WO2007087220A2 - The total synthesis of ecteinascidin 743 and derivatives thereof - Google Patents

Abstract

This invention provides a method of synthesizing ecteinascidin 743 and derivatives. This invention also provides intermediate compounds and methods of treating tumors.

Description

THE TOTAL SYNTHESIS OF ECTEINASCIDIN 743 AND DERIVATIVES THEREOF

The invention disclosed herein was made with Government support under grant no. HL25848 from National Institutes of Health. Accordingly, the U.S. Government has certain rights in this invention.

Throughout this application, various publications are referenced by numbers in parentheses, and their full citations may be found at the end of the specification. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.

Background of the Invention

Compounds that contain a two tetrahydroisoquiηoline aromatic carbon nitrogen framework have consistently demonstrated anti-tumor and anti-proliferative effects (see refs. 31-34). One such, compound is the powerful anti-tumor agent ecteinascidin 743. A drawback of this compound, however, is its natural scarcity.

Here, a new strategy was designed for the construction of the pentacyclic ring system of ecteinascidin 743 via a shorter total synthesis route than has previously been realized. Summary

In one embodiment, this invention provides a compound having the structure :

wherein

Ri is a Ci-C₄ alkyl, H, or -C(O) (Ci-C₄ alkyl),

R₂ is a Ci-C₄ alkyl, -0(C₁-C₄ alkyl), -S(C₁-C₄ alkyl),

R₃ is H, OH, -0(C₁-C₄ alkyl) or a halogen,

R₄ is H, OH, or a halogen,

R₅ is 0 and bond φ is present, or R₅ is -CN, OH or -

0(C₁-C₄ alkyl) and bond φ is absent,

R₆ is -0-benzyl, OH, H, -0(Ci-C₄ alkyl), or

OSi (CH₃) ₂ (t-butyl) , or R₆ and R₅ are joined to form an

-0- and bond φ is absent,

R₇ and R₈ form a methylenedioxy group, or are each independently -C₁-C₄ alkyl or -0(Ci-C₄ alkyl) ,

R₉ is a C₁-C₄ alkyl , -0 ( C₁-C₄ alkyl ) , or -S (Ci-C₄ alkyl ) , Ri₀ is H, methoxymethyl , tert -butyldimethylsiIyI, or a Ci-C₄ alkyl, -CH₂(C₆H₅), phenyl, allyl, or -C(O) (Q₁- C₄ alkyl) ,

Rn is H, OH, -0(Ci-C₄ alkyl), -O-benzyl, -0(C)OH, - OC(O)(C₁-C₄ alkyl), or -OSi (CHj) ₂ (t-butyl) , and bond η is absent, or Rn is 0 and bond η is present, Ri2 is H, or OH, and bond α is absent, or R₁₂ is absent and bond α is present, or Ri₂ and Rn are joined to form an -0- and bonds α and η are absent, R₁₃ is PMBO and bonds β, γ and δ are absent, or Ri₃ is H, or Ri3 is 0 and bond γ is present,

Ri₄ is H, CH₃ or Troc and bond ε is absent and Ri₅ is absent, or Ri₄ is CH₃, bond ε is present, R₁₅ is Boc and bonds β and δ are absent, and Ri₆ is OH, -O-benzyl, PMBO or -O-allyl, (C_x-C₄) alkyl , or -C(O) (C_x-C₄) alkyl,

wherein when R_X4 is CH₃ and R₁₅ is absent, then R_X2 is OH; or an enantiomer, tautomer or salt of the compound.

Brief Description of the Figures

Fig. 1 In a new synthesis of ectinascidin 743 the configurationally matched and enantiopure A is ultimately converted to B via a novel vinylogous Pictet-Spengler cyclyzation and to C via a stereospecific epoxidation and regioselective reduction sequence of the C3-C4 enamide.

Fig. 2 Desired Mannich cyclyzation of 3 to 2s. Ecteinascidin 743 is structure 1.

Fig. 3 Alpha-face hydration (3 OH_α, 4-0H_α) of the C3-C4 double bond.

Fig. 4 Envisioned cyclyzation via iminium derivative upon cleavage of Boc group from N12.

Fig. 5 Synthesis from Borchardt catechol. Reagents and conditions: a) i) Br₂ (1.01 equiv) , NaOAc (1.05 equiv) ,

AcOH, 0°C→25°C, 12 h, ii) BrCH₂Cl (1.5 equiv), Cs₂CO₃ (1.5 equiv), DMF, 105⁰C, 12 h, 65%; b) i) mCPBA (3 equiv),

25°C→64°C, 3 h, ii) HCl (0.3 equiv) , 0°C→25°C, 12 h, 78%; c) TBDPSCl (1.15 equiv), TEA (1.5 equiv), DMAP (0.1 equiv), 25°C, 12 h, 89%; d) i) 1.6 M n-BuLi (1.1 equiv), toluene:THF (9:1), -78⁰C, 20 min, ii) neat

Me(MeO)NC(O)CH₂OBn (1.5 equiv), -78°C, 50 min, 80%; e)

Noyori (R, R) catalyst (0.01 equiv), HCO₂H (13.2 equiv) ,

TEA (7.8 equiv), DMF, 0°C→40°C, 24 h, 78% (95% ee) ; f) DPPA (2 equiv), DBU (2 equiv) , toluene:DMF (9:1) , 5O⁰C, 24 h, 89% (95% ee) ; g) 1 atm H₂, 5% Pd/C, EtOAc, 25^°C, 15 h,

80%; h) i) (MeO)₂CHCHO (1 equiv) , AcOH (4 equiv) , NaCNBH₃ (1.3 equiv) , MgSO₄ (6 equiv) , MeOH, 0°C->65°C, 4 h, ii)

TBAF (1.5 equiv), THF, O⁰C, 30 min, 94%; i) allyl bromide (1.15 equiv), NaH (2.8 equiv), DMF, 0°C→25°C, 2 h, 84%; j) 7 M HCl (70 equiv), Dioxane, 0°C→25°C, 72 h, 90%.

Fig. 6 Reagents and conditions: a) BOPCl (1.1 equiv),

TEA (3 equiv), CH₂Cl₂, 0°C→25°C, 24 h, 85%; b) DDQ (1.6 equiv), CH₂Cl₂ :pH 7.00 Buffer solution (18:1), 25°C, 30 min, 90%; c) Cu(OTf)2 (0.2 equiv), benzene, 85°C, 15 min, 61%; d) DMP (1.5 equiv), CH₂Cl₂, 25⁰C, 5 h, 94%; e)

(Ph₃P)₂PdCl₂ (0.2 equiv) , Bu₃SnH (1.2 equiv), AcOH (5 equiv), 0°C→25°C, 1 h, 93%; f) CHF₂CO₂H (30 equiv), MgSO₄

(4 equiv), benzene, 100⁰C, 45 min, 42-58%.

Fig. 7 Functionalization of C3-C4 double bond.

Fig. 8 Reagents and conditions: a) DMDO (1.5 equiv), CH₂Cl₂, 0°C→25°C, 30 min; b) NaCNBH₃ (5 equiv) , 10 min, 75%.

Fig. 9 Reagents and conditions: a) TBSOTf (2.5 equiv),

TEA (3 equiv), CH₂Cl₂, O⁰C, 30 min, 100%; b) TrocCl (20 equiv), TBAI (3 equiv), toluene, 110⁰C, 3 h, 92%; c) i) TBAF (3 equiv), CH₂Cl₂, 0⁰C, 2 min, ii) MOMCl (3 equiv) , Hϋnig's base (5 equiv), 30 nun, 79%; d) DMDO (2 equiv) , CH₇Cl₂, 0°C→25°C, 1.5 h; e) NaCNBH₃ (5 equiv), 10 min, (27:26) 60%:10%; f) NaCNBH₃ (50 equiv), 10 min, (26) 78%.

Fig. 10 Mechanistic hypotheses for formation of ketone. Fig. 11 Installation of cyano function. Reagents and conditions: a) 1 atm H₂, 10% Pd/C, EtOAc, 25°C, 3 h, 77%; b) DIBAL : BuLi (1:1) (40 equiv) , THF, 0⁰C, 5 h, 78%; c) allyl bromide (20 equiv), Hϋnig's base (25 equiv), CH₂Cl₂, 5O⁰C, 16 h, 66%; d) KCN (9 equiv), AcOH, 25⁰C, 4 h, 79%; e) TFA (1 equiv), CH₂Cl₂, -20⁰C, 30 min, 54%.

Fig. 12 Asembley of pentacyclic ring system of cytotoxic tetrahydroisoquinoline alkaloids.

Fig. 13 Michael -like cyclization via cysteinic sulfur.

Fig. 14 Lynchpin Mannich cyclization.

Fig. 15 Asymmetric synthesis. Reagents and conditions: a) 8% (D)-DET, 5.6% Ti(Oi-Pr)₄, t-BuOOH (2 equiv), m.s. 4 A, -20⁰C, 24 h, 98% (95% ee) ; b) Ti (Oi-Pr) ₂ (N₃) _z (3.5 equiv) , benzene, 8O⁰C, 5 h, 76% (single isomer) ; c) (MeO)₂CMe₂: acetone (1:2), cat. p-TsOH»H2O, 25°C, 10 min, 100%; d) 1 atm H₂, 10% Pd/C, EtOAc, (BoC)₂O (1.2 equiv), 25⁰C, 5 h, 100%; e) TBAF (1.5 equiv) , THF, 25⁰C, 1 h, 99%; f) PMBCl (1.2 equiv), NaH (2 equiv), cat. TBAI, THF:DMF (5:1), 0°C->25°C, 5 h, 98%; g) MeI (xs) , NaH (5 equiv), THF:DMF (5:1), reflux, 12 h, 93%; h) i) 80% AcOH, 25⁰C, 12 h, ii) KMnO₄ (0.2 equiv), NaIO₄ (4 equiv), Na₂CO₃ (0.5 equiv), dioxane:H₂0 (2.5:1), 25°C, 10 h, 95%.

Fig. 16 Reagents and conditions: a) BOPCl (1.1 equiv),

Et₃N (2.5 equiv), CH₂Cl₂, 25⁰C, 12 h, 63%; b) DMP (1.5 equiv), CH₂Cl₂, 25°C, 30 min, 78%; c) DDQ (1.5 equiv),

CH₂Cl₂ :pH 7.00 Buffer solution (18:1), 25°C, 3 h, 84%; d)

SUBSΗTUTE SHEET (RULE 26) DMP (1.5 equiv) , CH₂Cl₂, 25°C, 30 min, 85%; e) formic acid, 100⁰C, 5 h, 75%.

Pig. 17 Reagents and conditions: a) MOMCl (1.2 equiv) , DIEA (1.5 equiv), CH₂Cl₂, 25⁰C, 12 h, 80%; b) BrCH₂CH=CHCH₂OTBS (1.1 equiv), K₂CO₃ (1.5 equiv), CH₃CN, 80^°C, 5 h, 95%; c) Me₂NPh (1.1 equiv), toluene, 21O⁰C, 12 h, 96%; d) MeI (xs) , K₂CO₃ (1.5 equiv), CH₃CN, 80⁰C, 12 h, 87%; e) TBAF (1.5 equiv), THF, 25°C, 1 h, 99%; f) PivCl (1.1 equiv), pyridine: CH₂Cl₂ (1:20), 25°C, 3 h, 99%; g) 3N HCl, THF:IPA (2:1) , 25⁰C, 12 h, 99%; h) Et₂AlCl (3 equiv) , (CH₂O)n (xs), CH₂Cl₂, 0°C→25°C, 12 h, 96%; i) (t- Bu₂)Si(OTf)₂ (1.2 equiv) , 2,6-lutidine (1.5 equiv), CHCl₃, O⁰C, 3 h, 85%; j) DIBAL-H (2.5 equiv), CH₂Cl₂, -78°C, 30 min, 94%; k) 8% (D)-DET, 5.6% Ti(Oi-Pr)4, t-BuOOH (2 equiv), m.s. 4 A, -20⁰C, 24 h, 98% (95% ee) ; 1) Ti(Oi- Pr)₂(N₃)₂ (3.5 equiv), benzene, 8O⁰C, 5 h, 76% (single isomer) ; m) (MeO) ₂CMe₂: acetone (1:2), cat. p-TsOH»H₂O, 25°C, 10 min, 100%; n) 1 atm H₂, 10% Pd/C, EtOAc, (Boc)₂O (1.2 equiv) , 25°C, 5 h, 100%; o) TBAF (1.5 equiv), THF, 25°C, 1 h, 99%; p) BnBr (1.2 equiv) , K₂CO₃ (1.5 equiv) , CHCl₃ :MeOH (2:1), 25⁰C, 12 h, 83% q) PMBCl (1.2 equiv), NaH (2 equiv) , cat. TBAI, THF:DMF (5:1) , 0°C-»25°C, 5 h, 98%; r) MeI (xs), NaH (5 equiv), THFiDMF (5:1) , reflux, 12 h, 93%; s) i) 80% AcOH, 25°C, 12 h, ii) KMnO₄ (0.2 equiv), NaIO₄ (4 equiv), Na₂CO₃ (0.5 equiv), dioxane:H₂O (2.5:1) , 25⁰C, 10 h, 95%; t) 46 (1.2 equiv) , BOPCl (1.1 equiv), Et₃N (2.5 equiv), CH₂Cl₂, 25°C, 12 h, 63%; u) DMP (1^'.5 equiv) , CH₂Cl₂, 25⁰C, 30 min, 78%; v) DDQ (1.5 equiv), CH₂Cl₂ :pH 7.00 Buffer solution (18:1), 25⁰C, 3 h, 84%; w) DMP (1.5 equiv) , CH₂Cl₂, 25°C, 30 min, 85%; x) formic acid, 100⁰C, 5 h, 75%.

