Ph OEt Ph O Ph O N Ph MeO O O O 3 Å MS O H + MeO + O O HN O H N toluene, rt HN H OEt

Multicomponent Reactions in Total Synthesis Generation of Complex Polyfunctionalized Molecules Using Convergent One-Pot Transformations

O OEt TFE HN N + + aq. HCHO H rt O NH2 OEt O OEt

Kevin Allan Stoltz Group Literature Meeting Monday, February 5, 2007 8:00 PM 147 Noyes

Ph Ph Ph OTBS Ph HN Ph PhHN 1. LDA (3.3 equiv) Ph HN N N Ph N Ph N 2. PhCN Ph Ph Ph Ph Ph Ph N Ph O Ph H

3-CR 4-CR 5-CR Multicomponent Reactions in Total Synthesis

· Introduction to Multicomponent Reactions

· Reactions Involving Activated Carbonyl Species · / Petasis ( Mannich) Reaction · Biginelli Dihydropyrimidinone Synthesis A · Passerini Reaction ·

· Cycloadditions · Povarov Reaction B C · Knoevenagel / Hetero-Diels-Alder Cycloaddition · 1,3-Dipolar Cycloadditions

· Multiple Anion Capture · Heterospirocyclic Compounds and Medium-Sized Lactones · Radialene-Shaped Pyrroles A · Allene Dianions and Nitrile Oligomers

· One-Pot Total Syntheses B D · Nitaramine · Glyantrypine, Fumiquinazoline F, Fiscalin B · Schlerotigenin, Circumdatin F, Asperlicin C C · Conclusions

Reviews: Dömling, A. Chem. Rev. 2006, 106, 17-89. Multicomponent Reactions. Zhu, J.; Bienaymé, H., eds. Wiley-VCH; Weinheim, 2005. Orru, R. V. A.; de Greef, M. Synthesis 2003, 10, 1471-1499. Ugi, I. Pure Appl. Chem. 2001, 73, 187-191. Bienaymé, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321-3329. Ugi, I. J. Prakt. Chem. 1997, 339, 499-516. Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115-122. Multicomponent Reactions An Introduction

"Multicomponent reactions (MCRs) are processes involving sequential reactions among three or more reactant components that co-exist in the same reaction mixture. In order to be efficient, MCRs rely on components that are compatible with each other and do no undergo alternative irreversible reactions to form other products or by-products."

-- Jieping Zhu in Multicomponent Reactions

· Addendum: The products of multicomponent reactions comprise a portion of each individual reactant component.

· Multicomponent reactions are sometimes referred to as tandem or domino reactions.

· Multicomponent reactions may be further classified by the number of molecules and the number of functional groups participating in the reaction.

Example:

A + B + C + D A B C D 4-component reaction

A + B C + D A B C D 3-component-4-center reaction

· Multicomponent reactions are also classified by the reversibility of steps leading to the product.

Type I Substrates Intermediates Product

Type II Substrates Intermediates Product

Type III Substrates Intermediates Product

Ugi, I. J. Prakt. Chem. 1997, 399, 499-516. Bienaymé, H. Chem. Eur. J. 2000, 6, 3321-3329. Multicomponent Reactions A New Approach to Total Synthesis

· Linear total syntheses require significant amounts of time and money to advance starting materials to complex targets. A B C A D 1 mol 1 mol 1 mol A A B B D 50% 50% 50% B C C 1 mol 0.5 mol 0.25 mol 0.125 mol

· MCRs minimize cost in the form of time and material by generating complex targets in a single convergent step.

A

50% A + B + C + D B D

C 1 mol 1 mol 1 mol 1 mol 0.5 mol

· MCRs typically run at mild temperatures and do not require many reagents in excess of the participating substrates. This has made them ideal for combinatorial library synthesis as well as industrial pharmaceutical synthesis.

(1) 1 1 1 1 A B C D A1 An (2) A2 B2 C2 D2

· · + · + · + · B1 D1 · · · Bn Dn · · · · · · · · · · (n) An Bn Cn Dn C1 Cn

m component reaction with n types of each component → nm products n = 5 (20 SM cmpds) → 625 products n = 10 (40 SM cmpds) → 10,000 products n = 50 (200 SM cmpds) → 6.25 mill products Mannich Reaction Three-Component Synthesis of β-Aminocarbonyls

· In 1903, B. Tollens and C. M. van Marle observed the formation of a tertiary from the treatment of an aqueous solution of acetophenone and formaldehyde with ammonium chloride.

O O O NH4Cl + N H H H2O 3 Tollens, B.; van Marle, C. M. Ber. 1903, 36, 1347-1351. · In 1917, Carl Mannich (Berlin, Germany) reported the formation of a number of β-aminoketones under the same conditions. O O H O O H 2 + + N N H H 100 °C

O O H2O + + NH4Cl several products H H 100 °C O

O O H2O + + NH4Cl + several side products H H 100 °C N

Mannich, C. Archiv. Pharm. 1917, 255, 261-276. Mannich, C. J. Chem. Soc. Abstr. 1917, 112, 634-635. · The Mannich reaction is a Type I MCR that proceeds under both acidic and basic conditions, though acidic conditions are more common. In 1969, Stephen Benkovic (Penn State) performed kinetics experiments over a broad pH range that supported the formation of a pH-dependent steady state iminium intermediate under acidic conditions. Under basic conditions, a carbinolamine intermediate presides.

H N H Lewis or Bronsted acid H N N Polar N HN N Ar N H N HN H N Base CO2Et Apolar solvent N CO2Et HN HO Ar

Benkovic, S. J. J. Am. Chem. Soc. 1969, 91, 1860-1861. Mannich Reaction Select Total Syntheses Robinson's Synthesis of Tropinone:

O O O N O N OMe HO OH OH + N N H2O HO O Me NH2 O rt, 50 h O - CO2 + O HO O O O H H O Atropine Cocaine O O

Robinson, R. J. Chem. Soc. 1917, 762-768.

