Literature Seminar (B4 part) January 17, 2012 Seiko KITAHARA (B4) Total synthesis of Laulimalide
OH H O O 15 23 20 17 O O OH 1 H H O 3 5 9
1: Laulimalide (fijianolide B)
Contents
1. Introduction 2. Previous Total Synthesis 2-1. Retrosynthetic Analysis 3. Trost's Total Synthesis -toward the atom economy- 3-1. What is "synthetic efficiency" ?? 3-2. Retrosynthetic Analysis 3-3. Total Synthesis Marine Sponge, 3-4. Asymmetric Direct Aldol Reaction Cacospongia mycofijiensis via a Dinuclear Zn Catalyst 3-5. Rh-Catalyzed Cycloisomerization 3-6. Ru-Catalyzed Alkene-Alkyne Coupling
Barry M. Trost 1. Introduction
OH OH H O H O 15 O OH 20 O 23 17 17 15 20 O O OH 1 H H On exposure to acid O O O 5 9 3 (within two hours) H H O
1: Laulimalide : intrinsically unstable isolaulimalide (fijianolide B) (fijianolide A)
Although more than 10 syntheses were reported, the retrosynthetic route was limited. (route0 the combination of route1-4)
3. Trost's Total Synthesis
3-1. What is "synthetic efficiency"?? Trost, B. M. et al. Science. 1991. 254, 1471. Efficienct synthetic methods require to chemo-/regio-/diastereo-/enantio-selectivity atom economy = how much of the reactatns end up in the product
An process that is both selective ant atom economical remains a challenge. Transition metal catalysis enable this ??
Cycloisomerizations offer opportunities for enhancing efficiency for construction of difficult medium and large rings
converted to a unsaturation a ring unsaturation (with only a hydrogen shift)
Trost used 3 atom economic reactions in total synthesis of laulimalide, and 2 of these is cycloisomerization
1. synthesis of syn-diol 2. synthesis of dihydropyran 3. synthesis of 1.4-diol Zn-cat. H Ru-cat. 3-2. Retrosynthetic Analysis Trost's retrosynthetic anlysis is based on the notion that laulimalide 1 could be formed from 1,4-diene 3.
asymmetric OH epoxidation OPMB H O H O 15 O 15 20 20 23 17 23 17 O O OH O O OH 1 H H 1 H H O O 3 5 9 3 5 9 1: laulimalide 2
allylic transposition Ru-catalyzed alkene-alkyne OPMB OPMB coupling H H O 17 O 17 15 20 20 23 15 23 OH OH O O O O 1 H H 1 H H O O Still-Gennari 3 5 9 3 5 9 olef ination 4 3
Julia-Kocienski PMP olefination OPMB N O H H N N O 17 O H 17 20 S N 20 23 15 23 + O O 15 O O OMOM Ph O O OMOM 1 O 5 P 6 7 F CH CO 3 2 OCH2CF3
+
H H H O HO H 3 O 9 9 5 9 O
OBn OBn 8 9 10 3-3. Total Synthesis Trost, B. M. et al. J. Am. Chem. Soc. 2009, 131, 17087.
N N MesN NMes N N H N 1) 15 mol% Mo7O24(NH4)6 4H2O, O N Cl O H O , EtOH (83%) S N Ru S N 2 2 O Ph Cl Ph O Ph PCy3 6 13 2) 3 mol% G2, CH2Cl2(0.015 M) (95%) G2
1) H C=CHMgBr, CuI,THF (95%) S 2 H OH 2) MOMCl, i-Pr2EtN, N O + S CH2Cl2 (97%) O OMOM Et O 3) MeI, CaCO3, 14 15 9:1 MeCN/H2O (85%) 16
15 mol% (R,R)-I, Et Ph THF (53%, 10:1 dr) O O Ph Ph Zn Ph PMP Zn 1) p-MeOPhCH(OMe) , N O N 2 OH O 10-CSA, CH2Cl2 (81%) H 2) NaBH4, THF (86%) N Et O O OMOM 3) Dess-Martin periodinate, O OH OMOM CH2Cl2 Me 7 17 (R,R)-I 1) 6, LiHMDS, 3:1 DMF/HMPA 64% (64% over 2 steps) 2) DIBAL-H, CH2Cl2 (61%)
OPMB OPMB H (CF CH O) P(O)CH CO H, H O 3 2 2 2 2 O 2,4,6-trichlorobenzenoylchloride, OH OMOM i-Pr2EtN, THF, O O OMOM O 18 then DMAP, PhH (99%) P 5 F3CH2CO OCH2CF3 12 13: Pd-catalyzed allylic etherification using Zn(II) alkoxides Kim, H. et al. Org. Lett. 2002, 4, 4369.
