Discodermolide A Synthetic Challenge

Me Me Me

HO Me

O O OH O NH2 Me Me

OH O Me Me

OH

Nicole Goodwin MacMillan Group Meeting April 21, 2004

Me Me Me HO Discodermolide Me O O OH O NH2 Isolation and Biological Activity Me Me OH O Me Me OH

! Isolated in 1990 by the Harbor Branch Oceanographic Institution from the Caribbean deep-sea sponge Discodermia dissoluta

! Not practical to produce discodermolide from biological sources ! 0.002% (by mass) isolation from frozen sponge ! must be deep-sea harvested at a depth in excess of 33 m

! Causes cell-cycle arrest at the G2/M phase boundary and cell death by apoptosis

! Member of an elite group of natural products that act as microtubule-stabilizing agent and mitotic spindle poisons ! Taxol, epothilones A and B, sarcodictyin A, eleutherobin, laulimalide, FR182877, peloruside A, dictyostatin

! Effective in Taxol-resistant carcinoma cells ! presence of a small concentration of Taxol amplified discodermolide's toxicity by 20-fold ! potential synergies with the combination of discodermolide with Taxol and other anticancer drugs

! Licensed by Novartis from HBOI in 1998 as a new-generation anticancer drug

1 Cell Apoptosis M - Mitosis

G0 Discodermolide disrupts the G2/M phases of the cell cycle. Resting Discodermolide, like Taxol, inhibits microtubule depolymerization by binding G1 - Gap 1 to tubulin. G2 - Gap 2 cells increase in size, cell growth control checkpoint no microtubules = no spindle fiber new proteins formation

S - Synthesis DNA replication

Me Me Me HO Discodermolide Me O O OH O NH2 Isolation and Biological Activity Me Me OH O Me Me OH

! Considerable synthetic effort to produce discodermolide because of dearth of biological supply ! Taxol is semi-synthesized from an intermediate extracted from the European Yew tree ! the epothilones are obtained from fermentation

! Several total syntheses and numerous fragment syntheses ! 1993 - Schrieber ! 1995 - Smith 1998 - Smith, second generation ! 1997 - Myles (UCLA) ! 1998 - Marshall (UVa) ! 2000 - Paterson

! Novartis synthesis is a combination these total synthesis

! Smith - fragment syntheses from a common precursor (CP) ! Marshall - !-alkyl Suzuki coupling of C14 to C15 ! Paterson - endgame

2 Discodermolide A Synthetic Challenge

(Z)-olefin

Me Me Me 8 HO 9 22 Me 7 14 O O OH O NH2 terminal (Z)-diene Me 13 Me OH O Me Me

OH tri-substituted (Z)-olefin

! Repeating stereotriad from common precursor (CP)

Me Me Me 20 HO 18 Me 19 OMe Me Me 10 12 O O OH O NH2 N OPMB Me 11 Me Me 2 4 OH O O OH Me 3 Me CP OH

Me Mee Mee HO Mee 18 20 Discodermolide 10 Outline O O OH O NNHH22 Mee 12 Me OH O Me 2 4 Mee OH

! Paterson Synthesis (1998, 2001) ! selectivity from intrinsic bias of molecule ! boron-mediated anti Aldols ! Claisen rearrangement to set C13 olefin ! Nozaki-Hiyama/Petersen elimination - diene formation ! selective reductions at C7 or C5

! Smith Synthesis (1995, 2003) ! stereotriad from a common precursor (CP) - Evans aldol ! Negishi coupling at C14 ! Yamamoto diene formation ! Wittig olefination at C8 - first and second generation

! Marshall Synthesis (1998) ! Allenylstannane additions to chiral aldehydes for stereotriads ! !-alkyl Suzuki coupling with vinyl iodide

! Novartis synthesis - over 60 g produced!

3 Paterson 2001 Retrosynthesis

24 Me Me Me 8 HO Me

O O OH O NH2 Me Me 1 13 OH O Me Me OH

CO Ar 2 24 Me Me 6 PMBO 16 Me Me 9 Me Me H 17 MeO2C 1 Me Me OTBS O O OPMB OTBS

Boron -mediated Anti Aldols

Me Me Me Me Me Me BnO PMBO OBz O O O

Me HO ethyl (S)-lactate CO2Me

Me Me Me HO Paterson 2001 Me O O OH O NH2 Preparation of C1 to C6 Fragment Me Me OH O Me Me OH

Me Me Me Me Me Cy2BCl MeCHO HO BnO BnO CO2Me Et3N O O BCy2

H BnO BnO H Cy Cy Cy H minimize H LiBH Me B Cy Me 4 O Me B B Me Me O Cy Me O Cy O Me A1,3 Me 1,3 syn reduction O O BnO H Me

H O Me Me 5 steps* Me Me 2 2 6 BnO Me Me 86% yield MeO2C 76% yield 1 >97% d.s. OH OH OTBS O

* 1. TBSOTf 2. CSA, MeOH/CH2Cl2. 3. Pd(OH)2/C, H2, EtOH. 4. Swern. 5. i. NaClO2. ii. CH2N2.

