Titanium-mediated fragment union processes in complex molecule synthesis: Development of a branched reaction pathway of high step economy for the synthesis of complex and diverse polyketides

FEATURE ARTICLE

627

Titanium-Mediated Fragment Union Processes in Complex Molecule

Synthesis: Development of a Branched Reaction Pathway of High Step

Economy for the Synthesis of Complex and Diverse Polyketides

S

ynthesis of Co

a

mplex and

rDiverse

P

olyketide

s

J. Perez, Glenn C. Micalizio*

Department of Chemistry, Yale University, P.O. Box 208107, 225 Prospect Street, New Haven, CT 06520-8107, USA

Fax +1(203)4326144; E-mail: glenn.micalizio@yale.edu

Received 19 October 2007; revised 20 November 2007

cules by iterative carbon–carbon bond formation.⁶This

strategy is in sharp contrast to the numerous biosynthetic

pathways that access complexity and diversity through

oligomerization by carbon–heteroatom bond formation

Abstract: We describe a synthetic pathway to structurally complex

and diverse polyketides based, in part, on regio- and stereoselective

titanium-mediated coupling reactions. The sequences described al-

low for rapid assembly of polyketide-inspired architecture while

providing significant flexibility for the establishment of diverse ste- (biopolymers including DNA, RNA, proteins, and carbo-

hydrates).⁷

reochemical relationships and substitution patterns along the carbon

backbone (including stereodefined alkenes and 1,3-dienes, saturat-

Synthetic pathways of great efficiency have been devel-

ed and unsaturated lactones, hemiketals, a,b-unsaturated carbonyls,

oped to prepare novel biopolymers. Mirroring biosynthet-

ic pathways, these synthetic accomplishments embrace

carbon–heteroatom bond formation to achieve oligomer-

ization.⁸The development of a general pathway for the

synthesis of complex and diverse polyketide-based che-

motherapeutic agents represents a synthetically more

challenging problem. Whereas significant contributions

in synthetic methodology have been made to enable the

total syntheses of numerous members of this natural prod-

uct class,⁹chemistry to define synthetic pathways to col-

lections of complex and diverse polyketide-like

molecules is underdeveloped.¹⁰

and spiroketals).

Keywords: polyketides, diversity-oriented synthesis, alkyne com-

plexes, titanium, cross-coupling, regioselectivity

Introduction

Natural products of polyketide biosynthetic origin display

an impressive array of potent and diverse biological activ-

ities (Figure 1). Members of this class have therapeutic

importance based on their known function as antibiotics,

anticancer agents, antifungals, antiparasitics, immunosup-

pressants, and cardiovascular agents.¹This impressive

functional diversity is a direct result of the large structural

diversity observed throughout this natural product class.

New synthetic methods and strategies are required to ad-

dress the combined requirements of diversity, complexity,

and efficiency for a unified synthetic pathway to

polyketide-like molecules. Here, we describe a flexible

synthetic pathway of great step economy¹¹for the synthe-

sis of complex and diverse polyketides based, in part, on

titanium-mediated coupling reactions between a variety

of substituted p-systems.

The biological activity of polyketide-derived natural

products is a function of their intricate structure,²whereby

conformational preferences lead to the defined projection

of an array of functional groups in space.³Conformational

preferences of polyketides are, in turn, a function of ste-

reochemistry, substitution, and oxidation state of the car-

bons that define their skeletons.⁴All of these structural

features are varied in nature by modular type 1 polyketide

synthases (PKS1). Within this pathway, iterative Claisen

condensation and diverse functionalization serve as the

basis for chain elongation and structural variation.⁵Post

PKS1 modifications, performed by tailoring enzymes,

provide an additional mechanism for the generation of

molecular complexity and structural diversity via func-

tionalization processes including glycosylation, cycliza-

tion, methylation, and oxidation.^6a

Background

Advances in acyclic stereocontrol have provided a means

to mimic the basic C–C bond-forming strategy used in

PKS1¹²and have enabled numerous total syntheses of

polyketides (Scheme 1).⁹The synthetic oligomerization

of propionate and acetate units can be accomplished

through the use of aldol or allylmetal chemistry and typi-

cally proceeds via the intermediacy of protected b-hy-

droxy carbonyls (i.e., 8 and 9; R², R³= protecting groups).

Based on contributions of numerous investigators over the

last thirty years, these C–C bond-forming reactions can

predictably deliver complex stereochemically dense

polyketides in a selective manner.¹³

The polyketide biosynthetic pathway represents an ele-

gant example of a system well equipped for the synthesis

of a large collection of structurally diverse small mole-

Whereas these advances have provided a general stereo-

controlled pathway to complex polyketide targets, they

typically rely on extensive protecting group manipula-

SYNTHESIS 2008, No. 4, pp 0627–0648

Advanced online publication: 08.02.2008

DOI: 10.1055/s-2008-1032160; Art ID: E19707SS

x

.

x

.2

0

8

628

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

Me

OMe

Me

HO

OH

O

OH

Me

O

RO

OMe

HO

Et

Me Me

Me

O

Me

O

Me

O

Me

O

Me

OH

Me

NH

Me

HO

OH

MeO

OH OH

O

Me OH

Me

R = CONH₂

oligomycin A

target: F0/F1-ATPase

dictyostatin

target: tubulin

geldanamycin

target: Hsp90

Me

O

Me Me

S

HO

Me

MeO

OAc

Me

N

OH

Me

H

Me

Me Me

O

H

O

H

O

OH

O

OH

H

Me

OH

O

epothilone B

target: tubulin

Me

O

Me

OMe

OH

O

Me

O

Me

bryostatin 1

target: PKC isozymes

O

callystatin A

target: CRM1

H

Me

Figure 1 Natural products from polyketide biosynthetic origin and their known biological targets

tions and suffer from the requirement of multistep carbo- further complication, these reactions are typically incom-

nyl redox processes to accomplish chain elongation.¹⁴

patible with free hydroxy groups.

