H
H
R
Oxidative Addition
Ph3P
Ph3P OMs
ZnEt2
EtZnOMs
Pd
H
H
R
Ph3P
Ph3P EtEtZnOMs
Transmetallation
Zn
H
H
R
OMs
Et2Pd(PPh3)2
2 PPh3
CH2CH2Ch3CH3
Part II: Coordination Controlled Nucleophilic Addition
Zn
H
H
OMs
O
H
RSpiroKetal
OPMB
O
Me
O
Me
OBz
HO
a
b
46a
• The aldehyde coordinates to zinc, leading to complete control at (a)
• A Zimmerman-Traxler transition state favors shown stereochemistry at (b).
Final Modifications
OPMB
O
Me
O
Me
OBz
HO
TBSOtf,2,6-lutidineCH2Cl2
OPMB
O
Me
O
Me
OBz
TBS
46a 46d
K2CO2, MeOH
OPMB
O
Me
O
Me
OH
TBS46e
Bu3SnH
Pd(PPh3)2Cl2THF, then I2
OPMB
O
Me
O
Me
OH
TBS
I
47a
Synthesis of Aliphatic Fragment and Completion of the Synthesis
O
OH
Me
O O
O
Me
OHMe
HO
HO Me
OH
O
(-)- Ushikulide A
Restrosynthetic Analysis of Aliphatic Fragment
O
Me
OHMe
HO
HO Me
OH
RO2C
MeO
Me OH
Me CMe
HO
O
H
Ketone Aldehyde
-Form ketone and aldehyde separately and join them together by a dinuclear zinc aldol reaction
First Approach: Scheme 9The first step towards the synthesis of the aliphatic fragment 4 began with reacting the dibromide 48 with n-BuLi in THF to yield the Fritsch-Buttenberg Wiechell rearrangement, resulting in the lithium acetylide.
Br
Br
OTBS
Me
H
n-BuLi, THF
Br
Br
OTBS
Me
Li
LiOTBS
Me
Scheme 9The lithium acetylide was quenched with N-methoxy-N-methylacetamide to yield 49
The ketone in 49 was reacted with (S,S) prophenol (a chiral catalyst), diethyl zinc and an aldehyde in an aldol reaction to obtain the alkene in 51.
LiOTBS
Me
Me N
O
OMe
Me
49 76% yield
(S,S) Prophenol
Et2Zn, iPrOH, THF
CHO
EtO OEtOTBS
Me
Me
O
Transition State of Zn Aldol Reaction
O
Me
NN
Ph
PhO
PhO Ph
Zn
Zn
Et
O
Me
NN
Ph
Ph O
PhO Ph
Zn
Et
H
EtOEtO O O
R
The aldehyde with two ethoxy groups is held by the two zinc atoms, acting as a bidentate ligand and bridging the two zincs. This transition states allows for the OH to be pushed to the front.
The prophenol-zinc complex
Attempted Hydrosilation
OTBS
Me
OOH
EtO OEt
51
[Cp*Ru(CH3CN)3]+ PF6-
Bn(Me)2SiH, acetone
H3CH2C-O OEt
OH O BDMS
OTBS
Me
Caused deprotection of diethoxyketal
Possible mechanism: ethoxy group is protonated and leaves as ethanol.
Mukaiyama Allylation -Enantioselective due to the chiral allylating reagent generated in situ from tin(II) catecholate, allyl bromide, diisopropyl tartrate, DBU, and CuI.
Proposed TS
Ligand Association
Oxidative Addition
Allylation and DIBAL MechanismsMe
OBn
O
O
O
O
SnIVO
O
CO2CH(CH3)2
CO2CH(CH3)2
OBn
O
HO Me
PMBO(C=NH)CCl, 1 mol % Sc(OTf)3, tol OBn
O
PMBO Me
DIBAL-H, CH3Cl2, 90% PMBO Me
O
H
52
intermediate
OBn
O
PMBO Me
AlH
iBuiBu
OBn
O
PMBO Me
Al
iBu
iBu
H
OBn
O
PMBO Me
AliBu
iBu
HH+
O
PMBO Me
H
Mechanism of DIBAL-H
53
Transition State
Termination of First Approach
• 53 undergoes several more reactions, including the zinc aldol reaction, as seen before and an epoxidation (which gives no stereoselectivity).
• Several attempts to open the epoxide of 57 and 58 failed to yield the desired product, 59.
• Scheme 10 overviews the resolution to this problem and the completion of the aliphatic fragment.