4 Me Me Me HO Paterson 2001 Me O O OH O NH2 Preparation of C9 to C18 Fragment Me Me OH O Me Me OH

O Me Me Me Me H Me Me Me Cy2BCl i. HO PMBO PMBO CO2Me Et3N ii. H2O2 O 95% yield, >97% d.s. O OH

Me Me Me Me Me Me Me4NBH(OAc)3 PhSeCH CH(OEt) PMBO 2 2 PMBO or PPTs, PhMe 1. SmI2, EtCHO OH OH 94% yield O O 2. K2CO3, MeOH CH2SePh

Me Me Me PMBO O Me NaIO4 Me H Me Et OPMB Holmes protocol O

O O Sm O

Me Me Me HO Paterson 2001 Me O O OH O NH2 Ring Expansion Claisen Rearrangement Me Me OH O Me Me OH

Me Me Me Me Me Me H PMBO PMBO Me Me NaIO4 O O O Holmes O O O PMBO Me CH2SePh

Me Me H Me Claisen Me PMBO 3 steps* O Me 82% yield O O 86% yield PMBO Me O

Me O O

PMBO 16 Z olefin geometry set 9 Me Me without other isomer present!

Me Me OTBS Holmes, et al. J. Am. Chem. Soc. 1997, 119, 7483

* 1. KOH, MeOH. 2. 2,6-Me2phenol, DCC, DMAP. 3. TBSOTf

5 Me Me Me HO Paterson 2001 Me O O OH O NH2 C17 to C24 Fragment Me Me OH O Me Me OH

Me TBSO H Me Me Me Me Me Me Me BCy Cl (S)-ethyl 2 O TBSO lactate OBz OBz OBz Me2NEt 99% yield O O >97% d.s. OH O Cy2B

1. PMBO(C=NH)CCl3 Me Me 2. NaBH ; K CO , MeOH 4 2 3 TBSO H

3. NaIO4 H PMBO O R H H CrL O n TMS Me TMS CrCl2 LnCr TMS THF Br

H Me Me TMS Me Me 24 R H KH H OH TBSO TBSO TMS 98% yield 17 Me PMBO OH from diol OPMB

Me Me Me HO Paterson 2001 Me O O OH O NH2 C17 to C24 and C9 to C16 Fragment Union Me Me by a syn Aldol OH O Me Me OH

Me O O ArO OLi

16 LiTMP, LiBr Me Me 24 PMBO 9 -100 °C PMBO Me Me Me H 17 Heathcock conditions Me Me to give (E)-enolate Me Me O OPMB OTBS OTBS

ArO C Me Me H 2 R OAr PMBO LiAlH H Li Me 4 O R O OR OPMB -30 °C Me Me Me 88% yield OTBS

R = H, !-elim. of OAr, epimerizes C18 HO R = Li, no epimerization, in situ reduction Me Me PMBO Me OH OPMB Me Me OTBS Clark, D. L.; Heathcock, C. H. J. Org. Chem. 1993, 58, 5878. Hall, P. L.; Gilchrist, J. H.; Collum, D. B. J. Am. Chem. Soc. 1991, 113, 9571.

6 Me Me Me Paterson 2001 HO Me Alternate Syn Aldol Approach is Unsuccessful O O OH O NH2 Me Me OH O Me Me OH

Me Me Me Me PMBO LiTMP, LiBr PMBO Me Me -100 °C H O Me O Me O OPMB O LiO

Me Me OH OPMB OH OPMB

H H Me Me Me Me Me Me O O O O Me Me 55% yield 39% yield PMBO PMBO 3 steps

Me Me Me PMBO 5 steps, 17% overall yield from lactone Me or OTBS OPMB 7 steps, 42% yield fromacyclic aldol route Me Me OTBS

Me Me Me HO Paterson 2001 Me O O OH O NH2 Finishing the C9 to C24 Fragment Me Me OH O Me Me OH

HO Me Me Me Me Me PMBO 1. MesSO2Cl, Et3N PMBO Me Me 2. LiAlH4, -10°C OH OPMB OH OPMB Me Me Me Me OTBS OTBS

Me Me Me 1. TBSOTf HO Me 2. DDQ OTBS OH Me Me OTBS

ArO2SO Me Me O OPMB PMBO PMBO Me Super-Hydride Me OH OPMB Me Me Me Me 66% yield Me Me OTBS OTBS

7 Me Me Me HO Paterson 2001 Me O O OH O NH2 Final Coupling at C7 Me Me OH O Me Me OH

Me Me Me Me Me Me HO 1. TEMPO MeO Me Me OTBS OH 2. Still-Gennari HWE O OTBS OH Me Me OC F Me Me MeO 2 5 P OC F OTBS 2 5 OTBS O O

O Me Me Me Cl C N chiral boron reagent control 3 C 1. O ; K2CO3 O of a mismatched case Me 2. DIBAL OTBS OBL2 3. DMP OTBS O NH2 Me Me MeO2C

OTBS O Me Me

Me Me Me HO Me * O OTBS O NH2 1. Me4NBH(OAc)4 (+)-Discodermolide MeO2C Me Me OH O 2. HF pyr or 10.3% overall yield Me Me 3N HCl/MeOH 23 steps (longest linear) OTBS