-Generally, WIlliamson ether synthesis (SN2 type O-alkylation) is impractical. DMF O RX + R'O Na R R' SN2 Due to the strong basicity of Nu E2 Other products -Also in this case, allylation under basic or acidic condition were ineffective.
N N N N N O HO base O N S N S N -SR ?? Ph Ph 12
Alternative approach: Pd-catalyzed allylic etherification The addition of O-nucleophile to an 3-allylmetal intermediate
Mild & Stereoselective
MISMATCH ! modulating the apparent "hardness" of RO = Hard RO aliphatic alcohols: Can the Zinc effect lead to "softening" ?? poor nucleophilicity Zn(II)-bound alkoxides possess weakened basicity Soft R' strong hardness while reatining sufficient nucleophilicity !! -allylpalladium the zinc effect in biochemistry: the Zn enzyme LADH Kimura, E. et al. J. Am. Chem. Soc. 1992, 114, 10134. Parkin, G. et al. Chem. Commun. 2000, 1971.
II Zn-containing The pKa of alcohols(normally ~16) liver alcohol dehydogenases (LADH) can be reduced by about 9 units upon coordination to ZnII ?? Nucleophilicity is reatined.
LADH catalyze the hydride transfer from alcohol to NAD. + deprotonation
hydride transfer 13 6: oxidation of the sulfide into the corresponding sulfone using H2O2 and Mo(VI)catalyst
-Altough sulfoxides and sulfones are important in synthetic oranic chemistry, only a few reports are available for selective oxidation of sulfides to sulfoxides and sulfones
The oxidation of sulfides to sulfoxides with H2O2 Kaczorowska, K. et al. Tetrahedron. 2005, 61, 8315.
Several disadvantages of sulfide oxidation: H2O2 is the most attractive oxidant : selectivesulfide oxidation long reaction times relative mild conditions inconvenient reaction conditions an ideal waste-avoiding oxidant: water is only byproduct ! expensive oxidants only a small excess of H2O2 undesired reactions at other FGs high yield low yield liquid-phase reactions good solubility in water and many organic solvents
Moreover,aqueousH2O2 has further advantages: safty in storage, operation, and transportion commercially available reatively cheap
However, H2O2 alone has possibility of an over-oxidation reaction.
The oxidation of sulfides to sulfoxides with H2O2 & catalyst Controlled oxidation of sulfides to sulfoxides and sulfones Chiral oxidation is possible !
Mo(VI) catalyst/H2O2 system at room temperature Jeyakumar, K. et al. Tetrahedron. Lett. 2006, 47, 4573. Jeyakumar, K. et al. Catalysis. communications. 2009, 10, 1948.
MoO2Cl2/H2O2 system New system used in this time
R R
commercially available (NH4)6Mo7O24 4H2O is cheap air stable
Substrate Scope of (NH4)6Mo7O24 4H2O/H2O2 System
-Both systems provide excellent yield with short time.
-In both systems, various sensitive functional groups are tolerated such as alkyl, allyl, vinyl, propargyl, alcohol, ketone, ester, and remarkably oxime !