Omura's Synthesis of (+)-Madindoline A and B:

HO

HO HO HO O N H H 37% aq. HCHO O O O Sc(OTf)3 (10 mol%) N TAS-F N N + H H + H Me Me Me H2O, rt, 24 h DMF, rt, 20 min O O O O O Me CO2Me (11% yield) (77% yield) TMSO CO2Me TMS n-Bu n-Bu n-Bu

TMS n-Bu (+)-Madindoline A (+)-Madindoline B TAS-F = (Me2NH)3S Me3SiF2

Omura, S. Tetrahedron Lett. 2006, 47, 6761-6764. Petasis (Boronic Acid Mannich) Reaction Three-Component Synthesis of Allyl, Propargyl, and Benzylamines · In 1993, Nicos A. Petasis (USC) described the preparation of tertiary allylic from paraformaldehyde, secondary amines, and vinyl boronic acids under acid-free conditions. Yields ranged from 75-96%.

NH N OH

B (CH2O)n + OH dioxane 90 °C, 30 min

OH O (CH2O)n O + B NH N n-C H n-C5H11 OH dioxane 5 11 90 °C, 30 min Petasis, N. A. Tetrahedron Lett. 1993, 34, 583-586. · The Petasis reaction is a Type II reaction, though the precise mechanism is still disputed:

· Petasis noted that in the absence of acid, it was unlikely that significant amounts of the iminium salt would form. Also, boronic acids did not readily add to preformed iminium salts, though they did react with diamines. Based on these observations, Petasis proposed the formation of an intermediate ammonium borate complex followed by internal delivery of the vinyl nucleophile.

OH SLOW 2 3 + R R B N N R N 2 H HO R Cl H OH R R2 HO B O N OH + O R3 R1 N R3 B OH FAST 1 1 + N R HO R H H R H H B N N HO R

· However, the vast majority of cases in the literature employ an substrate containing a directing group near the carbonyl, indicating a necessity for formation of a two-center ionic complex. In these cases, a protic solvent is typically used (MeOH, EtOH, TFE).

R2 R3 2 3 R2 R3 R R O O N N OH H N O O H R H OH R H O + H H OH R1 O B OH N O OH HO R O B OH OH R R R OH R

Bryce, M. R.; Hansen, T. K. Tetrahedron Lett. 2000, 41, 1303-1305. Petasis, N. A. Tetrahedron Lett. 2001, 42, 539-542. Schreiber, S. L. Angew. Chem. Int. Ed. 2006, 45, 3635-3638. McReynolds, M. D.; Hanson, P. R. Chemtracts 2001, 14, 796-801. Petasis (Boronic Acid Mannich) Reaction Substrate Scope

O O S N O

H H N NH2 N NH2 N H OH OMe R1 OR2 R N O H R = H, OH, OMe H N R1 = Me, t-Bu, Bn, Cy N NH2 N NH H 2 O R = H, Me N N N NH H 2 O O N NHR2 1 NH2 H R O N R N H NH N 1 2 R = H, OH, OMe N R = t -Bu, Bn, NH2 HO 2 R = H, Ph, Bn, CH2Cy N Ph H O CH2CO2Me HO O R O O Ph Ph NH O H S R = H, Me, Et, Ph, Bn t-Bu NH2 Ph NH2 Ph

O B(OH)2 Br B(OH) R 2 B(OH) B(OH)2 2 B(OH)2 O O Br R R = H, Me, n-Bu, Ph R = H, Me, OMe R B(OH)2 B(OH) BF3 B(OH)2 O 2 N B(OH)2 K SO Ph S 2 R = H, OMe, Cl, Br Petasis (Boronic Acid Mannich) Reaction Pyne's Total Synthesis of Uniflorine A

OH HO HO Ph H 1. Boc2O, Et3N HO OH B HO Ph EtOH 2. TrCl, pyr + OH O rt, 16 h HN st HO HO 3. Grubbs 1 gen. CH Cl , reflux H N 2 2 L-xylose 2 (73% yield) OH single diastereomer (30% yield, 3 steps)

HO BnO OBn H 1. K OsO ·2H O, NMO H HO 2 4 2 BnO / H2O, rt TFA OBn N 2. NaH, BnBr N anisole, CH Cl HO BnO 2 2 Boc Boc 0 °C TrO (67% yield) TrO

BnO BnO HO H OBn H OBn H OH BnO BnO HO PdCl2, H2 OBn + OBn OH HN N MeOH, rt N BnO BnO HO HO (63% yield) Uniflorine A 37% yield 54% yield converted to peracetate for crystallography

Ph3P, CBr4

Et3N, CH2Cl2, 0 °C

(54% yield) Pyne, S. G. J. Org. Chem. 2004, 69, 3139-3143. Biginelli Reaction Three-Component Synthesis of Substituted Dihydropyrimidinones

· In 1891, Pietro Biginelli (Florence, Italy) discovered a three-component condensation of , ureas, and β-ketoesters under strongly acidic conditions that produced dihydropyrimidinones.

Ph

EtO C EtO2C Ph 2 NH2 cat. HCl * NH + + H O H N O EtOH, reflux O 2 N O H

Biginelli, P. Ber. 1891, 24, 2962-2967, Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360-416.

· In 1973, Sweet et al. proposed a Type II mechanism in which the first, rate-limiting step involved aldol condensation of the β-ketoester and aldehyde substrates, followed by SN1 loss of H2O to form a β-carbocation. Quenching with urea and condensation with the then closed the ring.

Ph Ph NH2 Ph O EtO2C EtO C + EtO C H N O EtO C NH 2 H 2 2 2 - H2O Ph N NH2 + H - H O + N O O H O 2 O - H O H

Sweet, F.; Fissekis, J. D. J. Am. Chem. Soc. 1973, 95, 8741-8749.

· In 1997, Kappe et al. proposed at alternate mechanism in which the urea and aldehyde substrates first condensed to form an N-acyliminium intermediate that was then quenched by addition of the β-ketoester.