Fig. 18 Cyclization of potential ecteinascidin precursors. Reagents and conditions: a) 18 (1.2 equiv) ,

BOPCl (1.1 equiv) , Et₃N (2.5 equiv) , CH₂Cl₂, 25°C, 24 h,

85%; b) DMP (1.5 equiv) , CH₂Cl₂, 25⁰C, 30 min, 83%; c) DDQ

(1.5 equiv) , CH₂Cl₂:pH 7.00 Buffer solution (18:1) , 25°C,

3 h, 90%; d) DMP (1.5 equiv) , CH₂Cl₂, 25°C, 30 min, 94%; e) formic acid, 100°C, 10 min, 70%.

Fig. 19 Azidolysis. Reagents and conditions: a) Ti(Oi- Pr)₂(N₃J₂ (3.5 equiv) , benzene, 8O⁰C, 5 h, 76% (single isomer) ; b) (MeO) ₂CMe₂ : acetone (1:2) , cat. p-TsOH«H₂O, 25⁰C, 10 min, 100%; c) 1 atm H₂, 10% Pd/C, EtOAc, (BoC)₂O (1.2 equiv) , 25°C, 5 h, 100%; d) TBAF (1.5 equiv) , THF, 25°C, 1 h, 99%; e) PMBCl (1.2 equiv) , NaH (2 equiv) , cat. TBAI, THF:DMF (5:1) , 0°C→25°C, 5 h, 98%; f) MeI (xs) , NaH (5 equiv) , THF=DMF (5:1) , reflux, 12 h, 93%; g) i) 80% AcOH, 25°C, 12 h, ii) KMnO₄ (0.2 equiv) , NaIO₄ (4 equiv) , Na₂CO₃ (0.5 equiv) , dioxane:H₂0 (2.5:1) , 25°C, 10 h, 95%; h) BOPCl (1.1 equiv) , Et₃N (2.5 equiv) , CH₂Cl₂, 25⁰C, 12 h, 63%; i) DMP (1.5 equiv) , CH₂Cl₂, 25°C, 30 min, 78%; j) DDQ (1.5 equiv) , CH₂Cl₂:pH 7.00 Buffer solution (18:1) , 25⁰C, 3 h, 84%; k) DMP (1.5 equiv) , CH₂Cl₂, 25°C, 30 min, 85%; 1) formic acid, 100⁰C, 5 h, 75%.

Fig. 20 Route from iodo aromatic precursor. Reagents and conditions: a) see reference 6; b) Rh[ (COD) - (S, S) -Et- DuPhOs]⁺TfO^" (0.008 equiv) , 100 psi H₂, CH₂Cl₂:Me0H (1:1) ,

25°C, 72 h, 93%, 99% ee ; c) LiOH (3 equiv) , MeOH:THF:H₂O (1:3:1) ), 0°C→25°C, 11 h, 93%; d) MeI (2.2 equiv) , NaH

(3.3 equiv), THF), 0°C→25°C, 15 h, 82%; e) 1 atm H₂, 10% Pd/C, EtOAc, 25°C, 2 h, 99%; f) Fremy's salt (10 equiv), 2 M aq. NaH₂PO₄, acetone, 25°C, 75%; g) Zn (400 equiv) , AcOH (400 equiv) , CH₂Cl₂, 25°C, 95%; h) MeI (5 equiv) , Cs₂CO₃ (5 equiv), DMF, 25°C, 75%; i) 42 (1 equiv), BOPCl (1.1 equiv), Et₃N (2.5 equiv), CH₂Cl₂, 25⁰C) 12 h, 66%; j) DMP (1.5 equiv), CH₂Cl₂, 25⁰C, 30 min, 78%; k) DDQ (1.5 equiv), CH₂Cl₂ :pH 7.00 Buffer solution (18:1), 25°C, 3 h, 90%; 1) DMP (1.5 equiv), CH₂Cl₂, 25⁰C, 30 min, 95%; in) formic acid, 100⁰C, 5 h, 75%.

Detailed Description

This invention provides a compound having the structure:

wherein

R₁ is a C_x-C₄ alkyl, H, or -C(O) (C₁-C₄ alkyl) ,

R₂ is a Ci-C₄ alkyl, -0(Ci-C₄ alkyl), -S(Ci-C₄ alkyl), R₃ is H, OH, -0(Ci-C₄ alkyl) or a halogen,

R₄ is H, OH, or a halogen,

R₅ is 0 and bond φ is present, or R₅ is -CN, OH or -0(C₁-C₄ alkyl) and bond φ is absent,

R₆ is -0-benzyl, OH, H, -0(Ci-C₄ alkyl), or -OSi (CH₃) ₂ (t- butyl) , or R₆ and Rs are joined to form an -0- and bond φ is absent,

R₇ and R₈ form a methylenedioxy group, or are each independently -Ci-C₄ alkyl or -0(Ci-C₄ alkyl) ,

R₉ is a Ci-C₄ alkyl, -0(Ci-C₄ alkyl) , or -S(Ci-C₄ alkyl), R₁₀ is H, methoxymethyl, tert-butyldimethylsilyl, or a Ci-

C₄ alkyl, -CH₂(C₆H₅), phenyl, allyl, or -C(O) (C₁-C₄ alkyl), Rn is H, OH, -0(C₁-C₄ alkyl), -O-benzyl, -0(C)OH, -

OC(O) (C₁-C₄ alkyl), or -OSi (CH₃) ₂ (t-butyl) , and bond η is absent, or R₁₁ is 0 and bond η is present,

R₁₂ is H, or OH, and bond α is absent, or R₁₂ is absent and bond α is present, or R₁₂ and R₁₁ ^' are joined to form an -0- and bonds α and η are absent,

R₁₃ is PMBO and bonds β, γ and δ are absent, or R₁₃ is H, or R₁₃ is O and bond γ is present,

R₁₄ is H, CH₃ or Troc and bond ε is absent and R₁₅ is absent, or R₁₄ is CH₃, bond ε is present, R_1S is Boc and bonds β and δ are absent, and

Rie is OH,. -0-benzyl, PMBO or -0-allyl, (C₁-C₄) alkyl, or -

C(O) (C₁-C₄) alkyl, wherein when R₁₄ is CH₃ and R₁₅ is absent, then R₁₂ is OH,- or an enantiomer, tautomer or salt of the compound.

In embodiments of the instant compound,

R₁ is methyl,

R₂ is a methyl, R₃ is H,

R₄ is H,

R₅ is 0 and bond φ is present, or R₅ is CN and bond φ is absent, or R₅ is joined directly to R₆ to form an -0- and bond φ is absent, R₆ is -O-benzyl or OH,

R₇ and Rs form a methylenedioxy group,

R₉ is methyl,

R₁₀ is methyl, H, methoxymethyl, tert-butyldimethylsilyl , or allyl, R₁₁ is H or OH and bond η is absent, or Ri₁ is joined directly to R₁₂ to form -0-, or R_1I is 0 and bond η is present , Ri₂ is joined to R₁₁ by an 0 atom, or R₁₂ is H, or OH, or is absent ,

Ri₃ is PMBO and bonds β, γ and δ are absent, or R₁₃ is H, or Ri₃ is 0 and bond γ is present, and R₁₄ is CH₃ or Troc and bond ε is absent and R₁₅ is absent, or R₁₄ is CH₃, bond ε is present, and R₁₅ is Boc and bonds β and δ are absent , and Ris is OH, -O-benzyl, PMBO or -0-allyl .

In embodiments of the instant compound, R₂ is -OCH₃, OC₂H₅, -SCH₃ or -SC₂H₅.

In an embodiment of the instant compound, R₃ is -OCH₃.

In an embodiment of the instant compound, R₅ is -OCH₃.

In embodiments of the instant compound, R₉ is -OCH₃, OC₂H₅, -SCH₃ or -SC₂H₅.

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure :

One embodiment of the instant compound has the structure :

One embodiment of the instant compound has the structure ;

One embodiment of the instant compound has the structure;

One embodiment of the instant compound has the structure;

One embodiment of the instant compound has the structure :

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure :

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure :

One embodiment of the instant compound has the structure :

One embodiment of the instant compound has the structure:

This invention provides a compound having the structure :

wherein

R₁₇ is -OTBDPS or -O-allyl, and wherein Ri₈ is a halide, -C(O)CH₂OBn, -C(OH)(H)CH₂OBn, -C(N₃)CH₂OBn, -C(NHCH₂C(OMe)₂H)CH₂OBn, or

C(H)CH₂OBn)NHCH₂C^H(OH) wherein carbon ξ is covalently attached to carbon ψ to form a ring, and Rig is a C1-C4 alkyl, -0(Ci-C₄ alkyl) , -S(Ci-C₄ alkyl) .

In one embodiment of the instant compound, R₁₇ is -OTBDPS or -O-allyl,

R₁₈ is a halide, -C(O)CH₂OBn, -C(OH) (H)CH₂OBn, C(N₃)CH₂OBn, -C(NHCH₂C(OMe)₂H)CH₂OBn, or

C (H) CH₂OBn) NHCH₂C^ξH (OH) wherein carbon ξ is covalently attached to carbon ψ to form a ring, and Ri₉ is CH₃.

In one embodiment of the instant compound, Ri₉ is -OCH₃, OC₂H₅, -SCH₃ or -SC₂H₅.

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure:

One embodiment of the instant compound has the structure:

One embodiment of the instant compound the structure :

One embodiment of the instant compound has the structure:

This invention also provides a process for making a compound having the structure :

comprising:

a) exposing a compound having the structure:

to Br₂; NaOAc, in AcOH, then

BrCH₂Cl, Cs₂CO₃, in N,N-dimethylforτnamide, then m-choloroperoxybenzoic acid and then acidifying with HCl, then tert-butyldiphenylsilyl-Cl, triethylamine, in 4- (dimethylamino) pyridine so as to produce a compound having the structure:

b) exposing the product of step a) to nBuLi in toluene/THF, then neat Me-(MeO)NC(O)CH₂OBn so as to produce a compound having the structure:

c) exposing the product of step b) to Noyori R₁R catalyst, HCO₂H, and triethylatnine, in N, N- dimethylformamide so as to produce a compound having the structure:

d) exposing the product of step c) to diphenylphosphoryl azide, 1,8- diazabicyclo [5.4.0] undec-7-ene, in toluene/N,N- dimethylformamide so as to produce a compound having the structure:

e) exposing the product of step d) to H₂ and Pd/C, in EtOAc then

(MeO)₂CHCHO, AcOH, NaCNBH₃, MgSO₄, in MeOH, then tetrabutylammonium fluoride in THF, then allyl bromide, NaH, in N, N-dimethyIformamide so as to produce a compound having the structure :

f) exposing the product of step e) to HCl and dioxane so as to produce a compound having the structure:

g) expos ing the product of step f ) to a compound having the structure :

and bis (2-oxo-3-oxazolidinyl)phosphinic chloride, triethylamine, in CH₂Cl₂ so as to produce a compound having the structure :

h) exposing the product of step g) to 2, 3-dichloro-5, 6- dicyano-1 , 4 -benzoquinone , in CH₂Cl₂ at or about pH 7.0, then

Cu(OTF)₂ in benzene, then

Dess-Martin periodinane in CH₂Cl₂ then [(PPh₃J₂PdCl₂], Bu₃SnH, in AcOH so as to produce a compound having the structure :

i) exposing the product of step h) to CHF₂CO₂H, MgSO₄, in benzene so as to produce a compound having the structure :

j) exposing the product of step i) to tert- butyldimethylsiIy1-0-trifluoromethanesulfonyl , triethylamine, in CH₂Cl₂ then

2,2, 2-trichloroethoxycarbonyl-Cl, tetrabutylammonium iodide, in toluene so as to produce a compound having the structure :

k) exposing the product of step j) to tetrabutylammonium fluoride in CH₂Cl₂ then methoxymethyl-Cl and HDnig base so as to produce a compound having the structure:

1) exposing the product of step j) to DMDO in CH₂Cl₂ so as to produce a compound having the structure:

m) exposing the product of step 1) to a large excess of sodium cyanoborohydride so as to produce a compound having the structure:

n) exposing the product of step m) to H₂, Pd/C, in EtOAc, so as to produce a compound having the structure :

o) exposing the product of step n) to diisobutylaluminum hydride/BuLi in THF so as to produce a compound having the structure:

p) exposing the product of step o) to allyl bromide , Hηnig base , in CH₂Cl₂ then,

KCN in AcOH so as to produce a compound having the structure :

q) exposing the product of step p) to trifluoroacetic acid in CH₂CI2 so as to produce a compound having the structure:

r) treating the product of step q so as to produce the compound.