OBn OH 19 OBn 20 21 22
DIBAL-H,CH2Cl2, then Dowex 50W 8a), MeOH (99%)
HO MeO 1) TEMPO, NaOCl, MeO AcOH, H SO , KBr, NaCO , O 2 4 O 3 O H2O (82%) CH2Cl2/H2O (97%)
2) ethynylmagnesium bromide, OBn OBn THF (77%) OH 3) NaH, BnBr, DMF (96%) 25 24 23
dimethyl-1-diazo-2- oxopropylphosphonate, K2CO3, MeOH (57%, 69% brsm)
a) Dowex:
-One of the more common ion-exchange resins. -A copolymer of styrene and 4-12% divinylbenzene HO which has been sulfonated to produce a strong-acid cation exchanger
OBn 10
preparation of 19
NaNO , KBr, BF , THF, O NH2 2 O Br 3 Br H SO , -5 C, 2 h 0 C to rt, 5 h OH 2 4 OH OH HO HO HO O O D-aspartic acid 1) NaH, THF, -10 C, 0.5 h 2) BnBr, TBAI -10 C to rt, 1 h
O BnO 19
CH =CHOTBS, 5 mol% [Rh(COD)Cl]2, 2 Montmorillonite K-10, 10 mol% [m-F(C6H4)]2PCH2CH2P[m-F(C6H4)]2, H CH Cl (82%) H H HO DMF (55%) O 2 2 H O
O
OBn OBn 10 9 8
OPMB H 5, KHMDS, 18-crown-6, O THF (E/Z = 1:5, 62%, 50% (isolated Z isomer)) H H OMOM H O O O H H O O
8 4
5 mol% [CpRu(CH3CN)3]PF6, acetone (0.001M), 50 C, 15min (99%)
OPMB H O 26 R=MOM PPTS, OR O O t-BuOH (66%) 3 R=H H H O
1,3-allylic transposition ?? oxidation
OPMB OPMB H H O intramolecular O [2,3]-sigmatropic shift OH ArSe O O O O O H H H H O O 2
1. Payne rearrangement under basic condition OPMB OPMB H H O O diastereoselective O epoxidation OH OH O O O O H H H H O O 3 28
Payne rearr.
OPMB OPMB H O H O O O
OH O OH O O O H H H H O O 27 corresponding ring-contracted lactone
OPMB OPMB H H O O O3ReOSiPh3, OH Et2O, 5min (78%, 97% brsm) OH O O O O H H H H O O 3 2
1) Dess-Martin periodinane, CH2Cl2 (+)-DET, Ti(i-PrO)4, TBHP, 2) (R)-Me-CBS, BH3 THF, 4 Å MS, CH2Cl2 (86%) THF (93% over 2 steps) 3) (+)-DET, Ti(i-PrO)4, TBHP, 4 Å MS, CH2Cl2 (88%)
OPMB OPMB H O H O O O
OH OH O O O O H H H H O O
28 R=PMB 27 R=PMB
29 R=H 1 R=H laulimalide analogue laulimalide DDQ, DDQ, CH Cl /pH 7 buffer/t-BuOH 2 2 CH2Cl2/pH 7 buffer/t-BuOH (71%) (89%)
3 2: 1,3-allylic transposition utilizing Re oxo catalysis These catalyst are very sensitive to presence of water.
= more active 2 Me Si Me3Si SiMe3 + H O 3 OH O 2 form inhibit the catalytic process O OH Re O O Proposed mechanism According to kinetic study,
Some calculations confirm the involvement of a cyclic transition state.
rds = intramolecular rearrangement 3-4. Asymmetric Direct Aldol Reaction via a Dinuclear Zinc Catalyst
a semi-crown compound High binding affinity vs. Catalysis Too high binding affinity inhibit an exchange of products for others.
a semi-crown design meets both requirement: -good chiral recognition 4 steps a phenoxide moiety(as a base) -turnover at reasonable rates OH 1.The alkoxide generated in the aldol reaction would be rapidly protonated by this. 2.The phenoxide might still be adequate to form the enolate. Me
simple ketone -hydroxyketone the enolate apporaches to the si face to the re face
-hydroxyketone serves as a bidentate ligand. 3-5. Rh(I)-Catalyzed Cycloisomerization of Homo- and Bis-homopropargylic Alcohols
Trost, B. M. et al. J. Am. Chem. Soc. 1992, 114, 5579.