Me Me Me HO Me Paterson 2001 * O O OH O NH2 Chiral Boron Reagent Addition Me Me OH O Me Me OH

Me Me Me OTBS OBL 2 O Me MeO2C + OTBS OH Me Me Me Me OTBS

Me Me Me Me Me Me HO HO Me Me + O OH O NH2 O OH O NH2 MeO2C Me Me MeO2C Me Me OH O OH O Me Me Me Me OH OH R S yield nu Me Cy2BCl 88 12 67 O H H Me (+)-Ipc2BCl 16 84 87 RL O (—)-Ipc2BCl* 97 3 88 H H RL nu “..the first example of a chiral boron reagent overturning the intrinsic stereoselectivity of a complex aldol coupling between chiral carbonyl compounds”

8 Me Me Me HO Paterson 2003, Second Generation Me O O OH O NH2 Tri-substituted olefin Me Me OH O Me Me OH

1. MeO O C2F5O C F O P Me Me Me 2 5 Me Me CO Me O 2 PMBO H 18-C-6, KHMDS PMBO 1. DIBAL Me OH O 2. TBSOTf OTBS 2. PPh3, I2, imid 72% yield (from diol precursor)

CO2Ar I Me Me Me Me Me LiHMDS PMBO PMBO Ar = OMe Me O Me OH Me OAr * OH Me 65% yield, 3 steps

* the electron-donating 4-OMe aryl ester was needed to alkylate the iodide, no loss in yields for subsequent steps in comparison to previous route

Me Me Me HO Paterson 2003, Second Generation Me O O OH O NH2 Remote 1,6-Asymmetric Induction in Aldol Coupling Me Me * OH O Me Me OH

Model Studies on 1,6 Induction: Me i-PrCHO 6 Me Me OH O 1 Me Me TBSO OTBS 81:19 d.r. Me Me O Me Me Cy2BCl Et2N, Et2O; OTBS O Me Me Me OTBS OH O Me TBSO OTBS Me TBSO OTBS 82:18 d.r. Me Me O Me Me

OTBS OPMB Rlarge Me Me OTBS OPMB OH O Me 1 Me H L TBSO OTBS >95:5 d.r. match!! H B O L - enolate is constrained in lower energy conformation 6 O R - A(1,3) strain is minimized - other steric clashes avoided

9 Me Me Me HO Paterson 2003, Second Generation Me O O OH O NH2 Remote 1,6-Asymmetric Induction in Aldol Coupling Me Me on Real System OH O Me Me OH

Me Me Me Me Me Me Cy2BCl*, O Me Et3N, Et2O Me Me HO OH O NH Me Me 2 MeO2C Me Me O OTBS O NH2 Me Me MeO2C OH O TBSO O Me Me TBSO O OTBS 64% yield, >95:5 d.r.

Me Me Me 1. AcOH, THF/H2O HO 2. K-Selectride Me

O O OH O NH2 3. HCl, MeOH Me Me OH O 68% yield, 3 step Me Me 97:3 d.r. on reduction OH 5.1% overall yield, 24 linear steps (35 total)

previous coupling: 5:1 d.r. for Aldol present: >19:1 d.r. for Aldol

* the lithium enolate proceeds with Felkin-Ahn induction and gives the wrong stereochemistry at C5

Smith 1995 Retrosynthesis

Me Me Me 8 HO 15 9 Me 21 O O OH O NH2 Me Me 13 OH O Me Me OH

8 TBSO Me Me Me O Me Me X X Z O PMBO * * * 21 * * * Me 15 9 13 OTBS O O * * OTBS Me * Me PMP OTBS

Me Me OMe PMBO N * * * Me OTBS O Common Precursor (CP)

Smith, A. B. III.,et al. J. Am. Chem. Soc. 1995, 117, 12011. Smith, A. B. III.,et al. J. Am. Chem. Soc. 2000, 122, 8654.

10 Me Me Me HO Smith 1995 Me O O OH O NH Synthesis of Common Precursor Me Me 2 OH O Me Me OH

! Smith's approach to proceed from a common precursor was adopted by Novartis ! Utilizes Evans oxazolidinone Aldol chemistry to set the stereotriad Bn

N O Bn Me Me Me Me Me 3 steps* O O HO OMe PMBO H PMBO N O 64% yield Bu2BOTf, Et3N O O 89% yield OH O O oil

Me Ph 1. HN(Me)OMe HCl Bu2BOTf, Et3N AlMe3, THF N O 89% yield Me 52-55% for 4 steps 2. TBSOTf O O

1. HN(Me)OMe HCl Me Me OMe Me Ph AlMe3, THF PMBO N Me Me 98% yield * * * Me PMBO N O 2. TBSOTf OTBS O OH O O Common Precursor (CP) crystalline, mp 112-113°C

! Yield of norephedrine-based Aldol was 64-70% on 60-70 g scales, 55% for all 4 steps with recrystallization, auxiliary recovery was 80-90% * 1. PMBO(C=NH)CCl3, PPTs. 2. LAH. 3. Swern.