O Ph O + NH2 EtO2C EtO2C NH H EtO2C NH - H2O NH Ph + 2 2 - H O Ph N O H O H2N O 2 Ph N O N O H H H

Kappe, C. O. J. Org. Chem. 1997, 62, 7201-7204. Kappe, C. O. Acc. Chem. Res. 2000, 32 879-889. Biginelli Reaction Three-Component Synthesis of Substituted Dihydropyrimidinones · Two observations support Kappe's mechanism:

1. Ethyl acetoacetate and benzaldehyde are slow to condense under the reaction conditions, while urea and benzaldehyde quickly form bis-ureides. In addition, the expected dihydropyrimidine product forms upon addition of ethyl acetoacetate to the bis-ureide. O O O O O O O O Ph HN NH2 EtO2CH2 O EtO C EtO EtO H2N NH2 Ph EtO2C 2 OR NH HN NH SLOW Ph H 2 Ph OH Ph FAST N O O H Kappe, C. O. J. Org. Chem. 1997, 62, 7201-7204. 2. Thioureas form dihydropyrimidine-2-thiones under the 3-CR conditions, but form 2-amino-1,3-thiazines when

added to enones. Ph

EtO C EtO2C Ph 2 NH2 NH + + H O H N S O 2 N S H

Ph Ph EtO C 2 EtO2C NH2 S + O H N S 2 N NH2

Kappe, C. O. J. Heterocycl. Chem. 1989, 26, 55-64. · Additionally, isolation of sterically and electronically modified intermediates support urea-ketone condensation as the last step (supports both proposed mechanisms).

Ph O Ph

Et2OC EtO2C N NH2 NH H HO O N O F3C H

slow to cyclize slow to eliminate

Hu, E. H. J. Org. Chem. 1998, 63, 3454-3457. Kappe, C. O. Heterocycles 1999, 51, 77-84. Biginelli Reaction Application to the Total Synthesis of the Batzella Alkaloids

NH2 O NH2 O H H H H N NH O N N NH O N

6 6 Me N N (CH2)8Me Me N N (CH2)8Me H H H H H H H2N N H2N N O O O O NH2 Batzelladine A NH2 Batzelladine B

O O H H H H H H2N N H2N N O N O N

NH2 NH2 N N (CH2)6Me Me N N (CH2)8Me H H H Dehydrobatzelladine C Batzelladine D

O O H H H H N O H2N N O N H H 14 H2N Me N N O N N N H H O H H O

Me N N (CH2)8Me H H Batzelladine F Ptilomycalin A

O O O O H H H H N N O N H N N O N 2 14 2 H2N H2N N N N N O H H O H O OH OH HO

Crambescidin 800 Crambidine Isolations: Batzelladines A-E: Patil, A. D. J. Org. Chem. 1995, 60, 1182-1188. Batzelladines F-I: Patil, A. D. J. Org. Chem. 1997, 62, 1814-1819. Ptilomycalin A: Kashman, Y. J. Am. Chem. Soc. 1989, 111, 8925-8926. Crambescidin 800: Minale, L. Tetrahedron 1995, 51, 3675-3682. Crambidine: Kashman, Y. J. Am. Chem. Soc. 1992, 114, 8472-8479. Biginelli Reaction 2-Component 3-Center: Overman's Synthesis of (—)-Batzelladine D

MeO OH 11 steps n-C9H19 AcOH MeO N n-C9H19 H2O O (47% yield) H2N NH OH H2N NH NH·HCl

O O O OH O H H H O(CH2)4NHCbz 1. MsCl, Et N n-C H 3 CbzHN(CH2)4O N 9 19 CbzHN(CH2)4O N 2. Et3N, CHCl3 O NH·HOAc Me N NH·HOAc reflux Me N N (CH2)8Me H H H (55% yield, 2 steps) (60% yield) Cl

N O N O H H H H H H2N N H2, Rh/Al2O3 HCl·HN NH2 H2N(CH2)4O N O N

HCO2H, MeOH/H2O i-Pr2NEt, DMF NH2 Me N N (CH2)8Me Me N N (CH2)8Me H H H H (68% yield) (75% yield) TFA TFA TFA 1:1.2 d.r. (desired is minor) (—)-Batzelladine D

Overman, L. E. J. Org. Chem. 1999, 64, 1512-1519. Overman, L. E. Org. Lett. 1999, 1, 2169-2172. Biginelli Reaction Modified Biginelli: Kishi's Total Synthesis of (±)-Saxitoxin

OBn

CO Me O 2 S CO2Me CO2Me RHN OBn N O · PhH O H O 100 °C + HN N S N S N O Si 4 O O (75% yield)

OBn OBn OBn 1. NH NH ·H O, MeOH H H CO Me 2 2 2 2 2. NOCl, CH Cl , - 50 °C N NH2 HS SH N NH2 TFA / AcOH HN 2 2 HN HN O 3. PhH, 90 °C O BF3·OEt2 O 50 °C S N S N S N 4. NH3, PhH O S O (63% yield) (50% yield) (75% yield, 4 steps) O S

OBn OH H2N O O H 1. Et3O·BF4, NaHCO3 H · SO Cl H N N 2 O N HN 2. EtCO2NH4 (33%, 2 steps) HN N HN O NH2 NH2 3. BCl , 0 °C (75%) hot H O S N NH 3 HN N N 2 HN N N S 4. NBS, MeCN / H2O (30%) OH work-up OH S OH (50% yield) OH (±)-Saxitoxin

Busby, G. W., III. Ph.D. Dissertation, Harvard University, 1974. Kishi, K. Y. J. Am. Chem. Soc. 1977, 99, 2818-2819. Passerini Reaction Three-Component Synthesis of α-Acyloxyamides

· In 1921, Mario Passerini (Florence, Italy) discovered the three-component condensation of , acids, and aldehydes/. It was the first synthetically useful reaction involving isocyanides. The reaction is typically run in apolar (THF, CH2Cl2) to avoid cleavage of the acyl substituent, but can be run in alcohol to generate α-hydroxyamides.