A The close examination of the mechanism ?? C -Ligand subsitution -Kinetic and deuterium experiments B -Identity of the reactive profile
A. Vinylidene Formation Deutrium labeling stoichiometric condition -alkyne complex
1,2-hydrid catalytic condition migration
C-H insertion & deprotonation -acetylide complex
(1) the NMR spectrum of 2 in CDO3D containing of NDPF4 the absense of the vinylic hydrogen & the disappearance of13C signal for the vinylidene carbon (with all the other13C siganls remaining)
(2) deutrium loss of 3 in eq 6 reversibility of vinylidene formation (3) litte deutrium loss of 3 in eq7 -protonation of -acetylide > reversal to -alkyne complex faster summary: -Vinylidene complex is formed. -The equiliration of the vinylidene complex with starting alkyne is more slow then its further reaction.
B. Addition of Allylic Alcohols
(1) the extremely facile loss of PPh3 from cat.1
(2) addition of PPh3 retardation or the rate of the condensation reaction under identical conditions except the addition addition of PPh3
excess PPh3 within 1 h (1eq. /Ru) 4 h (3) comparison of the reactivity of 3-buten-2-ol 5 with other alcohols 5, starically equivalent to IPA, reacted much mroe rapidly than MaOH.
MeOH EtOH, IPA
NO addition (for steric reasons)
precoordination of the olefinic group of 5
(4) placing Me directly on the double bond of the allylic alcohols
OH or OH condensation products steric inhibition of olefin coordination
(5) replacing PPh3 with the chelating ligands dppe and dppb
inhibition of the condensation reaction P P preclusion of preccordination of the olefinic group of the allylic alcohols (due to relactance of the ligands to dissociate a phosphine) dppe dppb summary: -Precoordination of the olefinic goup is required and actually takes place.
C. The Nature of the Allyl Intermediate : evidence regarding the role of - vs. -allyl complexes (0) precedents of Ru-catalyzed coupling intrinsic preference for C-C bond formation to the more substituted allyl terminus Tsuji, Y. et al. J. Organomet. Chem. 1989, 369, C51.
(1) regiochemical outcome from eq 12 retaining the positional identity of the allylic alcohol a) Slower C-C bond rotation than reductive elimination
slower
faster faster -coordination enhance the barrier (2) geometrical outcome from eq 13 to rotation ... ?? retaining olefin geometry NOT reasnable
b) Slower 3 to 1 allyl slippage than reductive elimination slower
scramble the olefin geometry little intervention of -complex (See the right column.)
summary: -Judging from almost no scramble of both regimochemistry and olefin geometry, 3- -allyl complex undergos reductive elimination much faster than borh allyl rotation and 3 to 1 allyl slippage . This scheme accommodates all of the preceding observations.
If R=H (unsubstituted allyl alcohol), D should be sufficiently destabilized to ensure rapid reductive elimination (Due to the presence of the acyl group faster than on an already electron-poor Ru(IV) species) allyl rotation relatively slow 3 to 1 allyl slippage
But if R H(substituted allyl alcohol), the competition between the rate for reductive elimination and 3 to 1 allyl slippage is changed ! (See below.)
A dramatic difference with a substituted allylic alcohol
The high regioselectivity & The loss of olefin geometry
-Scrambling of olefin geometry -complex E as an obligatory intermediate or a species in dynamic equilibrium -The high regioselectivity reminiscent of eq11 (the reaction of monosubstituted allyl organomethallics at the more substituted allyl terminus)
Why C-C bond formation the more substituted allyl terminus is favored ??
Precedents: 6-membered transition state
Trost, B. M. et al. J. Am. Chem. Soc. 2002, 124, 2528.
Like such a reaction, the metal itself prefers the less substituted allyl terminus and cyclic transition state invokes allyl inversion ??
Trost, B. M. et al. J. Am. Chem. Soc. 2002, 124, 2528.