Me Me Me HO Smith 1995 Me O O OH O NH Elaboration of Common Precursor Me Me 2 OH O Me Me OH

! Polypropionate elaboration for C15-C21 ! A subsequent Evans syn Aldol - one diastereomer for stereopentad Bn Bn Me Me N O Me Me Me Me Me OMe 1. HF·pyr Me H N O PMBO N 2. DDQ (86%) O O Me 3. LAH O O O Bu2BOTf, Et3N O O OH O O OTBS O all crystalline 89% yield (CP) PMP PMP

! A diastereoselective diathiane addition for C1-C8 Me Me OMe Me Me OBn Me Me PMBO N 5 steps S OMe t-BuLi, THF, HMPA OMe Me 66% yield S S OTBS O S OTBS OMe BnO OH OTBS OMe O (CP)

OBn Me Me 1. PhI(CF3CO2)2 OMe 2. Me4NBH(OAc)3 >99:1 anti:syn OH OH OTBS OMe

11 Me Me Me HO Smith 1995 Me O O OH O NH Elaboration of Common Precursor for Trisubstituted Olefin Me Me 2 OH O Me Me OH ! Vinyl Bromide for Cuprate Addition to alkyl iodide

Me Me Br Me Me PMBO [Ph3PCBr2Me] Br CP PMBO H Me nBuLi, THF OTBS B OTBS O 40%, 4:1 Z:E

LiBHEt3 Me Me Br 91% PMBO R Ph3P=CBrCO2Et, PhH, ! 84%, 8.5:1 Z:E OTBS R = CO2Et DIBAL, 85% R = CH OH 2 MsCl, Et N, 99% R = CH2OMs 3 ! Cuprate Addition is Unsuccessful

t-BuLi (2 equiv) THF, -78 °C Me Me Me Me B + Bu4NCu(CN)2 A, -78 °C 8% yield Me Me Me O O OTBS OTBS I Me i. t-BuLi (2 equiv), Et O, -78 °C 2 PMP O O OTBS ii. MgBr2 Me A iii. B, PdCl (dppf), Et O, RT OPMB PMB 2 2 14% yield

Me Me Me HO Smith 1995 Me O O OH O NH Elaboration of Common Precursor for Trisubstituted Olefin Me Me 2 OH O Me Me OH ! Vinyl Iodide for Negishi coupling to alkyl iodide

Me Me Me Me I NaHMDS, THF PMBO O PMBO 40-46% yield Me IPh3P I 8-17:1 Z/E OTBS OTBS C Me Zhao-Wittig: Chen, J.; Wang, T.; Zhao, K. Tet. Lett. 1994, 35, 2827.

! loss of I in C is major byproduct due to poor solubility of iodine in THF, addition of 0.1M I2 in THF circumvents this

! Negishi coupling is efficient

Me Me Me Me Me Me I t-BuLi (3 equiv) Zn

O O OTBS Et2O O O OTBS + ZnCl2 (premixed) -78 °C to RT PMP A PMP

Me Me Me Me

b) C, Pd(PPh3)4 (5 mol %) Et O, RT O O OTBS OTBS C9 for Wittig 2 Me 66% yield PMP OPMB Me

12 Me Me Me HO Smith 1995 Me O O OH O NH Wittig Olefination for Cis C8-C9 Olefin Me Me 2 OH O Me Me ! Problems in making alkyl iodide OH

Me Me Me Me Me Me Me Me R = Ts: I R = OH: PPh3, I2 O O OTBS OTBS O O OTBS OTBS Me Me PMP OR PMP I Me Me ! Turn to model systems and solvent effects Me Me Me OTBS OH OTBS I PPh3, I2, imid Me Me + Me + Me CH3CN/Et2O: 9:1:1 Me Me Me CH3CN/PhH: 18:1:1 Me Me Me TBSO Me TBSO Me

Ph3PO I H H H Me OTBS OTBS OTBS Me Me Me Mr Me Me Me I Me Me

! More polar solvents promote cyclization (MeCN or MeCN/Et2O), less polar solvents favor iodide

Me Me Me HO Smith 1995 Me O O OH O NH Wittig Olefination for Cis C8-C9 Olefin Me Me 2 OH O Me Me ! High pressure necessary to form Wittig OH

Me Me Me Me Me Me Me Me PPh3 (4 equiv) DIPEA (0.5 equiv) O O OTBS OTBS PhH/PhMe (7:3) O O OTBS OTBS Me 12.8 kbar, 6d Me PMP I 70% yield PMP PPh3I Me Me

! addition of base necessary to absorb HI that forms and causes decomposition of starting iodide

! Wittig reaction proceeds smoothly Me Me Me Me

Me Me Me Me NaHMDS, THF; O O OTBS OTBS Me TBSO CHO Me PMP O O OTBS OTBS Me Me TBSO TBSO PMP PPh3I Me Me O Me TBSO SEt O -78 °C to RT Me 76%, >49:1 Z/E SEt

13 Me Me Me HO Smith 1995 Me First Generation Endgame O O OH O NH Me Me 2 OH O Me Me ! Installation of (Z)-diene by Yamamoto protocol OH followed by thiol oxidation and deprotection