This invention also provides a process for making a compound having the structure:

wherein R₉ is a Ci-C₄ alkyl , -0(Ci-C₄ alkyl) , or -S(Q₁-

C₄ alkyl) , comprising: a) exposing a compound having the structure:

to Br₂, NaOAc, in AcOH, then

BrCH₂Cl, Cs₂CO₃, in N,N-dimethylformamide, then m-choloroperoxybenzoic acid and then acidifying with HCl, then tert-butyldiphenylsilyl-Cl , triethylamine, in 4- (dimethylamino) pyridine so as to produce a compound having the structure:

b) exposing the product of step a) to nBuLi in toluene/THF, then neat Me-(MeO)NC(O)CH₂OBn so as to produce a compound having the structure:

c ) expos ing the product of step b) to Noyori R, R catalyst , HCO₂H , and triethylamine , in N , N-

SUBSΗTUTE SHEET (RULE 26) dimethylformamide so as to produce a compound having the structure:

d) exposing the product of step c) to diphenylphosphoryl azide, 1,8- diazabicyclo [5.4.0] undec-7-ene, in toluene/N,N- dimethylformamide so as to produce a compound having the structure:

e) exposing the product of step d) to H₂ and Pd/C, in EtOAc then

(MeO)₂CHCHO, AcOH, NaCNBH₃, MgSO₄, in MeOH, then tetrabutylammonium fluoride in THF, then allyl bromide, NaH, in N, N-dimethylformamide so as to produce a compound having the structure:

f) exposing the product of step e) to HCl and dioxane so as to produce the compound. In an embodiment of the instant process, R₉ is methyl.

This invention also provides a process for cyclizing an ortho-hydroxystyrene having the structure:

wherein R₁, R₂, R₆, R7, Ra, Rg and Ri₆ are as defined above comprising exposing the compound to CHF₂CO₂H, MgSO₄ and benzene so as to produce a pentacycle having the structure :

In an embodiment of the instant process , the ortho- hydroxystyrene has the structure :

and the pentacycle has the structure :

This invention also provides a process for hydrating a carbon-carbon double bond α in a compound having the structure :

comprising: a) exposing the compound to dimethyl dioxirane in CH₂Cl₂ so as to produce a compound having the structure :

b) exposing the product of step a) to NaCNBH₃ so as to hydrate the carbon-carbon double bond and so produce a compound having the structure :

In an embodiment of the instant process, the compound comprising the carbon-carbon double bond to be hydrated has the structure:

the product of step a) has the structure :

and the product of step b) has the structure

In an embodiment of the instant process, the compound comprising the carbon-carbon double bond to be hydrated has the structure:

the product of step a) has the structure :

and the product of step b) has the structure :

This invention also provides a composition comprising anyone of the instant compounds and a pharmaceutically acceptable carrier.

The abbreviations used are defined below:

PhH = benzene

MeOH = methanol mCPBA = meta-chloroperbenzoic acid DMF - N,N-dimethylformamide

DCC - NjN-dicyclohexylcarbodiimide

DMDO - 2, 2-dimethyldioirane mCPBA - meta-chloroperoxybenzoic acid

Tf - trifluoromethanesulfonyl NaCNBH₃. sodium cyanoborohydride

The compounds disclosed herein are useful in the manufacture of the anti-tumor compound ecteinascidin 743 and derivatives thereof.

In addition, compounds disclosed herein are useful in their own right in the treatment of tumors and cancers. It is noted that compounds which contain a two tetrahydroisoquinoline aromatic carbon nitrogen framework, such as ecteinascidin 743 (as well as phalascidins and saframycins) have consistently exhibited pharmacological, antibiotic, cytotoxic, antitumor, anti- tumorigenic and cellular anti-proliferative activity both in vitro and in vivo (see refs. 31 to 34 and U.S. 6,686,470). Thus the similar compounds of this invention are expected to exhibit these properties. The invention further contemplates the use of prodrugs which are ' converted in vivo to the compounds of the invention (see, e.g., R. B. Silverman, 1992, "The Organic Chemistry of Drug Design and Drug Action", Academic Press, Chapter 8, the entire contents of which are hereby incorporated by reference) . Such prodrugs can be used to alter the biodistribution (e.g., to allow compounds which would not typically enter a reactive site) or the pharmacokinetics of the compound.

Certain embodiments of the disclosed compounds can contain a basic functional group, such as amino or alkylamino, and are thus capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable acids, or contain an acidic functional group and are thus capable of forming pharmaceutically acceptable salts with bases. The instant compounds may be in a salt form. As used herein, a "salt" is salt of the instant compounds which has been modified by making acid or base salts of the compounds. In the case of compounds used for treatment of cancer, the salt is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as phenols. The salts can be made using an organic or inorganic acid. Such acid salts are chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, malates, citrates, benzoates, salicylates, ascorbates, and the like. Phenolate salts are the alkaline earth metal salts, sodium, potassium or lithium. The term "pharmaceutically acceptable salt" in this respect, refers to the relatively non-toxic, inorganic and organic acid or base addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or by separately reacting a purified compound of the invention in its free base or free acid form with a suitable organic or inorganic acid or base, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, napthylate, mesylate, glucoheptonate , lactobionate, and laurylsulphonate salts and the like. (See, e.g., Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

As used herein, the term "effective amount" refers to the quantity of a component that is sufficient to yield a desired therapeutic response without undue adverse side effects (such as toxicity, irritation, or allergic response) commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. For example, an amount effective to inhibit or reverse tumor growth, or for example to inhibit, attenuate or reverse neurodegenerative disorder symptoms. The specific effective amount will vary with such factors as the particular condition being treated, the physical condition of the patient, the type of mammal being treated, the duration of the treatment, the nature of concurrent therapy (if any) , and the specific formulations employed and the structure of the compounds or its derivatives. "Treatment" of a tumor or cancer as used herein shall include ameliorating, slowing, stopping or reversing the tumor or cancer and/or ameliorating or alleviating symptoms associated with the tumor or cancer.

As used herein, a "pharmaceutically acceptable carrier" is a pharmaceutically acceptable solvent, suspending agent or vehicle, for delivering the instant compounds to the animal or human. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Liposomes are also a pharmaceutical carrier.

The dosage of the compounds administered in treatment will vary depending upon factors such as the pharmacodynamic characteristics of a specific chemotherapeutic agent and its mode and route of administration; the age, sex, metabolic rate, absorptive efficiency, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment being administered; the frequency of treatment with; and the desired therapeutic effect.

A dosage unit of the compounds may comprise a single compound or mixtures thereof with anti-cancer compounds, or tumor growth inhibiting compounds or other drugs used in cancer therapy. The compounds can be administered in oral dosage forms as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, or introduced directly, e.g. by injection or other methods, into the cancer, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts.

The compounds can be administered in admixture with suitable pharmaceutical diluents, extenders, excipients, or carriers (collectively referred to herein as a pharmaceutically acceptable carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices. The unit will be in a form suitable for oral, rectal, topical, intravenous or direct injection or parenteral administration. The compounds can be administered alone but are generally mixed with a pharmaceutically acceptable carrier. This carrier can be a solid or liquid, and the type of carrier is generally chosen based on the type of administration being used. In one embodiment the carrier can be a monoclonal antibody. The active agent can be co-administered in the form of a tablet or capsule, liposome, as an agglomerated powder or in a liquid form. Examples of suitable solid carriers include lactose, sucrose, gelatin and agar. Capsule or tablets can be easily formulated and can be made easy to swallow or chew; other solid forms include granules, and bulk powders. Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may- contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents. Oral dosage forms optionally contain flavorants and coloring agents. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

Specific examples of pharmaceutical acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in U. S. Pat. No. 3,903,297 to Robert, issued Sept. 2, 1975. Techniques and compositions for making dosage forms useful in the present invention are described-in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979) ; Pharmaceutical Dosage Forms: Tablets (Lieberman et al . , 1981); Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976); Remington's Pharmaceutical Sciences, 17th ed. (Mack Publishing Company, Easton, Pa., 1985); Advances in Pharmaceutical Sciences (David Ganderton, Trevor Jones, Eds., 1992); Advances in Pharmaceutical Sciences VoI 7. (David Ganderton, Trevor Jones, James McGinity, Eds., 1995) ; Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms (Drugs and the Pharmaceutical Sciences, Series 36 (James McGinity, Ed., 1989); Pharmaceutical Particulate Carriers: Therapeutic Applications: Drugs and the Pharmaceutical Sciences, VoI 61 (Alain Rolland, Ed. , 1993) ; Drug Delivery to the Gastrointestinal Tract (Ellis Horwood Books in the Biological Sciences. Series in Pharmaceutical Technology; J. G. Hardy, S. S. Davis, Clive G. Wilson, Eds.); Modern Pharmaceutics Drugs and the Pharmaceutical Sciences, VoI 40 (Gilbert S. Banker,

Christopher T. Rhodes, Eds.).

Tablets may contain suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. For instance, for oral administration in the dosage unit form of a tablet or capsule, the active drug component can be combined .with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. The compounds may be administered as components of tissue-targeted emulsions. The compounds may also be coupled to soluble polymers as targetable drug carriers or as a prodrug. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol , polyhydroxyethylasparta-midephenol, or polyethyleneoxide- polylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans , polycyanoacylates , and crosslinked or amphipathic block copolymers of hydrogels .

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parentally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient compounds and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. For oral administration in liquid dosage form, the oral drug components are combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Examples of suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules and effervescent preparations reconstituted from effervescent granules. Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol . Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing

Company, a standard reference text in this field.

The instant compounds may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen .

Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.

The present invention also includes pharmaceutical kits useful, for example, for the treatment of tumors and cancers, which comprise one or more containers containing a pharmaceutical composition comprising an effective amount of one or more of the compounds. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. , as will^' be readily apparent to those skilled in the art. Printed instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit. It should be understood that although the specified materials and conditions are important in practicing the invention, unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. Thus, Ci-C_n as in "C₁-C_n alkyl" is defined to include groups having 1, 2, ...., n-1 or n carbons in a linear or branched arrangement. As used herein, "alkyl" means C₁-C_n, and is defined to include groups having 1, 2, 3, 4, 5, 6 etc. carbons in a linear or branched arrangement, and specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and so on.

The term "alkyl" as used in the term, for example, "- C(O) alkyl refers to a Ci-C_n alkyl as defined above, i.e. they include groups having 1, 2, 3, 4, 5, or n carbons in a linear or branched arrangement. For example methyl, ethyl, propyl, butyl, pentyl, or hexyl in a linear or branched arrangement .

As appreciated by those of skill in the art, "halo", "halide" , or "halogen" as used herein is intended to include chloro, fluoro, bromo and iodo.

The alkyl substituents may be unsubstituted or unsubstituted, unless specifically defined otherwise. For example, a (Ci-C₆) alkyl may be substituted with one or more substituents selected from OH, oxo, halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl, piperidinyl, and so on. In the compounds of the present invention, alkyl groups can be further substituted by replacing one or more hydrogen atoms be alternative non-hydrogen groups. These include, but are not limited to, halo, hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.

The term "substituted" shall be deemed to include multiple degrees of substitution by a named substitutent . Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties, singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different.

It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results .

In choosing compounds of the present invention, one of ordinary skill in the art will recognise that the various substituents, i,.e. R¹ through R¹⁹ are to be chosen in conformity with well-known principles of chemical structure connectivity. Synthesis of saframycin-ecteinasicidn series compounds are disclosed in U.S. 6,686,470 and U.S. S.N. 10/728,580, the contents of each of which are hereby incorporated by reference .

All combinations of the various elements are within the scope of the invention

Experimental Results

Synthesis of Ecteinascidin 743

A new strategy was designed for the construction of the pentacyclic ring system of the scarce but powerful antitumor compound ecteinascidin 743. Key features in the successful route include: i) highly concise routes to the enantiopure configurationally matched subunits (cf. Fig. 1, structure A) , ii) a novel vinylogous Pictet-Spengler cyclization to assemble pentacycle (B) , and iii) a stereospecific epoxidation and regioselective reduction sequence of the C₃-C₄ enamide to secure the backbone of C.