Mechanistic Rationale
If it is If it is electron rich less enough electron rich
3 = (C4H9)4NPH6, 4 = N-hydroxysuccinimide
Ideal catalysis of the Alder en reaction Alternative catalytic concept
-the simplest form -catalysis : only TS energy -catalysis : precoordination of two reactant partners -one-step process -one or more steps
cat.
"branched" "linear"
the same as the above
Extremely high chemoselectivity & control of olefin geometry free OH, TBS ehters, ketones, and esters in either the alkene or alkyne Generally, the major produt is the branched one.
Branching at propargylic position has significant effect on regio selectivity. (the linear product )
Replacing an alkyl branch by an oxygen inverts the regioselectivity.
= the more reactive cationic complex
As the size of R3 then the linear
This model may explain the effect of a propargylic oxygen substituent .
Ru coordinates the oxygen.
If the alkyne coordinates with the opposite orientation ... (possible in principle)
Syn- -hydrogen elimination of Hb
Electronic effect vs. Steric effect Electronically, 35 is favored. Normally,electronic rather than steric effects Which effect is Carbametalations normally prefer to attach dominate leading via 35 to the branched 39. the less substitued terminus of the alkyne. dominant ?? On the other hand, as R increases in size, Sterically, 36 is favored. steric effects bacome more important: 17 19 should be disfavored relative to 16 18. When -hydrogen elimination is inhibited ... Normally,electronic rather than steric effects dominate liadingvia via another35 to the process branched 39.
On the other hand, as R increases in size, [5+2] cycloaddition steric effects bacome more important: 17 19 should be disfavored relative to 16 18.
an insertion into the C-C bond -hydrogen of the cyclopropane -hydroxy elimination elimination -hydrogen elimination methylenecyclopropane
anti-Bredt olefin
The ruthecycle 81 cannot achieve the required geometry. -hydrogen elimination would generate anti-Bredt olefin. Then, if even -hydroxy elimination is impssible, what occurs ??
Path 1: allyl mechanism Path 2: Ruthenacycle mechanism
Initially, path 1 seemed more possible than path 2 due to absence of homo-coupling product. -If Path 2 operates, the formation of a ruthenacyclopentadiene should be preferred to that of a ruthenacyclopentene. lead to homo-coupling products lead to cross-coupling products
However, the validity of path 1 was questioned, because the regioselectivity about alkene was disrurbing. -In light of other work, the formation of a -allylruthenium complex should undergo reductive elimination with formation of the new C-C bond to the more substitued allyl terminus.
precedents of reductive elimination
Left: Tsuji, Y. et al. J. Organomet. Chem. 1989. 369, C51. Reight: Trost, B. M. et al. J. Am. Chem. Soc. 1990. 112, 7809.
Path 1 was abondoned by the experimental support. -To probe the involvment of a -allylruthenium chemistry, the reaction of (E)-2 butene was explored.
If path 1 operates, this reaction should result in the same regioisomer as a 1-alkene: obtaining 15 as the product.
Spectral data clearly show the adduct is 14 and not 15.
This experiment suggests NOT involving -allylruthenium mechanism and supports path 2, which, furthermore, more consistently rationalizes the regioselectivity.
If the ruthenacyclopentene and ruthenacyclopentadiene are in dynamic equilibrium, the products then depend upon the rate of further reactions. Fsst reversible formation
1 +
R + 1
The unimolecular The bimoledcular paths -hydrogen elimination for the further reaction NOT observed the Alder ene type product numerous side product such as arenes of cyclopentadienes (formed via the same mechanism as "scheme 10")
The unimolecula reaction rmay dominate over the bimoledcular reaction.
So, although the rethenacyclopendadiene spiecies was formed, only the cross-coupling product was obtained.
If the reaction followed paths a and b exclusively... The branched to linear ration should be the same as for 1-octene, which is not the case.
Other paths should be involved !
the symmetric bidentate coordination
If 22 was formed, steric factors arising from interaction of R and the olefin are eliminated from consideration.
The bias for branched vs linear product may simply reflect the intrinsic steric and electronic factors associated with the tautomerization to the metallacycle (paths c and d)