Me Me Me Me Me Me Me Me O

OPMB OTBS OTBS OPMB OTBS OTBS Me Me

Ph2P 1. HgCl , MeCN, THF Me 2 Me

TBSO t-BuLi, Ti(Oi-Pr)4 2. DMSO, Ac2O TBSO Me MeI, THF Me TBSO 70%, 16:1 Z/E 82%, 2 steps TBSO

O O Me Me SEt O (—)-Discodermolide 4 steps 1.043 g after reacrystallization 24 steps, longest linear 47% yield 6% overall yield

! Second generation synthesis changes the order of steps and eliminates dithane approach to lactone in favor of an allylsilane Ti-mediated addition to the CP

Me Me Me HO Smith 2003 Me

Third Generation Synthesis Approaches High Pressure Wittig O O OH O NH2 Me 14 Me OH O Me Me OH

! Without high pressure, the same byproducts emerge as with the original iodination R Me R OP I various OP PPh3I Me Me + Me + Me conditions R Me Me (P= TBS) RR Me Me PO Me PO Me A B C

! Absense of methyl at C14 leads to highly efficiently olefination (99% yield) ! Choice of protecting group at C11 is crucial (model studies done with R = Me at 100 °C) ! Explained by cyclization transition state P A (%) B/C (%) I H Ac 59 41 Me OTBS 63 34 Me SEM Me BOM 69 30 Me MOM 69 24 H 62 38 ! larger OP might promote a puckering of the TS chair, giving TBS 35 63 a predisposition to cyclization, a "reactive rotamer effect"

! smaller OP increase the rate of SN2 displacement by PPh3

Smith, A. B. III.; Freeze, B. S.; Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405.

14 Me Me Me HO Smith 2003 Me

Third Generation Synthesis Approaches High Pressure Wittig O O OH O NH2 Me 14 Me OH O Me Me OH

! Newer synthesis amenable to larger scale without high pressure

Me Me Me Me

1. PPh3, I2 (PhH/Et2O) i. MeLi LiBr, -78 °C OPMB OTBS OMOM Me 2. PPh3, DIPEA, 100 °C ii. TBSO CHO 70%, 2 steps Me Me TBSO

OH O Me 51%, 4:1 cis:trans O Me Me Me Me (90% BRSM)

OPMB OTBS OMOM Me 3 steps Me (+)-Discodermolide TBSO Me TBSO

O Me O Smith, A. B. III.; Freeze, B. S.; Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405.

Marshall 1998 Retrosynthesis 24 Me Me Me 8 HO 15 Me 7

O O OH O NH2 Me Me 1 13 OH O Me Me OH

24 Me Me Me Me Me Me Me O 15 1 + 8 13 + 7 OR2 OR2 OR1 R OR2 OR2 OR2 OR2 OR1

Me Me Me Me

1

OR2 OR2 OR2 OR2 OAc OPiv

Me SnBu3 R O Me 1 H + H R O

Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.

15 Diastereoselective Additions of Chiral Allenyl Stannanes Marshall reports diastereoselective additions of allenyl stannanes to aldehydes by SE' addition

O Me X R 1 H MLn + Y Me Y Bu3Sn M = B, Mg, Sn, Ti, In X R1 OH ! Preparation of Chiral Allenyl Stannanes in about 90% e.e.

O Me Darvon-OH ent-Darvon-OH Me R1 Bn NMe2 LAH Me LAH Bn NMe2 HO Ph HO Ph

OR OR R = H R = H R R 1 MsCl, Et3N 1 Me H H R = Ms R = Ms Me

Bu3SnLi Bu3SnLi CuBr Me2S CuBr Me2S R1 = Et, n-C7H15 R OP (P = H, TBS, Ts) R 1 Me 1 H H OP (P = H, TBS, Ac) Me Bu3Sn Bu3Sn

! Allenyl stannanes are stable to storage, silica, and excess cuprate without racemization or isomerization ! Cuprate addition is highly ANTI selective to give one allene isomer

Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1992, 57, 1242. Ruitenberg, K. et al. J. Organomet. Chem. 1983, 241, 417.

Diastereoselective Additions of Chiral Allenyl Stannanes

! Achiral aldehyde additions - not so useful

Me Me C H 7 15 (R) (R) Me RCHO R R H + (S) A or B Bu3Sn C7H15 OH C7H15 OH

A: BF3 OEt2, CH2Cl2, -78 °C. B: MgBr2 OEt2, CH2Cl2, -23 to 0 °C

R conditions yield % syn:anti

C6H13 A 83 39:61 B 56 66:34

i-Pr A 80 99:1 B 68 88:12 t-Bu A 92 99:1

! Unbranched alkyl aldehydes are not selective ! Achiral aldehydes not useful for anti additions ! Move to !-substituted chiral aldehydes - more rigidity to transition state

Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1992, 57, 1242. Ruitenberg, K. et al. J. Organomet. Chem. 1983, 241, 417.