O R1 R2 O O apolar solvent 4 (1) + + 4 NHR R NC R3 O R1 R2 R3 OH O

R1 R2 O O Lewis or Br∅nsted acid 4 + + 4 NHR (2) R NC HO R1 R2 R3 OH polar or protic solvent O

3 * same product is formed if R CO2H is replaced by H2O in (2)

Passerini, M. Gazz. Chim. Ital. 1921, 51, 181-189.

· The originally proposed mechanism involved condensation between the acid and aldehyde, followed by attack by the . However, it was unclear how the second step would proceed to product. In 1951, Baker proposed the Type II mechanism that is accepted today involving isocyanide attack upon the aldehyde, followed by quenching of the cation by the carboxylate and subsequent rearrangement.

O R1 O O OH O R3 NC Passerini 3 + NHR (1921) R2 O R1 H HO R2 R1 O R2 ? O

O 1 OH 2 OH O R Baker O O R acyl 3 O R2 NHR3 + R NC 1 (1951) R R1 migration R2 O R1 H NR3 NR3 O O

Baker, R. H. J. Am. Chem. Soc. 1951, 73, 699-702. Passerini Reaction Semple's Total Synthesis of Eurystatin A

NHCbz Me O OBn Me FmocHN N 1. Et2NH, CH2Cl2 CH2Cl2 H (75% yield) OH + H + OBn O O O BocHN FmocHN CN 0 °C → rt 2. H2, Pd/C O O O 3-5 days NHCbz MeOH BocHN (80% yield) (95% yield)

HO O O Me O 1. HCl, EtOAc, 0 °C BocHN OH DPPA, NaHCO3 (quantitative) N N HN HN H H DMF, 0 °C O O 2. EDC, AcOH, DMF OH O (0.005 M) 5 days NH BocHN OH NH2 (75-85% yield) O (93% yield)

HO O O O

· 9-10 steps from HN HN pyr·SO3 HN HN commercial amino acids O O O O Et3N, DMSO · 20-26% overall yield NH 5 °C NH NH NH O (75% yield) O Eurystatin A

Semple, J. E. Tetrahedron Lett. 2001, 42, 6271-6274. Passerini Reaction 2-Component 3-Center: Falck's Four-Step Synthesis of (±)-Hydrastine

O O O

N N N O O O CO H H H H 2 H H MeO O O O O

O O HO OMe O MeO Noscapine (+)-Coryximine (+)-Egenine

O

H OH O MeO O LiCH NC O MeO O NH Br 2 O NC O O THF O CH2Cl2, rt - 78 °C → rt 3 h O (88% yield) (71% yield) O OMe O O MeO

NH N O O 1. POCl3, MeCN H H NaBH3CN H H approx. 1:1 mixture of naturally interconverting O O 2. PtO2, H2 HCHO isomers

(58% yield, O O OMe 3 steps) OMe MeO MeO (±)-Hydrastine

Falck, J. R. Tetrahedron Lett. 1981, 22, 619-620. Ugi Reaction Four-Component Synthesis of α-Acylamidoamides

· In 1959, Ivar Ugi (Ludwig Maximilians Universität, Munich) discovered the four-component coupling of isocyanides, carboxylic acids, amines, and aldehydes/ketones to form α-acylamidoamides.

O R1 R2 O O solvent 5 + 3 + + 5 NHR R NH2 R NC R4 N R1 R2 R4 OH R3 O

"Had Passerini been conversant with present day views on reaction mechanisms while studying the reaction which now bears his name, he would probably have added ammonia or the primary amines to his three starting materials and thereby discovered the α-amino alkylation of isonitriles and acids."

Ugi, I. Angew. Chem. 1959, 71, 386. Ugi, I. Angew. Chem. 1960, 72, 267-268.

· The reaction is a Type II MCR and the mechanism mirrors that of the Passerini reaction, only preceded by the condensation of the carbonyl and amine species.

O NHR3 NHR3 O 1 2 O 3 5 4 R R - H2O NR R NC R O acyl 3 O R4 NHR5 + R NH2 1 1 4 1 2 1 2 R R migration R N R R R R R2 NR5 R2 NR5 O R3 O

· The Ugi reaction has been applied to the synthesis of a broad range of product structures by substituting the amine and components.

6 R O R S R Se R NR6 OH NR R4 N N N N N 5 R3 NHR5 R3 NHR5 R3 NHR5 R3 NHR5 NHR 1 2 R1 R2 R1 R2 R1 R2 R1 R2 O R R

6 7 1 O R R R3 R N O R O O R N N 2 N R 4 R4 N N N R = H, R 5 3 6 N NHR R N R R3 N X NR5 1 2 1 2 N O R R R R R5 R1 R2 R5 H

X = O, S, NR6 Ugi, I.; Dömling, A. Endeavour 1994, 18, 115-122. Ugi Reaction Fukuyama's Route Toward (—)-Lemonomycin MeO H MeO O OPh MeO MeO MeO HN O MeO O O 1. CSA, quinoline O OPh TFE (73% yield, 2 steps) CN NH2 + NHBoc MeO 2. KOt-Bu O 25 → 50 °C N MsO MeO OTBDPS NHBoc MsO O

HO2C OTBDPS O O MeO N MeO OAc TMS MeO TMS O NBoc 1. NaBH4, THF / H2O NBoc BF3·OEt2 NBoc N N N MeO 2. TBAF, Ac2O, pyr MeO MeO 3. Grubbs 2nd gen. (95% yield) MsO O TMS MsO O MsO O OTBDPS OAc OAc

(35% yield, 4 steps)

MeO MeO MeO HO OMe Boc 1. TMSOTf Cbz Cbz N 2. CbzCl, DMAP N DMDO N 1. NaBH3CN, TFA N N N MeO 3. K2CO3, MeOH MeO MeOH MeO 2. KOTMS, MeCN, 0 °C 4. TIPSOTf, 2,6-lutidine then BnBr, 50 °C MsO O MsO O MsO O OAc (55% yield, 4 steps) OTIPS OTIPS (53% yield, 3 steps)

HO OH O H MeO HO MeO HO H H NH Cbz Cbz N 1. DMP, CH Cl N N 2 2 MeO N N MeO 2. TFA, CH2Cl2 MeO O OH O BnO O BnO O (76% yield, 2 steps) OTIPS OTIPS OH (—)-Lemonomycin O 9:1 d.r. N Fukuyama, T. Chem. Commun. 2005, 394-396. Ugi Reaction Beyond Four-Component Reactions

· Five-component reaction:

O O H MeOH + CO + n-Bu NH + + CH N N 2 2 H 2 MeO N n-Bu O

Haslinger, E. Monatsh. Chem. 1978, 109, 749-750.