In connection with a total synthesis of cribrostatin IV, a viable pathway from a 2a type compound to a 3,4-dehydro type compound (cf. 4) had been charted (see Fig. 2) (1) . Of course, in cribrostatin IV the final target pursued contains a 3,4-olefinic linkage. Accordingly, an indirect solution to the ET-743/saframycin total synthesis problem was envisioned by reaching a 2a species that would be converted to a 3,4-dehydro system (cf. 4) (2) . It was hoped to reach a key intermediate (cf. 5) required for the ET-743 series from .4 via an overall α- face hydration (i.e. C₃-H_α, C₄-OH₁₁) of the C₃-C₄ double bond (see structure 5, Fig. 3) .

On further reflection, a conceptually simpler possibility presented itself. Perhaps direct cyclization of an ortho- hydroxystyrene prototype 7 would occur at the styrenic double bond, with its regiochemical sense controlled by the phenolic hydroxyl group. The cyclization envisioned

(presumably via the iminium derivative 8, formed upon cleavage of the W-t-Boc group from N₁₂) would produce 9

(Fig. 4) . Given the importance of providing access to a broad range of biologically active tetrahydroisoquinoline alkaloids, it seemed prudent to gain reliable and convenient access to the required matched antipodes (3) . Indeed, as will be described, a new concise plan was devised to reach the configurationally defined tetrahydroisoquinoline moiety [C₁-R) . The latter was acylated with the enantiomerically defined L-aminoacyl CDE precursor, bearing the future pre-Cu aldehyde, see compound 6 (4) .

The synthesis started with a highly regiospecific bromination of Borchardt ' s catechol 10 (Fig. 5) (5). Methylenation of the corresponding bromide followed by Baeyer-Villiger oxidation followed by temporary protection of the intermediate free phenolic function as its t-butyldiphenylsilyl ether derivative, afforded compound 11. Lithiation of the aryl-bromo function followed by coupling of the organometallic agent with the Weinreb amide of benzyloxyglycolic acid, yielded compound

12 (6) . Controlled introduction of asymmetry was accomplished by submitting ketone 12 to Noyori's transfer hydrogenation conditions, thereby providing homochiral alcohol 13 (7) . A modified Mitsunobu reaction of alcohol

13 with diphenylphosphorylazide gave rise to 14, with complete inversion of stereochemistry (8). At this stage, the R-configuration at Ci was securely fashioned. Catalytic hydrogenation of 14 to the amine was followed by two carbon homologation and subsequent deprotection/reprotection of the phenol as its allyl ether, gave acetal 15. The Bobbitt modified Pomerantz-

Fritsch reaction of 15 provided the required tetrahydroisoquinoline 16, in which the Ci stereochemistry- was correctly defined (9) . That C₄ is, at this stage, presented as a mixture of epimers, is an awkwardness rather than an impediment {vide infra)^'.

Coupling of tetrahydroisoquinoline 16 and the previously described L-tyrosine derivative 17 (1) under the agency of BOPCl afforded amide 6 in excellent yield (Fig. 6) . After oxidative cleavage of the PMB group and dehydration of the benzylic alcohol (10), the primary alcohol was oxidized to the Cu aldehyde (11) , deprotection of the allyl group was achieved by treatment with tributyltin hydride in the presence of catalytic (Pht₃P)₂PdCl2 to yield cyclization precursor 7, as hypothesized above (12) . The resulting seco-phenol -aldehyde 7 was suited for the crucial intramolecular Pictet-Spengler cyclization. Various acidic conditions we screened for achieving the desired cyclization to 9. In the event, compound 7, generated as shown, successfully underwent cyclization to produce pentacycle 9 following exposure to 30 equivalents of difluoroacetic acid in benzene. For the moment, the product is obtained in a somewhat disappointing yield range of 42-58%.

With a viable route to pentacyclic alkene 9 accomplished, we were now faced with the need to functionalize the C₃-C₄ double bond (Fig. 7) . Implementation of this task, on a model basis, commenced with temporary protection ^" of phenol 9 as its methyl ether derivative 18. Due to the ease of obtaining ample quantities of 18, it was used as a model to probe eventual functionalization in a fully updated system. In the first attempts to functionalize the C₃-C₄ double bond, recourse was taken to hydroboration reagents such as BTHF, BMS, BH_3*Py, Br₂BH, and catecholborane. Remarkably, these reactions uniformly resulted only in recovery of 18 (13) . By contrast, dihydroxylation of the double bond of 18, using N- bromosuccinimide in an aqueous solution of THF was achievable, leading to a diol assigned as 19, wherein the dihydroxylation reaction was presumed to occur from the less hindered α-face (14) . However attempts to accomplish reductive removal of the now extraneous angular hydroxyl group at C₃ of 19 with a variety of reducing agents resulted in the recovery of starting material .

Given these results, it was concluded that to be successful, a highly reactive oxidizing agent to attack the double bond would be necessary. It was also desired to have functionality at C₃, which would be more reactive than a simple hydroxyl group to allow for introduction of the required C₃-H_α group. Accordingly, the use of peracid agents to accomplish epoxidation of the C₃-C₄ olefinic linkage was first explored. However at this stage W- oxide formation of the N-Me tertiary amine became a potential problem. A McCluskey reaction afforded W-Troc urethane 20 (15) . Unfortunately, screening of various epoxidizing conditions, addressed to this goal, with peracids were unsuccessful (possibly owing to the slowness of the desired reaction in the context of the highly oxidizable aromatic sectors) . With the options rapidly narrowing, it was fortunately found that reaction of 20 with 2 , 2-dimethyldioxarane (DMDO), did occur, giving rise to material formulated as the C₃-C₄ α-epoxide 21 (Fig. 8) . Treatment of this product with sodium cyanoborohydride did indeed provide the required C₃-H_α,

C₄-OH₀ hydration product of 20. Greater insight into this fascinating reductive cleavage of the novel enamide epoxide [cf. 21) was gained in the MOM ether series [vide infra, compound 25) .

Based on the experiences in this series, it was not certain that a compound such as 22, containing a methyl ether at C₅ could be advanced to conclude the synthesis . Moreover, in the same vein, it was decided to confirm the various assignments by connecting our series with a previously synthesized intermediate, from which ET-743 could definitely be reached. Accordingly, compound 32 was defined as our milestone target, which is an advanced intermediate in the Fukuyama total synthesis of ET-743 (20) . Phenol 9 was first converted to its t- butyldimethylsilyl ether derivative (Fig. 9). This step was followed by a McCluskey reaction of the W-Me amine, thereby providing 23. Deprotection of the TBS ether was conducted with TBAF, followed by addition of MOMCl and Hϋnig's base, thus leading to 24 in good yield (16). Treatment of this compound with DMDO lead, as before [cf. 20) , to epoxidation of the C₃-C₄ double bond affording the presumed 25. When this compound was treated with 5 equivalents of sodium cyanoborohydride the major product was assigned as ketone 27, though small amounts of 26 were also obtained. Two mechanistic hypotheses were entertained to account for the formation of the ketone product (Fig. 10). One could envision a concerted rearrangement with hydride migration, from C₄ to C₃, to afford ketone 27. Alternatively, the lactamic nitrogen opens the epoxide to produce amidonium alkoxide 28. This intermediate can undergo 1,2-hydride migration to lead to

27 or competitive reduction by an external hydride to provide 26. Apparently this duality is, in fact, operative, since recourse to a large excess of sodium cyanoborohydride does afford 26 as the primary product

(17) .

At this juncture, only the installation of the C₂i cyano- function (Fig. 11) remained. Toward this end, the two benzyl protecting groups were removed to give rise to triol 29, which upon treatment with a 1:1 ate complex of BuLi and DIBAL (18), underwent partial reduction of the lactam to provide oxazolidine 30. This reduction seemed to be highly dependent on the reactivity of the ate complex, which may differ from batch to batch. It was found that if there was a slight excess of "BuLi" in the ate complex, the Troc protecting group was easily reduced (19) . Selective protection of the phenolic hydroxyl group as its allyl ether could be achieved by treatment of oxazolidine 30 with allyl bromide in the presence of Hύnig's base, which upon exposure to KCN in acetic acid resulted in ring opening and simultaneous introduction of the C21 cyano group to give aminonitrile 31, as a single isomer. Cleavage of the MOM group was accomplished by treatment of 31 with TFA to give the goal compound 32. Since this compound is an advanced intermediate in the Fukuyama total synthesis of 1 (20) (hereby incorporated by reference) , the work described herein constitutes a formal total synthesis of ET-743.

The notable chemistry here is i) the very straightforward routes to the matched subunits 16 and 17, ii) the use of an unusual o-hydroxystyrene moiety for the vinylogous

Pictet-Spengler cyclization, iii) exploration of an unusual enamide epoxide to achieve hydration of the C₃-C₄ double bond, in the desired sense, through reductive interdiction of 25.

Stereochemistry

A comprehensive study directed to understanding the multifaceted stereochemical issues associated with the cascade-like reaction initiated by cleavage of the urethane function of an W-methyl-W- t-Boc ketoaldehyde of the type 3 was undertaken. Facile construction of subunits 33 and 34, allows for rapid assembly of the pentacyclic ring system (35) of the cytotoxic tetrahydroisoquinoline .alkaloids. A surprising A_Ei participation reaction was discovered, which challenges the stereochemical assignments of key intermediates en route to 35.

A total synthesis of ecteinascidin 743- (1) an extremely potent antitumor agent 1 had been accomplished by E.J. Corey and associates in 1996 (21) . A subsequent synthesis of 1 was described by Fukuyama. (22). While there are many fascinating features in the Corey total synthesis, the one most needed to establish the context for our work is captured in transformation 36-^37. An important message in these structures is that it was possible to build the entire saframycin (23) like platform of 1 without carrying pre-built functionality at C₄. Remarkably, the phenylselenenic anhydride oxidation served to functionalize C₄ (presumably as the β-carbon of an intermediate quinomethide) , setting the stage for' Michael-like cyclization via the cysteinic sulfur (Fig.

13) (24).

Regarding the ecteinascidin problem, a progression was focused on, wherein a useful functionality implement, would already be in place at C₄ as part of the unveiling of the pentacyclic platform. More specifically, the plan, as adumbrated in Pig. 14, would feature a lynchpin Mannich cyclization through which a Cu aldehyde would be interpolated between Ni₂ and C₃ (25) . In the initial conceptual model, C₃ would participate as the β-carbon of an enol . For this plan to be practical, the relationship between carbons 1 and 13 would be secured by joining two properly matched subunits [αf. 38 and 39) , to reach reactive intermediate 40 and thence pentacyclic product 41.

Needless to say, two additional stereogenic centers would be introduced, at carbons 3 and 11, in the lynchpin Mannich cyclization. Of course, the configuration at Cu would be strictly governed by the stereogenicity already in place at Ci₃ (i.e. the protons at Cu and C_i3 must, per force, emerge as syn in the pentacyclic compound 7) . The configuration likely to emerge at C₃ was less predictable. From the matched configurations shown in 40, there could arise product 41a corresponding to a syn saframycin skeleton while the alternate possibility, 41b could be termed an anti saframycin. At that time, all known saframycins, natural or synthetic, isolated from various sources and synthesized in a variety of different ways, were of the C₃-Cn syn series (26) . On this basis, it was assumed that in the pentacyclic setting, the C₃-Cu syn series is inherently more stable than the corresponding anti compounds. It was further anticipated that the forgoing logic could be applied either to ET-743 or to the broader family of saframycins. In the latter, the firings are hexasubstituted.

At the time, the AB system housing the future Ci was assembled (cf. 46) using asymmetric dihydroxylation technology (27) . It was also attempted to accomplish the synthesis of JV-methyltyrosine derivative 45, by reagent driven asymmetric synthesis (Scheme 3) . In particular, compound 42 was converted to epoxide 43, in high enantiomeric excess, by Sharpless epoxidation. Azidolysis of this epoxide, provided an azidodiol, presumed to be 44, from whence, by the steps shown, there was obtained an N-methyl-W- t-Boc amino acid accordingly formulated as the L-amino acid derivative 45. (Parenthetically, this scheme is attractive as one which connects the powerful and reliable Sharpless epoxidation reaction to the important goal of synthesizing non-natural amino acids and their derivatives) .

Coupling of 46 with 47 provided an amide, then assigned to be 48 (Pig. 16). Following appropriate steps, 48 was converted to the presumed aldehyde 49. Indeed, treatment of this substance, as shown, gave rise to a pentacyclic compound, formulated as 50. The assignment of the C₃-Cn stereochemistry as the syn relationship, followed very closely from the J_H3-_HH coupling constant (approximately 3.6 Hz). Since the proton at Ci₃ was ostensibly of the L- amino acid configuration, the proton at Cu was also defined to be α. Given the syn relationship of the C₃ and Cn protons, the proton at C₃ was accordingly assigned as α. At the time, these results seemed rather secure and most promising for a total synthesis program.