16 Diastereoselective Additions of Chiral Allenyl Stannanes

! Chiral aldehyde additions

Me OBn Me OBn R A or B (R) (R) Me + H CH3 CH3 (S) Bu3Sn OBn C7H15 OH A C7H15 OH B

CH3 Me OBn Me OBn R O (S) (S) H + Me CH3 CH3 (R) Bu3Sn A or B C7H15 OH C C7H15 OH D

(R/S) - R conditions yield % A:B C:D

(S) - CH OAc A 95 68:32 2 B 97 >99:1 A 97 97:3 (R) - CH2OAc B 97 1:99 A: BF3 OEt2, CH2Cl2, -78 °C. B: MgBr2 OEt2, CH2Cl2, -23 to 0 °C (S) - Et A 92 87:13 B 98 >99:1

(R) - Et A 89 >99:1 B 95 1:99

! No efficient ways to produce anti,anti B ! Selectivity governed by Felkin-Ahn (for B) or Cram-chelation (for Mg) transition states ! Anti products are rarely observed with crotylstannanes

Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1992, 57, 1242.

Diastereoselective Additions of Chiral Allenyl Stannanes Transition State Analysis for Non-Chelating Case with BF3OEt2

O H H Me H Me BnO BnO H O (S) sterics sterics Me H A antiperiplanar Me H (S) B antiperiplanar

Bu Sn R 3 O Bu3Sn R Me H Me H (R) H OBn sterics C antiperiplanar

R SnBu3

! Felkin-Ahn TS for (S)-allene is complicated by conformation mobility of the aldehyde - selectivity degradation

Me OBn Me OBn R A or B (R) (R) Me + H CH3 CH3 (S) Bu3Sn OBn C7H15 OH A C7H15 OH B

CH3 O Me OBn Me OBn R (S) (S) H + Me CH3 CH3 (R) Bu3Sn A or B C7H15 OH C C7H15 OH D

(R/S) - R conditions yield % A:B C:D

(S) - CH OAc A 95 68:32 2 B 97 >99:1 A: BF3 OEt2 B: MgBr2 OEt2 A 97 97:3 (R) - CH2OAc B 97 1:99

17 Diastereoselective Additions of Chiral Allenyl Stannanes Transition State Analysis for Chelating Case with MgBr2OEt2 Br Br Mg O H Me BnO H sterics Me H (S) A antiperiplanar Br Br Mg O Bu3Sn R Br H Me Br SnBu3 BnO Mg H O R sterics H sterics Me H (R) C antiperiplanar BnO (R) D antiperiplanar H Me H Me R SnBu3

! Unfavorable steric interactions are insufficient to overcome antiperiplanar preference

Me OBn Me OBn R A or B (R) (R) Me + H CH3 CH3 (S) Bu3Sn OBn C7H15 OH A C7H15 OH B

CH3 O Me OBn Me OBn R (S) (S) H + Me CH3 CH3 (R) Bu3Sn A or B C7H15 OH C C7H15 OH D

(R/S) - R conditions yield % A:B C:D

(S) - CH OAc A 95 68:32 2 B 97 >99:1 A: BF3 OEt2 B: MgBr2 OEt2 A 97 97:3 (R) - CH2OAc B 97 1:99

Diastereoselective Additions of Chiral Allenyl Stannanes

! Chiral aldehyde additions

Me Me Me Me R A or B (R) (R) Me OBn OBn H + (S) Bu3Sn Me C7H15 OH E C7H15 OH F OBn Me Me Me Me R O (S) (S) H OBn OBn Me + (R) Bu3Sn A or B C7H15 OH G C7H15 OH H

(R/S) - R conditions yield % E:F G:H

(S) - CH OAc A 98 83:17 2 B 95 >99:1 A 96 >99:1 (R) - CH2OAc B 96 >99:1 A: BF3 OEt2, CH2Cl2, -78 °C. B: MgBr2 OEt2, CH2Cl2, -23 to 0 °C (S) - Et A 88 84:16 B 93 >99:1

(R) - Et A 92 >99:1 B 94 50:50

! No efficient ways to produce anti,anti H or anti,syn F ! Transition state analysis is similar to previous cases

Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1992, 57, 1242.

18 Transition States for Products E to H (R)-allene leads to interesting observations

OBn O Br2 Br2 H Me Mg Mg BnO O BnO O H H Me H Me Me H (S) E 83-99% H H Me H (S) Me H (R) G 50-99% Bu3Sn R

Bu3Sn R Bu3Sn R R Br SnBu 2 O (S) 3 Mg R Me BnO O SnBu3 Me F H H 1-17% (R) H H H OBn H 1-50% Me H Me

O Me H Me ! the 99:1 G:H ratio when R=CH2OAc is hypothesized to result from H OBn coordination of MgBr2 to the acetate, thus disfavoring chelation (R) H G 99% ! the 1:1 G:H ratio when R=Et is hypothesized to result from comparable energies for the two (R)-allene transition states R SnBu3

Me Me Me Me R A or B (R) (R) Me OBn OBn H + (S) Bu3Sn Me C7H15 OH E C7H15 OH F OBn Me Me Me Me R O (S) (S) H OBn OBn Me + (R) Bu3Sn A or B C7H15 OH G C7H15 OH H

Diastereoselective Additions of Chiral Allenyl Stannanes Inversion of Allene Stereochemistry with SnCl4

! Looking for a single strategy to give all 4 stereotriads ! Previous work gives efficient syntheses of syn,syn and syn,anti Me Me Me Me ! Now define conditions for anti,anti and anti,syn

OH OH Me Me Me Me

OH OH

! Addition of SnCl4 inverts stereochemistry of allene. Use with chiral aldehydes again for better selectivities and access to stereotriads.