· Six-component (seven-center) reaction (Mannich-Ugi):

H N H OMe O 2 HN H H OH + + N + MeOH + + Me NC O H H O O NHMe N O

Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115-122.

· Seven-component reaction (Asinger-Ugi):

S H H N NaSH + Br + NH3 + + CO2 + MeOH + NC OMe O O N O H O

Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115-122. Povarov Reaction Three-Component Synthesis of Substituted Tetrahydroquinolines

· In 1965, L. S. Povarov discovered a Lewis acid-catalyzed cycloaddition between N-aryl and vinyl ethers.

2 2 OR OR R3 3 Lewis R R 4 + H R R N R1 acid R4 N R1 H

Povarov, L. S.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1963, 955. Povarov, L. S.; Mikhailov, B. M. Izv. Akad. Nauk SSSR, Otd. Khim. Nauk 1963, 2039. Povarov, L. S. Russ. Chem. Rev. 1965, 34, 639. Povarov, L. S. Doctoral Thesis, Institute of General and Inorganic Chemistry, Academy of Sciences of the USSR, Moscow, 1966. · The mechanism is disputed, though classified as Type II due to the irreversibility of rearomatization in the final step.

· Though casually referred to as an aza-Diels-Alder cycloaddition, the Povarov is most often proposed as a non-concerted, two-step ionic mechanism. This is supported by trapping experiments (Type I).

O O O CO Et MeOH 2 H H O + O2N N CO2Et O N N CO Et O2N N 2 H 2 H H CO Et O2N NH2 2 Sc(OTf)3 Sc(OTf)3 MeO O

Lavilla, R. Angew. Chem. Int. Ed. 2005, 44, 6521--6525.

· However, a step-wise mechanism does not explain the observation that only one stereoisomeric product is generated in reactions with dihydrofuran and dihydropyran.

O O O O

R R R N R N R Lewis acid Lewis acid N R H H single diastereomer single diastereomer Lucchini, V. J. Chem. Soc. Perkin Trans. I 1992, 259-266. Povarov Reaction Substrate Scope

OEt O OEt + O + H O NH2 N H

R2 SR N O 1 SR R + H + NH2 N Ph X H X

X = H, Me, CO2H R = Et, n-Bu R2 N O H O R1 O + + · H · The carbonyl component is typically NH 2 N Ph limited to aryl substituents due to H tautomerization of aliphatic imines to the corresponding enamines. HN O H N · Original conditions used p-TsOH as + H + the catalyst and heated to 100-200 °C. NH 2 N Ph · More recently, transition metal and H lanthanide triflates have been shown to catalyze the Povarov reaction O between RT and 50 °C. O H Me H N Ph N 2 O + H +

NH2 N Ph H O Me

O O Me O + + NH Povarov, L. S. Russ. Chem. Rev. 1967, 36, 656-670. 2 N Batey, R. A. Tetrahedron Lett. 2003, 44, 7569-7573. H Lavilla, R. J. Comb. Chem. 2005, 7, 33-41. Legros, J. Synlett 2006, 1899-1902. Povarov Reaction Total Syntheses of (±)-Martinellic Acid and (±)-Martinelline

NH N O H N

HO H H N N N H NH

Martinellic Acid

NH N O H N H H2N N O H H NH N N N H NH Martinelline

· Root extracts of the Martinella iquitosensis vine, found in Amazonian lowland rainforests.

· Used by indigenous peoples to treat eye ailments, including inflammation and conjunctivitis.

· Display modest antibiotic activity and micromolar binding of G-protein coupled receptors.

Cook, K. J. Ethnopharmacol. 1984, 11, 337-343. Witherup, K. M.; Varga, S. L. J. Am. Chem. Soc. 1995, 117, 6682-6685. Povarov Reaction Total Syntheses of (±)-Martinellic Acid and (±)-Martinelline Stevenson's Approach to the Tricyclic Core: Cbz N Cbz Cbz O N O N O MeO MeO MeO + H + N Ph N Ph NH2 O Ph H H

Conditions: A. InCl3 (12 mol%), MeCN, 25 °C, 12 h → 40% yield, 1.1:1 d.r. B. Y(OTf)3 (1 mol%), MeCN, 25 °C, 2 h → 47% yield, 1:1 d.r. C. LiBF4 (100 mol%), MeCN, 25 °C, 12 h → 43% yield, 1:1 d.r.

Stevenson, P. J. Tetrahedron 2006, 62, 3977-3984,

Batey's Approach (Modified Povarov):

O Cbz Cbz MeO N O N Exo 6 steps + Martinelline MeO NH2 NHCbz 1 equiv 2 equiv N H Conditions: +

Dy(OTf)3: 92% yield Cbz 15:85 exo:endo O O N Endo CSA: 74% yield 89:11 exo:endo MeO MeO NHCbz NHCbz N 3 N H Batey, R. A. Org. Lett. 2002, 4, 2913-2916. Povarov Reaction 2-Component 3-Center: Batey's Formal Total Synthesis of Camptothecin

MeO 1. K2CO3, LiBr H H MeO MeO OMe Bu4NBr, tol:H2O (100:1) DMF, 80 °C, 3 h N O 100 °C, 1 h N O + MeO O MeO N then O 2. AcOH / HCl / H O CN 2 O NC 60 °C, 1 h CN NH2 DMF, 100 °C, 3 h (86% yield)