Investigations were begun to use this chemistry to reach the saframycins as well as their closely related derivatives, most notably ET-743. The ultimately successful results of that foray are described in detail earlier here. However, before the route to the ET-743 series was accomplished, it was necessary to explore the requirements for the lynchpin Mannich cyclization in considerable detail. This study revealed some major unexpected teachings . An account of that learning experience is provided herein.

Turning to the ET-743 problem ultimately sought, a penta- rather than hexasubstituted E-ring system (such as was the case with 47) . Accordingly, compound 50 was prepared in much the same fashion as had been previously used to prepare 43 (Fig. 17) . Azidolysis of 50 produced 51 and thence, pentasubstituted amino acid 52. Coupling of 46 with 52 gave rise to an amide, which, on suitable processing exposed the required C₄ ketone-Cn aldehyde combination (cf. 53) . Cleavage of the W-t-Boc group triggered the Mannich closure giving rise to a pentacyclic product 54. Once again, the configuration at Ci was defined, and we relied on the fixed L-amino acid configuration at Ci₃ to enforce the α stereochemistry at Cii. Thus, it was most surprising that the proton NMR spectrum of this compound indicated it to be of the C₃-Cn anti type (J_H3-_HH= 0 Hz) . Accordingly, the proton at C₃ in the pentacyclic product is β as shown in 54 rather than α {cf. 50) . Needless to say, this was surprising. Further serving to deepen the mystery was that the results were strikingly clean. No C₃-Cn anti compound was found starting with 47, whereas no C₃-C11 syn compound was found starting with 52.

The cyclizations of potential ecteinascidin precursors were also studied (Pig. 18) . It was found that coupling of 55, prepared in the same manner as 46, and pentasubstituted amino acid 52, on further processing produced C₄-Cn keto-aldehyde precursor 56. Similarly, Mannich closure gave rise to anti pentacyclic compound 57.

Taking the seemingly incontrovertible data at face value, one would be obliged to conclude that the stereochemical outcome of the cyclization reactions (i.e. whether the C₃- Cn relationship emerges as syn or anti) is somehow a function of the degree of substitution of the remote E- ring. Unlikely as this situation would be, this is where the data first pointed. Accordingly, the matter was pursued in considerable detail . A variety of seco- aldehydes, pentasubstituted in the E-ring, were prepared and examined. They all lead to C₃-Cn anti compounds. At no point could the required C₃-Cn syn series be entered with any compounds in which the E-ring was pentasubstituted.

Of course, the heart of the anomaly rests on the implicit assumption that the relationships between carbon centers 1 and 13 (anticipating ET-743 numbering) are the same in compounds 49 and 53. This assumption seemed justified enough since we synthesized the two compounds by identical routes. Indeed the AB precursor 46, bearing the R-configuration at C₁, is identical in the sequences leading to 49 and 53. Since the routes to the two non- identical amino acid derivatives 47 and 52 were the same, it seemed reasonable to assume that these compounds were identically configured at the future Ci₃ center. The solution to the conundrum required abandoning of this seemingly reasonable but, in the end, incorrect assumption.

Specifically, to solve the problem the correctness of the original supposition was still assumed (i.e. that in the case of the pentasubstituted E-ring compounds such as 50, azidolysis of the epoxide was the sole inversion event) . This indeed led to the L-amino acid precursor, as previously formulated (cf. 52) . By contrast, in the hexasubstituted case, the conundrum could be solved by postulating that a "hidden" inversion takes place in the context of the azidolysis event, such that the azidolysis reaction had actually produced the D-amino acid derivative (Fig. 19) .

The unusual behavior of the hexasubstituted system could be a consequence of two factors. First, the trajectory for azidolysis is significantly more hindered when the aryl ring is fully substituted. Also perhaps the additional orfcho-alkoxy substituent at Cχ5, participates in a precedented but now arcane intramolecular Ar_x participation reaction, generating a methylated spirocyclohexadienone (cf. 59) (28) . This participation results in a hitherto unnoticed first inversion around Ci₃. Azidolysis of the activated cyclopropane again with inversion leads then to product 60, an azido precursor of a D-amino acid {cf. 61) . Ultimately in the hexasubstituted series, eventual processing leads to an aldehyde of the type 62. Cyclization does indeed produce the C₃-C₁₁ syn pentacyclic system, 63. However, this system is one in which the hydrogens at both Ci₁ and C₁₃ are β, while the hydrogen at C₃ is also β. In other words while C₃ and C₁₁ are indeed syn, they as well as C₁₃ are each of the opposite configuration to that required for the total synthesis of a saframycin. By contrast, in the pentasubstituted epoxide 50, azidolysis had occurred as a single inversion event, leading ultimately to the L-amino acid aldehydes 53 and 56, as formulated above en route to the anti products 54 and 57. In light of this hypothesis, optical rotation data taken for both penta- and hexasubstituted epoxides (cf. 43 and 50) and their respective azidodiol products {cf. 44 and 51) should have, in retrospect, seemed suspicious. Upon azidolysis of pentasubstituted epoxide 43 to azidodiol 44 a sign inversion, from plus to minus, had taken place. In contrast, in the hexasubstituted series the sign change was not present. However, in the end, unequivocal support of the hypothesis here was obtained through a crystal structure of anti pentacyclic compound de-Bn-54, fully verifying its assigned structure.

The thought was that if one could synthesize a precursor to the lynchpin Mannich cyclization in which the E-ring were hexasubstituted but of the L-amino acid series, one should generate a C₃-C₁₁ anti compound comparable to 54 and 57. Of course in principle this could be accomplished by repeating the sequence which initially produced 61 but using the ent-43 epoxide, as which would be available from ,the Sharpless epoxidation methodology (using the L-tartrate instead of the D-tartrate) . However, as has been described, this is a very lengthy route. Thus an incentive to develop a rather more streamlined approach arose.

The new route started with iodo aromatic precursor 64 (Fig. 20) . This compound was carried through a Jeffery-

Heck reaction (29) and a subsequent asymmetric Knowles type hydrogenation as previously described, leading to the L-amino acid system 52 (30) . In this E-ring pentasubstituted series, the amino acid produced by the Jeffery-Heck/hydrogenation sequence and that from the

Sharpless epoxidation/azidolysis sequence were identical in every respect, including optical rotation.

To obtain the hexasubstituted aromatic products by this new technology, we preceded via pentasubstituted precursors (31). Removal of the benzyl group of 52 was followed by oxidation to quinone 68 (Fig. 20). The latter, following reductive bismethylation afforded hexasubstituted L-amino acid 69. An important milestone in substantiating the hypothesis discussed above (Fig. 19) was reached when it was found that compound 69 was indeed the enantiomer of 61, as shown by optical rotation.

With the groundwork now secure the next question asked was as to the nature of the lynchpin Mannich cyclization in the case of the properly matched (i.e. Ci-R; Ci₃-S) hexasubstituted precursor 71 generated in the usual way from amide 70 (Fig. 20) . Indeed when 71 was subjected to the conditions shown, anti compound 72 was obtained in 62% yield. Thus, the degree of substitution in the E- ring is not determinative in terms of formation of syn versus ant± product. The degree of substitution was only important in determining the stereosense of azidolysis of the relevant epoxides (cf. 43 versus 50) and thus the handedness of the E-ring amino acid derivatives (cf. 52 versus 61) .

In summary, with the facts now fully documented the conundrum has been solved. In retrospect a pleasing consistency in the stereochemical sense of the lynchpin Mannich cyclization exists (see matched precursor 71 and mismatched precursor 62) . In each case cyclization of the iminium species onto the C₃-C₄ enol occurs from the face opposite to that of the resident Ci benzyloxymethyl group. When X=CH₂OBn and Y=H attack occurs from the α- face of the enol, leading to a anti pentacycle (cf. 41b). In contrast, when X=H and Y=CH₂OBn attack occurs from the β-face of the enol, leading to a syn pentacycle {cf. ent- 41a). For representative cartoon, see:

NMR Spectroscopy

Phenol 9. To a sealed tube were added 7 (215 mg, 281 μmol), MgSO₄ ( 413 mg) , CHF₂COOH (535 μL) and benzene (7 mL) . The reaction was refluxed for 2 hours. The reaction was then poured into aq NaHCO₃ and extracted with CHCI3

(3x). The organic layers were combined, dried with Na₂SO₄, and concentrated by rotary evaporation. The residue was purified by column chromatography with 50% EtOAc/ Hexanes to provide 99 mg (54%) of a glassy oil. ¹H NMR (CDCl₃, 400MHz) δ 7.53-7.50 (2H, m) , 7.43-7.33 (3H, m), 7.28-7.18 (3H, m) , 6.98-6.96 (2H, m) , 6.42 (IH, s) , 6.39 (IH, s), 6.00-5.97 (IH, dd, J= 8.3, 4.1 Hz), 5.88 (IH, d, J= 1.0 Hz), 5.83 (IH, d, J= 1.0 Hz), 5.08 (2H, s), 4.49 (IH, s), 3.98-3.95 (2H, d, J= 12.1 Hz), 3.73 (3H, s), 3.70-3.68 (IH, d, J= 12.1 Hz), 3.60 (IH, d, J= 6.7 Hz), 3.26-3.16 (2H, m) , 3.08-3.04 (IH, dd, J= 10.1, 8.4 Hz) , 2.92-2.88 (IH, d, J= 16.2 Hz) , 2.38 (3H, s) , 2.10 (3H, s), 2.08 (3H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ

169.5, 150.6, 149.5, 146.9, 146.7, 139.5, 138.7, 137.7, 132.7, 129.9, 129.5, 129.4, 128.9, 128.8, 128.7, 127.9,

127.6, 127.5, 126.9, 112.3, 109.2, 109.0, 106.2, 102.4, 75.5, 73.5, 71.1, 61.9, 60.7, 58.0, 41.5, 33.5, 16.1, 9.3 ppm; IR (NaCl) 3326, 2937, 1635, 1616, 1451, 1418, 1378, 1292, 1233, 1120, 1088, 1055, 751 cm^"1; HRMS (FAB) calcd for C₃₉H₃₈N₂O₇ [M+H] : 646.2679; found 646.2697; [α]_D ²¹ -103° (c= 1.0, CHCl₃) . 9a: ¹H NMR (CDCl₃, 400MHz) δ 7.29-7.26

(5H, m), 7.18-7.17 (3H, m) , 6.84-6.82 (2H, m) , 6.62 (IH, s), 5.84 (2H, d, J= 1.4 Hz), 5.65 (IH, dd, J= 6.4, 2.7 Hz), 5.08 (IH, d, J= 11.2 Hz), 4.90 (IH, d, J= 11.2 Hz), 4.17 (IH, s), 4.06 (IH, d, J= 12.4 Hz) , 3.96-3.86 (3H, m), 3.69 (3H, s), 3.59-3.56 (IH, dd, J= 10.7, 3.1 Hz), 3.47-3.43 (IH, dd, J= 10.7, 6.7 Hz), 3.10-3.04 (IH, dd, J= 17.0, 6.3 Hz), 3.01-2.97 (IH, d, J= 16.4 Hz), 2.71- 2.64 (IH, dd, J= 15.2, 12.0 Hz), 2.57-2.52 (IH, dd, J= 15.4, 3.7 Hz), 2.18 (3H, s) , 2.15 (3H, s) ppm; LRMS (APCI) 635.46.

Functionalization of the Double Bond

TBS ether 155. To a solution of 88 (46.4 mg, 72 μmol) in DCM (1.5 mL) were added TBSOTf (41 μL, 179 μmol) and Et₃N (30 μL, 215 μmol) in ice bath. The reaction was stirred for 30 min and quenched by methanol. The solution was concentrated by rotary evaporation. Preparative TLC afforded 55 mg (quant.) of a glassy oil. ¹H NMR (CDCl₃, 400MHz) δ 7.40-7.17 (8H, m) , 7.00-6.98 (2H, m) , 6.43 (IH, s), 6.12 (IH, t), 5.86 (IH, d, J= 1.2 Hz), 5.83 (IH, d, J= 1.2 Hz), 5.15-5.12 (IH, d, J= 11.0 Hz), 4.99-4.96 (IH, d, J= 11.0 Hz), 4.42 (IH, s), 3.97-3.94 (IH, d, J= 12.26 Hz), 3.85-3.81 (IH, d, J= 12.24 Hz), 3.74 (3H, s), 3.59- 3.57 (IH, d, J= 6.3 Hz), 3.26-3.18 (2H, m) , 3.05-2.95 (2H, m) , 2.42 (3H, s), 2.11 (3H, s) , 2.07 (3H, s), 0.97

(9H, 0.12 (3H, s), 0.07 (3H, s) ppm; 1¹3^JCΛ NMR (CDCl₃, 100MHz) δ 167.8, 149.0, 148.2, 145.6, 143.7, 138.3,

137.5, 137.3, 131.2, 130.2, 128.4, 128.3, 127.9, 127.8,

126.9, 126.8, 126.5, 125.9, 114.8, 111.0, 108.9, 105.0,

101.1, 74.7, 70.0, 61.0, 60.4, 57.0, 46.7, 42.2, 33.6,

28.4, 26.2, 18.7, 16.0, 10.6, -2.8, -3.5 ppm; IR (NaCl)

2935, 2857, 1672, 1634, 14S2, 1408, 1362, 1281, 1246,

—1

1128, 1098, 837 cm HRMS (PAB) calcd for C₄₅H₅₃N₂O₇Si

[M+H] : 761.3622; found 761.3636; [CC] _D 18 -28^C (C= 1.0, CHCl₃) .