Me Me R Me i-PrCHO (R) H Me (S) BF OEt Bu3Sn 3 2 acyclic TS R OH SnCl4 0 °C Me Me Cl Sn 3 i-PrCHO (R) Me Me H R (R) cyclic TS R OH

Marshall, J. A.; Wang, X.-j. J. Org. Chem. 1992, 57, 1242.

19 Diastereoselective Additions of Chiral Allenyl Stannanes Inversion of Allene Stereochemistry with SnCl4

! Solvent has a pronounced effect Me H Me Me Me Me R SnCl4 Cl3Sn Me 0 °C Me O OBn + H H (S) Bu3Sn R (R) -78°C R 1 OH OBn R 2 OH OBn

R solvent yield % 1 : 2

CH2OAc CH2Cl2 90 67 : 33 epimeric at aldehyde !-carbon!?!? CH2OAc hexanes 91 7 : 93 1 : 99 SnCl4 in CH2Cl2 leads to trace amounts of HCl C7H15 hexanes 81

! Cyclic transition states are very selective, and 1 is from aldehyde epimerization

Me H H Me Me H Me H Me H H OBn H (S) H H mismatch 2 (R) 1 (R) Me O OBn O OBn O R Sn Sn R Sn Sn R Sn Cl Cl Cl Cl 3 3 3 3 Cl3 anti,anti!!

Marshall, J. A.; Perkins, J. F.; Wolf, M. A. J. Org. Chem. 1995, 60, 5556.

Diastereoselective Additions of Chiral Allenyl Stannanes Inversion of Allene Stereochemistry with SnCl4 ! Mechanism of allene rearrangement

R SnCl4 SnCl4 SnCl Cl3Sn Me -78 °C 3 0 °C Me H R H (S) syn Me (R) Bu3Sn H R

! Propargyl stannane intermediate observed experimentally

Cl3 Sn H MeO Me OH Me -78 °C Me Me H Me R R 0 °C Marshall, J. A. et al. J. Org. Chem. 1995, 60, 5550

Cl3 Sn R O Me Me Me -78 °C Me Me R OH Me H

! Reproducibility can be problematic with SnCl4 - InI3 or SnBuCl3 also do allene inversion but have decreased selectivity (Marhsall, J. A.; Palovich, M. R. J. Org. Chem. 1997, 62, 2001.)

! Allenylsilanes can also be used with TiCl4 - all 4 stereotriads can be access by choice of chelating or non-chelating group on aldehyde (Marhsall, J. A.; Maxson, K. J. Org. Chem. 2000, 65, 603.)

20 Diastereoselective Additions of Chiral Allenyl Stannanes Summary

! Access to all 4 stereotriads from one allenyl stannane using reagent control

Me H OBn Me Me O OBn

BF3OEt2 R OH Me H OBn Me Me O OBn

MgBr2OEt2 R OH Me R H Bu3Sn

1. SnCl4, hexanes Me Me Me OBn H OBn 2. OH O R

1. SnCl4, hexanes Me Me Me OBn H OBn 2. R OH O

Marshall 1998 Retrosynthesis 24 Me Me Me 8 HO 15 Me 7

O O OH O NH2 Me Me 1 13 OH O Me Me OH

24 Me Me Me Me Me Me Me O 15 1 + 8 13 + 7 OR2 OR2 OR1 R OR2 OR2 OR2 OR2 OR1

Me Me Me Me

1

OR2 OR2 OR2 OR2 OAc OPiv

Me SnBu3 R O Me 1 H + H R O

Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.

21 Me Me Me HO Marshall 1998 Me O O OH O NH Stereotriad Syntheses Me Me 2 OH O Me Me OH

! C2-C4 and C10-C12 stereotriad from new allenylzinc addition (Marshall J. Org. Chem. 1998, 63, 3812) ! SnCl4 methodology proved to be problematic in reproducibility, BuSnCl3 gave 48% yield ! did not desire to use InI3 or InBr3 in large scale syntheses OMs Me Me Me Me H OTES H * OTES Pd(PPh3)4 (2.5 mol%) H O OH Et2Zn, THF 65-75% yield, 90:10 d.r.

! C16-C18 stereotriad from allenylstannane addition with BF3OEt2

OPiv H Me Me Me Me TBSO H SnBu3 TBSO

BF3OEt2 O OH 97% yield, >95:5 d.r. OPiv

Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.

Me Me Me HO Marshall 1998 Me O O OH O NH Stereotriad Syntheses Me Me 2 OH O Me Me OH

! C2-C4 and C10-C12 stereotriad from new allenylzinc addition (Marshall J. Org. Chem. 1998, 63, 3812) ! SnCl4 methodology proved to be problematic in reproducibility, BuSnCl3 gave 48% yield ! did not desire to use InI3 or InBr3 in large scale syntheses OMs Me Me Me Me H OTES H * OTES Pd(PPh3)4 (2.5 mol%) H O OH Et2Zn, THF

OMs C2H4, C2H6 Me 2 PPh3 Pd(PPh3)4 H

R Me H Et2Pd(PPh3)2 Ph3P Pd Ph P 3 OMs R Me R H Me Et Zn Zn H 2 Et Ph3P Pd Ph P EtZnOMs 3 Et EtZnOMs Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.