(29% yield)

H NH 2 O N O Dy(OTf) (10 mol%) N O [4+2] O 3 N N MeCN, 50 °C, 16 h N CN CN CN

71% yield

O N Eckert N O

OH O Camptothecin

Batey, R. A. Org. Lett. 2004, 6, 4913-4916. Eckert, H. Angew. Chem. Int. Ed. Engl. 1981, 20, 208-210. Knoevenagel Condensation / Hetero-Diels-Alder Cycloaddition Tietze's Total Synthesis of Hirsutine

NCbz N NCbz NCbz R ∗ ∗ H N N EDDA R OPMB R + ∗ OPMB O O O O O O O

O O O O O O

R = H or Boc

∗ NCbz ∗ N N N H2O R H2, Pd/C R ∗ OPMB ∗ - CO2 K2CO3, MeOH - O O O

O OMe R = Boc, 67% yield = H, 62% yield (converted to Boc before methanolysis) 3 N N 1. (remove Boc) H 15 (3R,15R) : Hirsutine 2. O (3S,15R) : Dihydrocorynantheine O OMe H OMe , acid 3. CH2N2 OMe Tietze, L. F. Synthesis 1998, 1185-1194. Tietze, L. F. Angew. Chem. Int. Ed. 1999, 38, 2045-2047. Knoevenagel Condensation / Hetero-Diels-Alder Cycloaddition Hirsutine: Origin of Stereoselectivity

· Either enantiomer—(3R) or (3S)—is available by condensation of piperidyl nitrogen with (—)-camphanic acid to form separable diastereomeric . Enantiomerically pure (3R) substrate advanced to hirsutine.

· During the cycloaddition, N-Boc causes Meldrum's acid moiety to swing away from , while N-H causes it to swing toward indole in order to participate in H-bonding and partial donation of the nitrogen lone pair into the enoate π-system.

· The enol approaches the (E)-1-oxa-1,3-butadiene over the H at C(3) instead of the alkyl chain.

3 NCbz 3 NCbz N N H H Boc H 15 15 O O O O

O O O O

β approach β approach to OPMB to (E)-enoate (E)-enoate

3 N H H 3 N N OPMB PMBO N H 15 15 H 15 15 O O O O

O OMe O O O O O OMe

OMe OMe Hirsutine 15-epi-Hirsutine Tietze, L. F. Synthesis 1998, 1185-1194. Tietze, L. F. Angew. Chem. Int. Ed. 1999, 38, 2045-2047. Dipolar Cycloadditions Methods for Dipole Construction Multicomponent dipolar cycloadditions typically involve two-component formation of the 1,3-dipole followed by reaction with a suitable dipolarophile.

3 2 3 2 R R O R O Yb(OTf) R O N 3 N Kerr, M. A. + 2 + R HN-OH Org. Lett. 2004, 6, 139-141. R1 CO2R R1 R1 CO2R RO2C CO2R

1 R R1 R1 CO2R O Boruah, R. C. Al2O3 O + Br + Org. Lett. 2003, 5, 435-438. R2 µwaves N N Müller, T. J. J. OR Helv. Chim. Acta 2005, 88, 1798-1812. N O R3 O 3 2 R R R2

2 2 O OR CO2R O CO2R Ar [CuOTf] ·C H N H 2 6 6 Ar CO R Scheidt, K. A. + 2 Ar + N 2 OR N Org. Lett. 2003, 5, 3487-3490. 1 R N 2 1 1 R CO2R R CO2R

RO C CO R O O CO2R 2 2 O Rh2(OAc)4 Ar Ar + O CO R O Nair, V. RO OR 2 + J. Org. Chem. 2004, 69, 1413-1414. R1 N2 R1 1 O2N R NO2

1 R1 R CO2R N HN NC CN CN Δ RO C Nair, V. 1 + 2 RO2C R NC + Org. Lett. 2004, 6, 767-769. CN Ar CO2R RO C 2 RO2C Ar Dipolar Cycloadditions Williams' Total Synthesis of (—)-Spirotryprostatin B

Ph Ph O Ph

O N Ph Ph OMe O O Ph H MeO N O + O O 3 Å MS, toluene MeO H HN O CO2Et O EtO2C CO Et HN 2 HN O N H 82% yield β-exo transition state single diastereomer

· 16% overall yield O N · (+)-spirotryprostatin available from enantiomer of oxazinone substrate. N O O 8 steps · Schreiber later used this reaction to construct a library of >3000 structural variants using split-pool synthesis on microbeads. HN Ph Ph i-Pr i-Pr O Si Linker N O O H (—)-Spirotryprostatin B CO NR1R2 HN 2

Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666-5667. Williams, R. M. Tetrahedron 2002, 58, 6311-6322. 3 Schreiber, S. L. J. Am. Chem. Soc. 2004, 126, 16077-16086. R Dipolar Cycloadditions Kerr's Total Synthesis of (+)-Nakadoumarin A

Br OBn

H BnO TBDPSO O Yb(OTf)3 PMB O N O (15 mol%) PMB O MeO C CO Me N 2 2 + O TBDPSO 4 Å MS single CO Me H furan enantiomer 2 NHOH tol, 100 °C CO Me Br 2 MeO 87% yield (single diastereomer)

1. DIBAL, CHCl2, -78 °C BnO OBn 2. O O 1. DDQ PMB O 2. O OBn OBn P N MeO OMe O N MeO , KOt-Bu Cl O CO2Me O 3. Pd(PPh3)4, Ag2SO4 3. SmI2 CO2Me 4. MsCl Et3N, DMF, reflux CO Me 2 4. KOt-Bu CO2Me (66% yield, 3 steps) OTBDPS OTBDPS

OBn OBn O N 1. NiCl2·6H2O, NaBH4 N H · 22 steps 2. LiAlH 4 9 steps H O N · Unnatural enantiomer 3. MsCl O N 4. · Absolute stereochem. of H NH2 OTBDPS OTBDPS determines absolute stereochem. of product OTBDPS (+)-Nakadoumarin A Kerr, M. A. Org. Lett. 2005, 7, 953-955. Kerr, M. A. J. Am. Chem. Soc. 2007, ASAP. Multiple Anion Capture Dianion Relay for Structural Elaboration

Multiple anion capture is a process by which a resonance-stabilized dianion attacks a relais ("relay", electrophile) species to form a secondary dianion, which is then quenched by a second electrophile. R O O S · Relais species = R C N R · R · · R R R N N R R O O O N Ar · Dianions = N N H Ar N · If the second electrophile contains one electrophilic site, then two equivalents are necessary and the product is a linear homologation of the substrate.