Wacker OxidationOTBS
Me
OPMB
MePdII
H3COTBS
Me
OPMB
Me
H2O
H+
PdIIOTBS
Me
OPMB
Me
HO
Pd0
2 CuII
2 CuII
2H+ +1/2 02
2 -OH
OTBS
Me
OPMB
MePdII
O
Ligand Association
1,2 inserction
Reductive elimination
Nucleophillic addition
Pd is re-oxidized
60, af ter PMB is added
61
Wacker oxidation of terminal alkenes yields the methyl ketone, rather than the aldehyde.
Completion of Aliphatic Fragment-Tried to optimize conditions for the reaction of 61 to 62. This is summarized in the table.-Entry 6 produced the best results. -t-BuOH > i-PrOH (prevents reduction of aldehyde 53 to alcohol 63)-Dioxane > THF-30 mol% (S,S) ProPhenol > 10 mol % (S,S) ProPhenol 65% yield, (>20:1 d.r.)
-From 62 to 64 a protecting group was added.-The completion of the aliphatic fragment (64 to 65) relied on three reactions: deprotection, oxidation, and a Horner Wadsworth Emmons olefination (shown below).
Completion of Aliphatic FragmentPMBO Me
O O OPMB
OTBS n-Bu4NF, THFPMBO Me
O O OPMB
OH
Deprotection
PMBO Me
O O OPMB
OHI
O
AcO OAc
OAcI
O
AcO
O C
H
H
R
O
I
O
AcO
+
OH
O
PMBO Me
O O OPMB
H
O
R =RED
DMP Oxidation
HWE Olefination
(EtO)2P
O
CH2 C
O
O TMS
n-BuLi
(EtO)2P
O
CH
C
O
O TMS
Li
(EtO)2P
O
CH
C
O
O TMS
Li
R H
OO P(EtO)2
O
O
R
H
O
TMS
R OH
OPMBO Me
O O OPMB
OH
O
Aliphatic Fragment 65
Optimization of Aliphatic Fragment-Considered another possible bond disconnection between C7-C8 bond instead of the C8-C9 bond.- This failed to give good yield or stereoselectivity, and therefore was not carried out any further.
O
OH
Me
O O
O
Me
OHMe
HO
HO Me
OH
O 9
8
7
-Another possibility was to convert 53 to a silyl ether, 68.
PMBO Me
H
O
53
MeMgBr, THF
SO3-Pyr, Et3N, DMSO(Parikh-Doering)
LiHMDS, TMSCl, THF
PMBO Me
OTMS68
Excess of 68 was reacted with boron trifluoride diethyl etherate to yield the Felkin Ahn product.
Mukaiyama Aldol
OTMS
PMBO Me
68R
+
O
Me Me
OTBS
OPMB
69R
Me
R
H
HO
69
HMe
R
F3BOH
CH2C-R
O
O
PMBO Me
OTBS
Felkin Ahn Product
OH
Me
OPMB
Me
70
Reduction of this ketone diol (70) with NaBH4 afforded the syn diol; 2,2 dimethoxypropane in p-TsOH and CH2Cl2 was then added as a protecting group to yield 64.
Completion of the Synthesis-Completion of the synthesis required a Suzuki coupling and an esterification to join together 47a and 65
O
OPMB
Me
OOH
OMe
OPMBMe
O
O MeOPMB
TBSO
I47a
HO
65
+
-Yamaguchi esterification allowed for the direct coupling of 47a and 65 to yield 72.-Unfortunately, Suzuki coupling is not usually utilized for the formation of macrocycles and failed to produce the desired product 73.
O
OPMB
Me
OO
TBSO
I
OMe
OPMBMe
O
O MeOPMB
72
Alternate Pathway for Completion of Synthesis
- Hydroboration, Suzuki coupling, then macrolactonization.O Me
OPMBMe
O
O MeOPMB
HO
65
O Me
OPMBMe
O
O MeOPMB
HO
R
B
THF
(BBN=R)
O
OPMB
Me
O
TBSO
COOH
Me
OPMBMe
O
OMe
OPMB
OH
10 mol% PdCl2, 10 mol% Ph3As
CsCO3, DMF, H2O
47a
Seco Acid - 75
O
O ONO2 NO2
R OH
O O
PMBO
Me
O
TBSO
Me
OPMBMe
O
OMe
OPMB
O
O
73
Intramolecularmacrolactonization
Finally, Deprotection and Oxidation.
O
PMBO
Me
O
TBSO
Me
OPMBMe
O
OMe
OPMB
O
O HF-PyridineDess Martin periodinane
DDQ, CH2Cl2, AcOH, H2O
O
OH
Me
O O
OMe
OHMe
HO
HO MeOH
O
(-) - Ushikulide A
-Upon isolation, this compound exhibited identical H1, C13, IR, HPLC properties as natural ushikulide.-Optical rotation experiments confirmed the absolute stereochemistry, as depicted in Scheme 12