22 Me Me Me HO Marshall 1998 Me O O OH O NH Approach to Tri-substituted olefin Me Me 2 OH O Me Me OH

! A new approach to olefin formation - !-alkyl Suzuki coupling

! First must selectively form (Z)-vinyl iodide - Wittig reagent EtO OEt ! Wittig reagent is low yielding and not as selective as other methods Paterson: but amenable for large scale synthesis SePH ! Paterson's selenium reagent is toxic ! Panek uses a large excess of Schwartz's reagent

Panek: R TMS R TMS R I Cp2ZrHCl MeZnCl I2 R TMS I , 50 °C Pd(PPh ) 65% overall 2 I 3 4 Me Me

! Marshall: from Lindlar

Me Me I Me Me

Ph3P Me Me Me I O O O O O O O O O Me NaHMDS Me Me TBS MOM 40% yield TBS MOM PMP OMOM PMP OMOM 85:15 mix of isomers

Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.

Me Me Me HO Marshall 1998 Me O O OH O NH Approach to Tri-substituted olefin Me Me 2 OH O Me Me OH

! A new approach to olefin formation - !-alkyl Suzuki coupling

Me Me Me t-BuLi Me Me Me I 9-BBN-OMe B -78 °C OMe OPMB OTES OPMB OTES

Me Me ! used by Novartis on a 2.5 kg scale Me I PdCl2(dppf) ! Smith's Negishi coupling gave several K3PO4 O O O O Me Me inseparable by-products on large scale 74% yield TBS MOM PMP OMOM

Me Me Me Me Me

8 steps Me (+)-Discodermolide 23 steps (linear) O O O O OPMB OTES Me Me 5.4% overall yield TBS MOM PMP OMOM

Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.

23 Novartis Commercial Synthesis A mixture of Smith/Paterson/Marshall Syntheses

Me Me OMe Me Smith Smith Me Me I HO PMBO N PMBO CO2Me Me Me 9 13 OH O A OH Smith Smith Me Me Me

Me Me OMe I 6 21 Me N 15 Me O O OTBS

O OH O C PMP B

Me Me Me Me Me Me PMBO Marshall Me Paterson O A + B Me OTBS O O Me Me OTBS OPMB Me Me OTBS PMP OTBS

Paterson Me Me Me HO C OMe Me Me Me Paterson * (+)-Discodermolide (+)-Ipc BCl N OTBS OPMB 2 Me Me Me over 60 g! Et3N O OTBS OH OTBS 37 steps 4:1 d.r. 17 chromatographic purifications 43 chemists, 20 months to complete

Summary Discodermolide

! Several total syntheses and numerous formal syntheses

! Smith and Paterson and Marshall approaches were combined for the commercial synthesis by Novartis

! Other approaches detail novel ways to access stereotriads or stereopentad.

! none are as efficient as the approaches described here ! Schrieber, Myles, and Smith (2nd generation) utilizes lewis acid-mediated crotylations with allylsilanes or allyl stannanes - not useful for larger scale

! There is no practical, original way to set polypropionates for discodermolide

! Large scale preparation of discodermolide will allow for significant testing for anti-cancer activity and other health issues

24 Useful References Discodermolide ! Novartis synthesis Mickel, S. J. et al. Organic Process Research & Development. 2004, 8, 92-100. Mickel, S. J. et al. Organic Process Research & Development. 2004, 8, 101-106. Mickel, S. J. et al. Organic Process Research & Development. 2004, 8, 107-112. Mickel, S. J. et al. Organic Process Research & Development. 2004, 8, 113-121. Mickel, S. J. et al. Organic Process Research & Development. 2004, 8, 122-130.

! Paterson synthesis Paterson, I.; Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535-9544. Paterson, I.; Delgado, O.; Florence, G. J.; Lyothier, I.; Scott, J. P.; Sereining, N. Org. Lett. 2003,5, 35-38.

! Smith synthesis Smith, A. B.; Qiu, Y.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 1995, 117, 12011-12012. Smith, A. B. III; et al. J. Am. Chem. Soc. 2000, 122, 8654-8664. Smith, A. B. III; Freeze, B. S.; Brouard, I.; Hirose, T. Org. Lett. 2003, 5, 4405

! Marshall synthesis Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885-5892. Marshall, J. A.; Lu, Z.-H.; Johns, B. A. J. Org. Chem. 1998, 63, 817-823.

! Myles synthesis Harried, S. S.; Yang, G.; Strawn, M. A.; Myles, D. C. J. Org. Chem. 1997, 62, 6098-6099. Harried, S. S.; Lee, C. P.; Yang, G.; Lee, T. I. H. J. Org. Chem. 2003, 68, 6646-6660.

! Scrieber synthesis Nerenberg, J. B.; Hung, D. T.; Somers, P. K.; Schreiber, S. L. J. Am. Chem. Soc. 1993, 115, 12621-12622. Hung. D. T.; Nerenberg, J. B.; Schreiber, S. L. J. Am. Chem. Soc. 1996, 118, 11054-11080.

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