155 156

TBS alkβne 156. To a sealed tube were added 155 (13 mg, 17 μmol) in toluene (0.4 mL) , TrocCl (70 μL, 513 μmol) and TBAI (3 mg) . The reaction was refluxed for overnight and then poured into water, extracted with ethyl acetate

(3x) , concentrated by rotary evaporation. Preparative TLC afforded 14.5 mg (92%) of a clear oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 7.45-7.20 (8H, m) , 7.00

(2H, ra) , 6.42 (IH, s) , 6^24 & 6.22 (IH, s) , 6.10-6.07

(2H, m) , 5.87 (IH, S), 5.83 (IH, s), 5.19-4.96 (3H, m) , 4.88-4.81 (IH, m) , 4.71-4.65 (IH, m) , 4.07-4.02 (IH, m) , 3.87-3.84 (IH, d, J= 12.1 Hz), 3.74 & 3.71 (3H, s) , 3.28- 3.02 (4H, m) , 2.09-2.06 (6H, m) , 0.94 & 0.92 (9H, s) , 0.10 (3H, s), 0.04 (3H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ

(mixture of rotamers) 165.6, 165.5, 151.3, 150.7, 149.4, 148.4, 148.1, 146.1, 144.5, 144.3, 138.2, 137.6, 137.5, 137.1, 137.0, 132.2, 132.1, 129.7, 128.42, 128.38, 128.1, 127.8, 127.6, 127.4, 126.9, 126.5, 126.3, 126.1, 124.9,

114.7, 111.2, 108.5, 104.8, 104.2, 101.2, 95.2, 77.2, 75.0, 74.83, 74.76, 72.4, 69.6, 60.5, 60.4, 54.3, 53.9, 50.9, 50.1, 47.5, 47.2, 33.0, 32.2, 29.8, 29.5, 26.2, 18.74, 18.67, 15.9, 10.5, -2.8, -2.9, -3.6 ppm; IR (NaCl) 2929, 2857, 1724, 1680, 1431, 1411, 1372, 1282, 1255, 1121, 1101, 837, 751, 698 cm^'1; HRMS (FAB) calcd for C₄₇H_5IN₂O₉Cl₃Si [M+H] : 920.2429; found 920.2427 [α]_D ¹⁸ +98° (c= 1.0, CHCl₃) .

Troc phenol 157. To a solution of 23 (10 mg, 11 μmol) in THF (1 mL) were added TBAF (IM, 33 μL) and HOAc (10 μL) . Stirred at 0 ⁰C for an hour. The solution was concentrated by rotary evaporation. Preparative TLC afforded 6 mg (68%) of a purplish oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 7.53-7.35 (5H, m) , 7.26-7.19 (3H, m) , 6.97- 6.95 (2H, m) , 6.50 & 6.48 (IH, s) , 6.17-5.73 (4H, m) , 5.25-4.92 (3H, m) , 4.89-4.82 (IH, m) , 4.67-4.59 (IH, m) , 4.10-4.03 (IH, m) , 3.90 & 3.88 (IH, s) , 3.77-3.72 (3H, m), 3.61 (0.42H, m) , 3.27-3.10 (3,38H, m) , 2.15-2.05 (6H, m) ppm; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 167.6, 150.8, 149.1, 147.2, 139.4, 137.6, 133.5, 129.8, 129.4, 129.1, 128.8, 128.5, 127.9, 127.5, 127.3, 126.1, 112.4, 109.0, 108.8, 105.6, 103.0, 102.4, 96.6, 76.2, 75.5, 75.3, 73.5, 70.9, 60.8, 55.7, 55.1, 52.2, 51.5, 33.0, 30.8, 20.9, 16.1, 14.6, 9.3 ppm; IR (NaCl) 3400, 2924 , 1724 , 1641 , 1433 , 1298 , 1123, 1097 , 1065 , 1029,

736 , 699 cm^"1; HRMS ( FAB) calcd for CaH₃₇N₂O₉Cl₃ [M+H] :

806. 1565 ; found 806 . 1559 ; [α] _D ¹⁷ +43° (c= 1 . 0 , CHCl₃) .

MOM alkene 24. To a solution of 23 (70 rag, 76 μmol) in DCM (1 mL) were added TBAF (IM, 228 μL) at 0 ⁰C. The solution changed to yellow. After 2 min, MOMCl (20 μL, 228 μmol) was added and followed by addition of Hunig base (66 μL) . The color changed to reddish. The reaction was stirred for 30 min and poured into water, extracted with DCM (2x) and EtOAc. The organic layer was combined and concentrated by rotary evaporation. Preparative TLC afforded 51 mg (79%) of a colorless oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 7.54-7.37 (5H, m) , 7.27- 7.19 (3H, m) , 6.99-6.97 (2H, m) , 6.50 & 6.47 (IH, ■ s) , 6.15-6.05 (3H, m) , 5.89 & 5.84 (2H, s) , 5.30-5.5.02 (3H, m), 4.91-4.79 (2H, m) , 4.74-4.68 (IH, m) , 4.61-4.53 (2H, m) , 4.47 S 4.46 (0.44H,s), 4.05-4.02 (IH, dd, J= 12.1, 3.4 Hz), 3.89-3.86 (IH, d, J= 12.1 Hz), 3.74-3.71 (IH, d, J= 10.3 Hz), 3.41-3.40 (3.76H, m) , 3.30-3.19 (2H, m) , 3.14-3.06 (2H, m) , 2.12 (6H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 165.6, 165.5, 151.2, 151.0, 149.5, 148.3, 147.9, 146.9,. 145.8, 139.5, 138.1, 137.5, 137.4, 132.3, 131.0, 130.8, 128.5, 127.9, 127.8, 127.5, 127.3, 126.9, 126.5, 126.3, 126.2, 124.9, 124.7, 116.8, 116.6, 113.4, 108.3, 108.2, 103.0, 102.5, 101.4, 100.22, 100.16, 95.1, 95.0, 75.3, 75.2, 74.3, 73.9, 72.5,

69.8, 60.4, 60.3, 57.5, 57.4, 54.3, 53.7, 50.8, 50.0, 47.4, 47.2, 32.7, 32.3, 29.8, 21.2, 16.0, 14.4, 9.9 ppm; IR (NaCl) 2928, 1723, 1681, 1649, 1435, 1370, 1299, 1122, 1067, 968, 744 cm^"1; HRMS (FAB) calcd for C₄₃H₄₂N₂Oi₀Cl₃

[M+H] : 851.1905; found 851.1926; [α] IB +50° (c= 1.0,

CHCl₃) .

6

MOM alcohol 26. To a solution of 24 (10 mg, 12 μmol) in

DCM (5 itiL) was added freshly prepared DMDO (0.08 M, 294 μL) . The reaction was stirred at 0 ⁰C for 1.5 hours, monitored by mass spectroscopy, then NaBH₃CN (37 mg, 0.59 mmol) was added in one portion. The reaction was stirred for 10 min, then poured into water, extracted by DCM (3x) and EtOAc. The organic layer was combined and concentrated by rotary evaporation. Preparative TLC afford 8 mg (78%) of a clear oil. ¹H NMR (CDCl₃, 400MHz) δ

(mixture of rotamers) 7.64-7.60 (2H, m) , 7.48-7.37 (3H, m) , 7.15-7.12 (3H, m) , 6.85-6.78 (3H, m) , 6.20 & 6.09

(IH, s), 5.85 & 5.83 (2H, s), 5.50 (IH, t, J= 3.04 Hz),

5.19-5.12 (IH, d, J= 9.5 Hz), 5.08 (IH, d, J= 5.4 Hz),

4.93-4.65 (6H, m) , 4.59-4.52 (1.5H, m) , 3.92-3.80 (3H, m) , 3.51 & 3.47 (3H, s) , 3.43-3.39 (IH, m) , 3.33-3.28

(2.5H, m) , 3.22-3.17 (3.6H, m) , 2.22 & 2.21 (3H, s) , 2.13

(3H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 167.5, 167.3, 151.6, 151.1, 149.5, 149.4, 148.6, 148.5, 148.3, 145.2, 145.1, 139.13, 139.07, 138.2,

135.8, 135.4, 132.7, 132.5, 129.7, 129.5, 129.3, 128.9, 128.8, 128.7, 127.9, 127.0, 126.9, 126.2, 122.6, 122.5, 122.1, 121.9, 113.8, 113.6, 111.6, 111.5, 101.3, 100.1, 100.0, 95.14, 95.06, 76.5, 75.4, 75.2, 72.5, 71.4, 65.7, 65.5, 65.4, 65.3, 60.2, 57.4, 57.3, 53.9, 53.2, 49.3, 49.2, 48.0, 47.3, 33.8, 33.4, 15.9, 10.1 ppm; IR (NaCl) 3498, 2925, 1720, 1658, 1440, 1300, 1126, 1061, 1028, 974, 749, 702cm^"1 ; LRMS (APCI) 867.14/869.10, 849.20/851.26, 823.37/825.40, 805.61/807.60;HRMS (FAB) calcd for C₄₃H^N₂OnCl₃ [M+H] : 869.2011; found 869.2017; [α]_D ¹⁷ -54° (c= 1.0, CHCl₃) .

MOM triol 29. A 10 mL flask, and a stirring bar were dried m oven, then to the flask were added EtOAc and 5 mg Pd-C catalyst. The solution were stirred for 10 min and poured it out. To this flask was added a solution of 26 (9 mg) in EtOAc (5 mL) and 5 mg of 10% Pd/C. The solution was hydrogenated by a H₂ balloon for 3 hours

(more than 5 hours Troc got reduced) , filtered through Celite. The solution was concentrated by rotary evaporation. Preparative TLC afforded 5.5 mg (77%) of a colorless oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 8.86 & 8.84 (IH, s), 6.99 & 6.97 (IH, s) , 6.55 & 6.54 (IH, s), 6.02-5.93 (3H, m) , 5.46 (IH, t, J= 4.0 Hz), 5.09-5.05 (2H, m) , 4.93-4.78 (3H, m) , 4.69 & 4.65

(IH, d, J= 11.94 Hz), 3.95-3.91 (IH, td, J= 10.2, 2.9 Hz), 3.82 & 3.81 (3H, s), 3.64-3.58 (4H, m+s), 3.34-3.28 (2H, m) , 3.17-3.10 (IH, d, J= 8.5 Hz), 2.23 (3H, s), 2.15 (3H, 5), 2.04 (3H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 169.2, 169.0, 151.2, 147.7, 147.5,

147.0, 146.3, 145.1, 140.2, 132.3, 132.2, 128.1, 127.8, 122.2, 122.1, 121.1, 115.3, 115.2, 113.1, 113.0, 111.2,

111.1, 101.9, 101.0, 95.1, 95.0, 75.2, 75.0, 67.3, 67.2, 66.3, 64.7, 64.4, 60.4, 60.1, 58.7, 53.6, 53.0, 52.3, 46.9, 46.3, 33.6, 32.9, 29.8, 21.2, 16.0, 14.4, 9.9 ppm; IR (NaCl) 3426, 3208, 2929/ 1720, 1654, 1442, 1302, 1129, 1060, 930, 755, 567 cm^"1; HRMS (FAB) calcd for C₂₉H₃₂N₂O_nCl₃

[M+H] : 689.1072; found 689.1076; [α] 17 -14^C (C= 1.0, CHCl₃) .