O O O O O RMe2SiO OSiMe2R 1. KH Ph Ph Ph Ph RMe SiCl Ph Ph 2 Ph Ph Ph 2. n-BuLi Ph Ph Ph Ph Ph K Li K Li 86% (R = Me) "Y-shaped" dianion 84% (R = t-Bu) · If the second electrophile contains two electrophilic sites, then only one equivalent is necessary and the product is a ring.

Ph Ph O O O O Si Ph O O O O Ph2SiCl2 Ph (COCl)2 Ph Ph Ph Ph Ph Ph Ph Ph Ph K Li Ph

76% yield 36% yield Langer, P. Eur. J. Org. Chem. 2001, 1511-1517. Langer, P. Chem. Eur. J. 2001, 7, 3858-3866. Padwa, A. J. Am. Chem. Soc. 1988, 110, 1617-1618. Ketchum, R. J. Org. Chem. 1985, 50, 3431-3434. Trimitsis, G. B. J. Org. Chem. 1983, 48, 2957-2962. Multiple Anion Capture Synthesis of Medium-Sized Lactones and Heterospirocyclic Isobenzofuranones

O N N N Ph Ph n-BuLi (2 equiv) Ph N THF, 0 °C N N O Ph H 2 Li O 2 Li Cl Cl (COCl)2 O

N N Ph N Ph Ph N N Ph LiCl O N O O Ph Ph O O O O O O

32% yield 40% yield - CO

N O O Lewis Ph acid Cl N O Cl O Ph Cl O Cl O 46% yield

AlCl3 catalyzed: Naik, N. Synth. Commun. 1988, 18, 625. Langer, P. Eur. J. Org. Chem. 2001, 1511-1517. Naik, N. Synth. Commun. 1988, 18, 625-632. Multiple Anion Capture Synthesis of Radialene-Shaped Pyrroles Radialenes are cyclic compounds containing only sp2-hybridized ring atoms and exocyclic double bonds.

O O N Mg2+ O

O 2 Magnesidin

N N N n-BuLi (2 equiv) Ph-CN N Ph THF, 0 °C N N N H

2 Li 2 Li

TolN NTol

Cl Cl

N

Ph N N TolN NHTol Not observed! Langer, P.; Döring, M. Synlett. 1998, 399-401. Langer, P. Eur. J. Org. Chem. 2001, 2617-2627. Multiple Anion Capture Synthesis of Radialene-Shaped Pyrroles Radialenes are cyclic compounds containing only sp2-hybridized ring atoms and exocyclic double bonds.

O O N Mg2+ O

O 2 Magnesidin

N N N n-BuLi (2 equiv) Ph-CN N Ph THF, 0 °C N N N H

2 Li 2 Li

Regioselectivity (C vs. N attack) proposed to be the product of relative TolN NTol HOMO energies (AM1: C lower than N) as well as HSAB effects. Cl Cl

N HN H2N N R N R N 1,3-proton R N N N Cl shift Cl NTol TolN TolN TolN NTol NTol 40% yield Langer, P.; Döring, M. Synlett. 1998, 399-401. Langer, P. Eur. J. Org. Chem. 2001, 2617-2627. Multiple Anion Capture Synthesis of Radialene-Shaped Pyrroles Radialenes are cyclic compounds containing only sp2-hybridized ring atoms and exocyclic double bonds.

O O N Mg2+ O

O 2 Magnesidin

N N N n-BuLi (2 equiv) Ph-CN N Ph THF, 0 °C N N N H

2 Li 2 Li

TolN NTol

Cl Cl

R O OMe R H N N N N 2 N MeO O NH R N N N toluene, 80 °C CO2Me NHTol NTol TolN TolN TolN CO2Me - TolNH2 68% yield Langer, P.; Döring, M. Synlett. 1998, 399-401. Langer, P. Eur. J. Org. Chem. 2001, 2617-2627. Multiple Anion Capture Synthesis of Nitrile Oligomers Using Allene Dianions

n-BuLi KOt-Bu PhCN N Ph Ph N 2 M 45% yield

Bates, R. B. J. Org. Chem. 1979, 44, 2290-2291. Bates, R. B. J. Org. Chem. 1980, 45, 168-169.

R R HN N R OTBS LDA R-CN R Ph Li Ph (3.3 equiv) (4.5 equiv) · 3-CR -78 °C Ph then H O Ph Li 2 quench R R R HN Ph Ph HN N N R N R R R 3-CR 4-CR 5-CR R N R O R H Ph 0 12 51 4-CR 5-CR t-Bu 0 66 0

4-Tol 0 28 0

3-Tol 40 0 trace

Langer, P. Eur. J. Org. Chem. 2003, 1948-1953. Multiple Anion Capture Synthesis of Nitrile Oligomers Using Allene Dianions

n-BuLi KOt-Bu PhCN N Ph Ph N 2 M 45% yield

Bates, R. B. J. Org. Chem. 1979, 44, 2290-2291. Bates, R. B. J. Org. Chem. 1980, 45, 168-169.