Oxazolidine 30. To a solution of 29(1.7 mg, 2.5 μmol) in THF (0.2 mL) was added freshly prepared ate complex BuLi- DIBAL (1/1, 164 μL, 99 μmol) at 0 ⁰C, stirred for 5 hours. The reaction was poured into water, added HOAc (50 μL) and extracted with EtOAc (3x) . The combined organic layer was concentrated by rotary evaporation. Preparative TLC afforded 1.3 mg (78%) of a colorless oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 6.44 S 6.43 (IH, s) , 6.10 (IH, s), 5.96 & 5.92 (IH, d, J= 3.4 Hz), 5.85 (2H, m) , 5.02-4.81 (5H, m) , 4.74-4.67 (IH, m) , 4.48-4.45 (IH, m) , 4.24 & 4.20 (IH, d, J= 2.5 Hz), 4.15-4.05 (1.62H, m) , 3.76 (3H, s), 3.67-3.61 (2H, m) , 3.57-3.49 (3H, m) , 3.27-

SUBSTTTUTE SHEET (RULE 26) 3.21 (IH, m) , 3.00-2.89 (2H, m) , 2.34 (IH, m) , 2.19 &

2.17 (3H, s), 2.07 & 2.05 (3H, s) ppm; ¹³C NMR (CDCl₃,

100MHz) 6 (mixture of rotamers) 153.7, 153.0, 150.4,

145.6, 142.9, 138.9, 132.0, 129.5, 123.9, 122.3, 122.1,119.2, 119.1,112.5, 101.4, 99.7, 95.5, 90.5, 77.2,

75.2, 75.1, 70.5, 64.5, 64.1, 60.6, 57.7, 56.0, 55.8,

49.4, 48.8, 47.7, 47.3, 33.7, 32.0, 29.7, 26.7, 24.4,

23.8, 22.7,15.7, 14.1, 9.8 ppm; IR (NaCl) 3416, 2924,

1712, 1432, 1263, 1120, 1052, 970 cm -1. LRMS (APCI)

673.32/675.31, 655.35/657.32, 639.41/641.38,

615.32/617.36; HRMS (FAB) calcd for C₂₉H₃₂N₂Oi₀Cl₃ [M+H] :

673.1123; found 673.1117; 22

[OC) -100° (C= 0.2, CHCl₃) .

Allyl ether 161. To a solution of 30 (1 mg, 1.6 μmol) in DCM (0.2 mL) was added allyl bomide (2.8 μL, 32 μmol) and Hunig' s base (6.7 μL, 39 μmol) . The solution was refluxed for 16 hours. Preparative TLC afforded 0.6 mg (66%) of a glassy oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 6.64 & 6.62 (IH, s) , 6.28-6.17 (IH, m) , 5.91-5.83 (3H, m), 5.54-5.49 (IH, d, J= 4.2 Hz) , 5.30-5.23 (IH, m) , 5.07-5.00 (2H, m) , 4.87-4.64 (5H, m) , 4.50-4.43 (2H, m) , 4.21-4.19 (IH, dd, J= 7.8, 4.3 Hz) , 4.11 & 4.05 (IH, d, J= 3.3 Hz), 3.80 & 3.78 (3H, s), 3.67-3.62 (5H, m) , 3.20- 3.18 (IH, m) , 3.01-2.83 (2H, m) , 2.17 & 2.16 (3H, s) , 2.03 (3H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 153.3, 153.1, 151.0, 148.8, 148.4, 148.0,

145.6, 138.9, 134.7, 132.1, 131.8, 131.4, 131.2, 126.1, 125.5, 124.7, 118.1, 117.6, 113.7, 112.7, 101.5, 99.7, 95.5, 91.0, 90.8, 78.8, 78.1, 75.5, 75.3, 74.6, 74.1,

70.8, 70.6, 66.2, 65.5, 62.8, 60.2, 58.0, 55.9, 49.7,

48.9, 48.3, 48.1, 29.8, 24.6, 24.2, 15.9, 10.0 ppm; IR (NaCl) 3431, 2918, 2850, 1712, 1432, 1337, 1263, 1120, 1054, 972 cm^"1; LRMS (APCI) 712.37/714.37, 694.38/696.37, 678.45/680.45, 660.46/ 662.48; HRMS (FAB) calcd for

C₃₂H₃₄N₂O₁₀Cl₃[M-H] 711.1279; found 711.1279; [α]^ 2"0 -137 (C= 0.5, CHCl₃) .

Aminonitrilβ 31. To a solution 161 (0.6 mg) in THF-H₂O (8/1, 0.2 mL) were added HOAc (0.2 mL) and KCN (1 mg) . The reaction was stirred at room temperature for 16 hours. Preparative TLC afforded 0.5 mg (79%) of a colorless oil. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 6.74 & 6.71 (IH, s) , 6.31-6.16 (IH, m) , 6.15- 5.88 (3H, m) , 5.54-5.45 (IH, m) , 5.35-5.29 (IH, -m), 5.00- 4.83 (4H, m) , 4.76-4.68 (2H, m) , 4.64-4.61 (IH, m) , 4.54- 4.42 (2H, m) , 4.30-4.25 (IH, m) , 4.01-3.94 (IH, m) , 3.82 & 3.80 (3H, s), 3.72-3.62 (IH, m) , 3.49 & 3.47 (3H, s) , 3.48-3.44 (IH, m) , 3.38-3.28 (2H, m) , 2.80 (IH, d, J= 17.7 Hz), 2.22 & 2.20 (3H, s), 2.17 (2H, s) , 2.12 (3H, s) ppm; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 152.9, 149.3, 148.8, 148.4, 145.8, 138.9, 133.8, 132.6, 132.4, 130.4, 130.0, 125.9, 125.0, 124.3, 122.3, 119.8,

115.7, 114-.0, 112.4, 112.2, 101.5, 99.9, 99.5, 95.3, 75.4, 75.1, 64.8, 62.7, 62.3, 57.8, 50.0, 48.8, 48.3, 48.0, 31.1, 29.8, 15.9, 9.9 ppm; IR (NaCl) 3485, 2921,

2847, 1721, 1432, 1259, 1110, 1065 cm^' -1 , LRMS (APCI)

739.47/741.32, 721.31/723.28, 712.39/714.37, 695.3 /697.31, 677.37/679.34, 668.40/670.38; HRMS (FAB) calcd for C₃₃H₃₇N₃Oi₀Cl₃ [M+H] : 740.1545; found 740.1573; [α] 17 + 92° (c= 0.1, CHCl₃) .

Triol 32. To a solution of 162 (0.5 mg) in DCM (0.2 mL) was added TFA (4 μL) . The reaction was stirred at -20 ⁰C for 90 min. Preparative TLC afforded 0.2 mg of product. ¹H NMR (CDCl₃, 400MHz) δ (mixture of rotamers) 9.59 & 9.56 (IH, s), 6.82 & 6.79 (IH, s) , 6.25-6.15 (IH, m) , 5.94- 5.74(4H, m) , 5.58-5.40 (2H, m) , 5.00-4.67 (4H, m) , 4.54- 4.47 (IH, m) , 4.40-4.20 (2H, m) , 4.00-3.95 (IH, m) , 3.84-

3.82 (3H, s), 3.64-3.56 (IH, m) , 3.35-3.20 (3H, m) , 2.88-

2.83 (IH, d, J= 17.7 Hz) 2.25 & 2.23 (3H, s) , 2.07 & 2.05 (3H, s) ppm; IR (NaCl) 3001, 2925, 2848, 1721, 1432, 1261, 1124 cm^"1; ¹³C NMR (CDCl₃, 100MHz) δ (mixture of rotamers) 153.0, 149.6, 148.9, 147.6, 146.0, 144.4, 138.7, 135.5, 133.0, 132.1, 130.7, 130.2, 126.7, 123.9, 121.9, 121.5, 115.9, 110.4, 109.7, 108.1, 101.1, 95.2, 81.4, 75.7, 75.4, 69.0, 65.5, 62.1, 61.6, 60.8, 59.4, 58.4, 50.0, 48.7, 47.6, 47.2, 39.6, 33.8, 32.1, 30.9, 29.8, 22.8, 16.0, 8.7 ppm; LRMS (APCI) 695.36/697.36, 677.38/ 679.34, 668.35/670.36; HRMS (FAB) calcd for

C_3IH₃₂N₃O₉Cl₃ [M+H] : 695.1204; found 695.1216; [α] _D ¹⁹ +43° (c= 0.25, CHCl₃) .

References

(1) C. Chan, R. Heid, S. Zheng, J. Guo, B. Zhou, T. Furuuchi, S. J. Danishefsky, J. Am. Chem. Soc. 2005, 127, 4596.

(2) X. Chen, J. Chen, M. De Paolis, J. Zhu, J. Org. Chem. 2005, 70, 4397.

(3) For an excellent review of the tetrahydroisoquinoline alkaloids, see: D. J. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669.

(4) For a previous example of connecting the subunits by- amide bond formation to a secondary amine, see: E. J. Martinez, E. J. Corey, Org. Lett. 2000, 2, 993.

(5) A. K. Sinhababu, A. K. Ghosh, R. T. Borchardt, J. Med. Chem. 1985, 28, 1273.

(6) R. M. Williams, P. P. Ehrlich, W. Zhai , J. Hendrix, J. Org. Chem. 1987, 52, 2615.

(7) A. Fujii, S. Hashiguchi, N. ϋematsu, T. Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 2521. (8) A. S. Thompson, G. R. Humphrey, A. M. DeMarco, D. J.

Mathre, E. J. Grabowski, J. Org. Chem. 1993, 58, 5886.

(9) a) J. M. Bobbitt, J. C. Sih, J. Org. Chem. 1968, 33,

856. b) J. M. Bobbitt, T. E. Moore, J. Org. Chem. 1968,

33, 2958. (10) K. Laali, R. J. Gerzina, C. M. Flajnik, C. M. Geric,

A. M. Dombroski, HeIv. Chim. Acta. 1987, 70, 607.

(11) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1982, 104, 902.

(12) P. Four, F. Guibe, Tetrahedron Lett. 1982, 23, 1825. (13) For a related example, see: M. J. Martin-Lopez, F.

Bermejo-Gonzalez, Tetrahedron Lett. 1994, 35, 8843. (14) E. J. Corey, J. Das, Tetrahedron Lett. 1982, 23, 4217. ( 15 ) J . D . Hobson, J. G. McCluskey, J. Chem. Soc. 1967 ,

2015 .

(16) Direct McCluskey reaction of a MOM derivative of the type 23 failed due to undesired reactivity centered at the MOM ether protecting group.

(17) For a related rearrangement versus selective reduction of an enamide epoxide, see: L. A. Mitscher, H. Gill, J. A. Filppi, R. L. Wolgemuth, J. Med. Chem. 1986, 29, 1277. (18) S. Kim, K. H. Ann, J. Org. Chem. 1984, 49, 1717.

(19) The use of LiAlH2 (OEt) 2 , LiAlH3 (OEt) , and Red-Al gave intractable reaction products. Along these lines, LiAlH (OtBu) 3 reduced lactam 29 to oxazolidine 30, however, in low conversion (10%) , while boranes afforded the corresponding amine due to exhaustive reduction of the lactam.

(20) A. Endo, A. Yanagisawa, M. Abe, S. Tohma, T. Kan, T. Fukuyama, J. Am. Chem. Soc. 1996, 118, 9202.

(21) Total syntheses of 1: E. J. Corey, D. Y. Gin, R. S. Kania, J. Am. Chem. Soc. 1996, 118, 9202;

(22) A. Endo, A. Yanagisawa, M. Abe, S. Tohma, T. Kan, T. Fukuyama, J. Am. Chem. Soc. 2002, 124, 6552.

(23) For a review of these compounds, see: D. J. Scott, R. M. Williams, Chem. Rev. 2002, 102, 1669. (24) C. Cuevas, M. Perez, M J. Martin, J. L. Chicharro, C. Fernandez-Rivas, M. Flores, A. Francesch, P. Gallego, M. Zarzuelo, F. de Ia Calle, J. Garcia, C. Polanco, I. Rodriguez, I. Manzanares, Org. Lett. 2000, 2, 2545. (25) For a previous example in the context of a total synthesis, see: C. Chan, R. Heid, S. Zheng, J. Guo, B. Zhou, T. Furuuchi , S. J. Danishefsky, J. Am. Chem. Soc. 2005, 227, 4596. (26) For an example of an anti renieramycin compound, see: J. W. Lane, Y. Chen, R. M. Williams, J. Am. Chem Soc. 2005, 227, 12684.

(27) a) K. B. Sharpless, Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune, J. Am. Chem. Soc. 1987,

109, 5765; b) K. B. Sharpless, J. Hartung, K. Jeong, H.

Kwong, K. Morikawa, Z. Wang, D. Xu, X. Zhang, J. Org

Chem. 1992, 57, 2768; c) M. Caron, P. R. earlier, K. B.

Sharpless, J. Org. Chem. 1998, 53, 5185. (28) S. Winstein, R. Baird, J. Am. Chem. Soc. 1957, 19,

756.

(29) a) T. Jeffery, J. Chem. Soc., Chem. Commun. 1984,

19, 1287; b) A. McKillop, R. J. K. Taylor, R. J. Watson,

N. Lewis, Synthesis 1994, 1, 31. (30) M. J. Burk, J. E. Feaster, W. A. Nugent, R. L.

Harlow, J. Am. Chem. Soc. 1993, 115, 10125.

(31) Okumoto, T. et al . , Activity of saframycins A and B, heterocyclic quinine antibiotics, on experimental tumors in mice, J. Antibiot. (Tokyo), 38 (6) : 767-771 (1985). (32) Kishi, K. et al . , Structure-activity relationships of Saframycins, J. Antibiot. (Tokyo), 37 (8) : 847-852

(1984) .

(33) Mikami, Y. et al , Saframycin S, a new saframycin group antibiotic. J. Pharmacobidyn. 4(4):282-286 (1981). (34) Reid, J. M. , et al. Preclinical pharmacology of ecteinascidin 729, a marine natural product with potent anti-tumor activity, 38 (4) : 329-334 (1996).

Claims

Claims

1. A compound having the structure:

wherein

Ri is a Ci-C₄ alkyl , H, or -C(O) (C₁-C₄ alkyl) ,

R₂ is a Ci-C₄ alkyl, -0(C_x-C₄ alkyl) , -S(C₁-C₄ alkyl),

R₃ is H, OH, -0(C₁-C₄ alkyl) or a halogen,

R₄ is H, OH, or a halogen,

Rs is 0 and bond φ is present, or Rs is -CN, OH or -

0(Ci-C₄ alkyl) and bond φ is absent,

R₆ is -0-benzyl, OH, H, -0(Ci-C₄ alkyl), or

OSi (CH₃) ₂ (t-butyl) , or R₆ and R₅ are joined to form an

-0- and bond φ is absent,

R₇ and R₈ form a methylenedioxy group, or are each independently -C_x-C₄ alkyl or -0(Ci-C₄ alkyl) ,

R₉ is a Ci-C₄ alkyl, -0(C_x-C₄ alkyl), or -S(C₁-C₄ alkyl) , Ri₀ is H, methoxymethyl , tert-butyldimethylsilyl, or a C₁-C₄ alkyl, -CH₂(C₆H₅), phenyl, allyl, or -C(O)(C₁-

C₄ alkyl) ,

Ri₁ is H, OH, -0(C₁-C₄ alkyl), -O-benzyl, -0(C)OH, -

OC(O) (C₁-C₄ alkyl), or -OSi (CH₃) ₂ (t -butyl) , and bond η is absent, or R₁₁ is O and bond η is present,

R₁₂ is H, or OH, and bond α is absent, or R₁₂ is absent and bond α is present, or R₁₂ and Ri₁ are joined to form an -O- and bonds α and η are absent,

R₁₃ is PMBO and bonds β, γ and δ are absent, or R₁₃ is

H, or Ri₃ is 0 and bond γ is present,

R₁₄ is H, CH₃ or Troc and bond ε is absent and Ri₅ is absent, or R₁₄ is CH₃, bond ε is present, R₁₅ is Boc and bonds β and δ are absent, and

Ri₆ is OH, -O-benzyl, PMBO or -0-allyl, (C₁-C₄) alkyl , or -C(O) (Ci-C₄) alkyl,

wherein when R₁₄ is CH₃ and R₁₅ is absent , then R₁₂ is

OH, or an enantiomer, tautomer or salt of the compound.

2. The compound of claim 1, wherein R₁ is methyl, R₂ is a methyl, R₃ is H, R₄ is H,

R₅ is 0 and bond φ is present, or R₅ is CN and bond φ is absent, or R₅ is joined directly to R₆ to form an -0- and bond φ is absent, R₅ is -O-benzyl or OH, R₇ and R₈ form a methylenedioxy group, R₉ is methyl ,

Rio is methyl, H, methoxymethyl , tert- butyldimethylsilyl , or allyl,

Rn is H or OH and bond η is absent, or Rn is joined directly to R_i2 to form -0-, or Rn is 0 and bond η is present,

Ri₂ is j oined to R₁₁ by an 0 atom , or R₁₂ is H , or OH , or is absent ,

Ri₃ is PMBO and bonds β, γ and δ are absent, or R₁₃ is

H, or Ri₃ is 0 and bond γ is present, and

Ri4 is CH₃ or Troc and bond ε is absent and R₁₅ is absent, or Ri₄ is CH₃, bond ε is present, and R₁₅ is

Boc and bonds β and δ are absent , and

Ris is OH, -0-benzyl, PMBO or -0-allyl.

3. The compound of claim 1, wherein R₂ is -OCH₃, -OC₂H₅, -SCH₃ or -SC₂H₅.

4. The compound of claim 1, wherein R₃ is -OCH₃.

5. The compound of claim 1, wherein R₅ is -OCH₃.

6. The compound of claim 1, wherein R₉ is -OCH₃, -OC₂H₅, -SCH₃ or -SC₂H₅.

7. The compound of claim 1 or 2, having the structure:

The compound of claim 1 or 2 , having the structure :

The compound of claim 1 or 2 , having the structure

The compound of claim 1 or 2 , having the structure :

11. The compound of claim 1 or 2 , having the structure

12. The compound of claim 1 or 2 , having the structure:

13 . The compound of claim 1 or 2 , having the structure :

14 . The compound of claim 1 or 2, having the structure:

15. The compound of claim 1 or 2 , having the structure:

16 . The compound of claim 1 or 2 , having the structure :

ompound of claim 1 or 2 , having the structure:

ompound of claim 1 or 2, having the structure:

ompound of claim 1 or 2 , having the structure :

20 . The compound of claim 1 or 2 , having the structure;

21. The compound of claim 1 or 2 , having the structure :

22 . The compound of claim 1 or 2 , having the structure :

23. A compound having the structure:

wherein

R₁₇ is -OTBDPS or -O-allyl, and wherein R₁₈ is a halide, -C(O)CH₂OBn,

C(OH) (H)CH₂OBn, -C(N₃)CH₂OBn, -C(NHCH₂C(OMe)₂H)CH₂OBn, or C(H)CH₂OBn)NHCH₂C⁵H(OH) wherein carbon ξ is covalently attached to carbon ψ to form a ring, and R₁₉ is a C1-C4 alkyl, -0(C₁-C₄ alkyl) , -S(C₁-C₄ alkyl) .

24. The compound of claim 23, wherein R₁₇ is -OTBDPS or -O-allyl,

And wherein Ri₈ is a halide, -C(O)CH₂OBn, C(OH) (H)CH₂OBn, -C(N₃)CH₂OBn, -C(NHCH₂C(OMe)₂H)CH₂OBn, or C (H) CH₂OBn) NHCH₂C^ξH( OH) wherein carbon ξ is covalently attached to carbon ψ to form a ring, and R₁₉ is CH₃.

25. The compound of claim 24, wherein R₁₉ is -OCH₃, OC₂H₅, -SCH₃ or -SC₂H₅.

26. The compound of claim 23 or 24, having the structure:

27. The compound of claim 23 or 24, having the structure:

28, The compound of claim 23 or 24, having the structure:

29, The compound of claim 23 or 24, having the structure:

30, The compound of claim 23 or 24, having the structure:

31 . The compound of claim 23 or 24 , having the .structure :

32. A process for making a compound having the structure :

comprising:

a) exposing a compound having the structure:

to Br₂, NaOAc, in AcOH, then

BrCH₂Cl, Cs₂CO₃, in N,N-dimethylformamide, then m-choloroperoxybenzoic acid and then acidifying with HCl, then tert-butyldiphenylsilyl-Cl, triethylamine, in 4- (dimethylamino) pyridine so as to produce a compound having the structure :

b) exposing the product of step a) to nBuLi in toluene/THF, then neat Me-(MeO)NC(O)CH₂OBn so as to produce a compound having the structure :

c) exposing the product of step b) to Noyori R, R catalyst, HCO₂H, and triethylamine, in N₁N- dimethylformamide so as to produce a compound having the structure :

d) exposing the product of step c ) to diphenylphosphoryl azide , 1 , 8 -

SUBSTTTUTE SHEET (RULE 26) diazabicyclo [5.4.0] undec-7-ene, in toluene/N,N- dimethylformamide so as to produce a compound having the structure:

e) exposing the product of step d) to H₂ and Pd/C, in EtOAc then

(MeO)₂CHCHO, AcOH, NaCNBH₃, MgSO₄, in MeOH, then tetrabutylammonium fluoride in THF, then allyl bromide, NaH, in N, N-dimethylformamide so as to produce a compound having the structure :

f) exposing the product of step e) to HCl and dioxane so as to produce a compound having the structure:

g) exposing the product of step f) to a compound having the structure:

and bis (2-oxo-3-oxazolidinyl)phosphinic chloride, triethylamine, in CH₂Cl₂ so as to produce a compound having the structure:

h) exposing the product of step g) to 2, 3-dichloro-5, 6- dicyano-1 , 4-benzoquinone, in CH₂Cl₂ at or about pH 7.0, then

Cu(OTF)₂ in benzene, then Dess-Martin periodinane in CH₂Cl₂ then [(PPh₃J₂PdCl₂], Bu₃SnH, in AcOH so as to produce a compound having the structure:

i) exposing the product of step h) to CHF₂CO₂H, MgSO₄, in benzene so as to produce a compound having the structure .-

j) exposing the product of step i) to tert- butyldimethylsiIyI-0-trifluoroinethanesulfonyl , triethylamine, in CH₂Cl₂ then

2,2, 2-trichloroethoxycarbonyl-Cl , tetrabutylammonium iodide, in toluene so as to produce a compound having the structure:

k) exposing the product of step j ) to tetrabutylammonium fluoride in CH₂Cl₂ then methoxymethyl-Cl and HOnig base so as to produce a compound having the structure:

1) exposing the product of step j) to DMDO in CH₂Cl₂ so as to produce a compound having the structure :

m) exposing the product of step 1) to a large excess of sodium cyanoborohydride so as to produce a compound having the structure:

n) exposing the product of step m) to H₂, Pd/C, in EtOAc, so as to produce a compound having the structure :

o) exposing the product of step n) to diisobutylaluminum hydride/BuLi in THF so as to produce a compound having the structure :

p) exposing the product of step o) to allyl bromide, HDnig base, in CH₂Cl₂ then,

KCN in AcOH so as to produce a compound having the structure :

q) exposing the product of step p) to trif luoroaceti c acid in CH₂Cl₂ so as to produce a compound having the structure :

r) treating the product of step q) so as to produce the compound.

33. A process for making a compound having the structure:

wherein R₉ is a Ci-C₄ alkyl , -0(Ci-C₄ alkyl) , or -S(Ci-

C₄ alkyl) , comprising:

a) exposing a compound having the structure:

to Br₂, NaOAc, in AcOH, then

BrCH₂Cl, Cs₂CO₃, in N,N-dimethylformamide, then m-choloroperoxybenzoic acid and then acidifying with HCl, then tert-butyldiphenylsilyl-Cl, triethylamine, in 4- (dimethylamino) pyridine so as to produce a compound having the structure:

b) exposing the product of step a) to πBuLi in toluene/THP, then neat Me-(MeO)NC(O)CH₂OBn so as to produce a compound having the structure:

.

c) exposing the product of step b) to Noyori R, R catalyst, HCO₂H, and triethylamine, in N, N- dimethylformamide so as to produce a compound having the structure :

d) exposing the product of step c ) to diphenylphosphoryl azide , 1 , 8 - diazabicyclo [5 . 4 . 0] undec- 7 - ene , in toluene/N , N-

SUBSΗTUTE SKDEET (RULE 26) dimethylformamide so as to produce a compound having the structure :

e) exposing the product of step d) to H₂ and Pd/C, in BtOAc then

(MeO)₂CHCHO, AcOH, NaCNBH₃, MgSO₄, in MeOH, then tetrabutylammonium fluoride in THF, then allyl bromide, NaH, in N, N-dimethylformamide so as to produce a compound having the structure :

f) exposing the product of step e) to HCl and dioxane so as to produce the compound.

34. The process of claim 33, wherein R₉ is methyl.

35. A process for cyclizing an ortho-hydroxystyrene having the structure:

wherein R₁, R₂, R₆, R₇, R₈, R₉ and Ri₆ are as defined in claim 1 comprising exposing the compound to CHF₂CO₂H, MgSO₄ and benzene so as to produce a pentacycle having the structure :

36 . The process of claim 35 , wherein the ortho- hydroxystyrene having the structure :

and the pentacycle has the structure :

37. A process for hydrating a carbon-carbon double bond α in a compound having the structure:

comprising: c) exposing the compound to dimethyl dioxirane in CH₂CI₂ so as to produce a compound having the

structure :

d) exposing the product of step a) to NaCNBH₃ so as to hydrate the carbon-carbon double bond and so produce a compound having the structure :

38. The process of claim 37, wherein the compound comprising the carbon-carbon double bond to be hydrated has the structure :

the product of step a) has the structure:

and the product of step b) has the structure:

39. The process of claim 37, wherein the compound comprising the carbon-carbon double bond to be hydrated has the structure:

the product of step a) has the structure

and the product of step b) has the structure

40. A composition comprising a compound of any one of claims 1-22 and a pharmaceutically acceptable carrier.