R R R R-CN N Ph N Ph N Li Ph (3 equiv) N N N · Ph R Ph Ph Ph Li · - RCN Ph R R R R N N 3-CR

R R R Ph Ph N Ph N Ph Ph N RCN N RCN N N Ph N N R R R N R R N R R N R

4-CR 5-CR

Langer, P. Eur. J. Org. Chem. 2003, 1948-1953. One-Pot Total Synthesis Poupon's Biomimetic Synthesis of Nitraramine

· isolated from the desert shrub Nitraria schoberi found O N in Asia, Australia, and the Middle East

· exhibits "serotonin-like" activity in in vitro bioassays N H · thought to be the product of condensation of three Nitraramine C5 subunits derived from lysine Nitraria schoberi

N N EtOH, reflux, 3 h (2-3% yield) H H O N - or - O O H2O, reflux, 3 h (0.5-1% yield) N H

Poupon, E. Org. Lett. 2005, 7, 2497-2499. One-Pot Total Synthesis Poupon's Biomimetic Synthesis of Nitraramine

· isolated from the desert shrub Nitraria schoberi found O N in Asia, Australia, and the Middle East

· exhibits "serotonin-like" activity in in vitro bioassays N H · thought to be the product of condensation of three Nitraramine C5 subunits derived from lysine Nitraria schoberi

H N N Nitraramine = C15H24N2O - H2O OH 3% overall yield → 5 steps = 50% avg. yield / step → 10 steps = 70% avg. yield / step → 15 steps = 79% avg. yield / step

N N N OH N O N N O N H H OH H N O O N N H

Nitraramine

NH

N O

- H2O

Poupon, E. Org. Lett. 2005, 7, 2497-2499. One-Pot Total Synthesis Liu's Synthesis of the Quinazolinone Fungal Metabolites

H H N · Substance P (neurokinin) antagonists N · Display analgesic / anti-inflammatory properties O O O O N O R2 N NH O NH N N N R NH N R = H, glyantrypine R1 Fumiquinazoline G = Me, Fumiquinazoline F = i-Pr, Fiscalin B pyrazino[2,1-b]quinazoline-3,6-dione core

R2 O O H2N O OH OH O H N N NH H O 2 O N anthranilic acid N NH2 NH HO H 1 N NH R N O O

Alantrypinone Glyantrypine: Mantle, P. G. J. Chem. Soc. Perkin Trans. I 1992, 1495-1496. Ardeemin Fumiquinazoline F: Numata, A. Tetrahedron Lett. 1992, 33, 1621-1624. Fiscalin B: Cooper, R. J. Antibiot. 1993, 46, 545-553. Fumiquinazoline G: Numata, A. J. Chem. Soc. Perkin Trans. I 1995, 2345-2353. Alantrypinone: Larsen, T. O. J. Nat. Prod. 1998, 61, 1154-1157. Ardeemin: McAlpine, J. B. J. Antibiot. 1993, 46, 374-379. One-Pot Total Synthesis Liu's Synthesis of the Quinazolinone Fungal Metabolites

L-amino acid D-amino acid O O 2 O O O R NHBoc NH2 HO MeO OMe OH R1 O R2 N H NHBoc O NH P(OPh)3, pyr N NH 2 microwave 1 R1 R O benzoxazinone NHBoc

O R2 O R2 O N CO2Me N NHBoc NH N N R1 R1 quinazolinone pyrazino[2,1-b]quinazoline-3,6-dione

Liu, J.-F. Tetrahedron Lett. 2005, 46, 1241-1244. Liu, J.-F. J. Org. Chem. 2005, 70, 6339-6345. One-Pot Total Synthesis Liu's Synthesis of the Quinazolinone Fungal Metabolites

O O H NHBoc N HO , P(OPh) OH 3 pyr, microwave O NH2 then O O Glyantrypine OMe N

NH2 NH (55% yield) N H N

O H O NHBoc N HO Me , P(OPh)3 OH O pyr, microwave O NH2 then O N Fumiquinazoline F OMe NH N NH2 (39% yield) N H Me

O H N O NHBoc HO i-Pr , P(OPh)3 OH O pyr, microwave O NH2 then O N Fiscalin B OMe NH N NH2 (20% yield) N H

Liu, J.-F. Tetrahedron Lett. 2005, 46, 1241-1244. Liu, J.-F. J. Org. Chem. 2005, 70, 6339-6345. One-Pot Total Synthesis Liu's Synthesis of the Quinazolinobenzodiazepine Fungal Metabolites

O O

NH2 OH HO R2 NH2

O O O NHBoc OH HO , P(OPh) 3 N Sclerotigenin pyr, microwave O NH (55% yield) 2 N NH 2 equiv

O O NHBoc HO N Circumdatin F Me , P(OPh)3 O (32% yield) NH pyr, microwave N Me

O O NHBoc N Asperlicin C HO O CH indole , P(OPh) (20% yield) 2 3 N NH pyr, microwave

Liu, J.-F. J. Org. Chem. 2005, 70, 10488-10493. Sclerotigenin: Gloer, J. B. J. Nat. Prod. 1999, 62, 650-652. Circumdatin F: Rahbæk, L. J. Nat. Prod. 1999, 62, 904-905. N Asperlicin: Lotti, V. J. J. Antibiot. 1988, 41, 875-877. H Multicomponent Reactions Summary and Conclusions

A A

D B B A A

C B C

· Multicomponent reactions are capable of condensing 3, 4, 5, 6, and even 7 reactant species in a single reaction mixture.

· MCRs are underused in total synthesis. Though the most obvious applications lie in the realm of library synthesis, the extreme convergence afforded by these reactions provides a quick, efficient, and low-cost alternative to current linear syntheses.

Remember: In comparison to an analogous multi-step sequence, a low-yielding MCR is not as costly.

· Most MCRs have a broad substrate scope capable of tolerating diverse functionality in addition to the reactive centers. This can set up MCR products for further cascade transformations.

· Limitation: The more components that a MCR employs, the more complex the target it generates. The more complex the target, the less generally applicable it becomes in total synthesis.

· The library of known multicomponent reactions is far from complete! New combinations of existing reactions are always possible and a firm understanding of reaction mechanism can lead to the discovery of novel modes of reactivity.

A

A + B + C + D B D

C