Aside from issues regarding efficiency (step economy),¹¹Although convergent aldol bond construction has proved

these methods have not yet defined a unified iterative ho- useful for target-oriented synthesis, where stereochemical

mologation procedure that allows for facile incorporation control can be engineered as a function of the aforemen-

of diverse skeletal motifs commonly found embedded tioned variables, the use of these processes for the effi-

within polyketide skeletons (i.e., stereodefined alkenes cient modular synthesis of diverse polyketide-like

and dienes, 1,5-diols, tertiary alcohols, and epoxides). Al- molecules is anticipated to be inherently limiting. This

though such structural motifs (outside of the common 1,3- statement is not meant to detract from the examples of

polyol) can be installed using a variety of synthetic meth- polyketide library synthesis reported where collections of

ods, they typically require deviation from a simple ideal- polyols can be accessed through such a strategy,¹⁶but

ized modular pathway, and often require the use of rather to emphasize that development of a synthetic path-

numerous additional functional group manipulations — way of high step economy to a variety of polyketides that

factors that ultimately further decrease step economy and differ in substitution, oxidation state, and stereochemistry

complicate synthetic pathways required for the installa- would represent a significant advance.

tion of each unique structural motif.

The goal of defining synthetic sequences useful for the ef-

Convergent assembly of polyketides by aldol-based bond ficient preparation of complex and diverse polyketide-like

construction provides a powerful pathway to these com- molecules requires the development of new synthetic

plex targets. Selectivity in these processes are a complex methods. Such methods need to be capable of illuminating

function of: (1) the relative and absolute stereochemistry a pathway that provides diversity in stereochemistry, oxi-

of each coupling partner, (2) the nature and position of dation state, and substitution along the carbon backbone

protecting groups on each coupling partner, and (3) the while maintaining high step economy.¹⁷These consider-

type, and geometry, of the metal enolate employed.¹⁵As a ations served as the foundation to drive the development

of the chemistry described herein.

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

629

Biosynthetic strategy: two chain-extending carbons/unit – PKS 1

O

a)

R³

2

S

1

O

2

OH

O

OH OH

O

Me

R¹

R²

R¹

R³

R¹

R⁴

repeat

steps

acetyl transferase

1

2

3

S

2

S

4

S

Me

b) β-ketoreductase

1

3

4

Chemical strategy: two chain-extending carbons/unit – aldol or allylmetal chemistry

Met*

O

1)

or

2

OR²

O

OR²OR³

O

1

2

X_Ψ

O

1

R¹

Me

repeat

steps

6

7

1

3

Me

1

2

4

H

2

2) protect 2° alcohol

3-4) generate a new

aldehyde

Me

5

8

9

Scheme 1 Stepwise oligomerization for polyketide synthesis

Results and Discussion

(1) To minimize dependence on complex protecting group

manipulations, common to modern strategies for

We describe a flexible synthetic pathway of high step polyketide synthesis, we targeted the development and

economy for the preparation of complex and diverse use of convergent C–C bond-forming processes that are

polyketide-like small molecules (Scheme 2). The path- tolerant of free hydroxy groups.

ways described (a–h), proceed from a tris-homopropar-

gylic alcohol 10 in just one to ten steps without protecting

group manipulations.

(2) To provide flexibility in the structural motif around

which a C–C bond is formed during modular assembly,

we planned on developing a suite of regio- and stereo-

At the outset of our studies, we focused on the following selective cross-coupling reactions between a variety of

considerations:

functionalized p-systems (alkyne–aldehyde, alkyne–

alkyne, alkyne–nitrile, alkyne–imine, etc.).

Biographical Sketches

Lark J. Perez was born in product research with Prof. research group of Prof.

Southampton, NY in 1982. D. John Faulkner at The Glenn C. Micalizio at Yale

During his undergraduate Scripps Institute of Ocean- University studying the util-

studies at Long Island Uni- ography before receiving ity of titanium alkoxide me-

versity, Southampton Col- his B.S. in 2003. He is cur- diated processes in organic

lege, he performed natural rently a Ph.D. student in the synthesis.

Glenn C. Micalizio was ies, he relocated to Harvard Professor in the Department

born in East Orange, NJ in University, where he was of Chemistry. His current

1973, and raised in Para- appointed as a Helen Hay research interests are fo-

mus, NJ. After receiving a Whitney Postdoctoral Fel- cused on the development of

B.S. degree in 1996 from low in the laboratory of Pro- new synthetic methods to

Ramapo College of NJ, he fessor Stuart L. Schreiber. facilitate the synthesis and

studied with Professor Will- Here, his studies were fo- discovery of complex mole-

iam R. Roush at the Univer- cused on the development of cules of therapeutic rele-

sity of Michigan, and synthetic methods for appli- vance. A topic of great

received a Ph.D. in 2001 cation to diversity-oriented current interest is the design

based on his research fo- synthesis. After completion of new reactions for site-

cused on methods develop- of his postdoctoral studies in and stereoselective conver-

ment and application to 2003, he moved to Yale gent coupling via carbon–

natural product synthesis. University and began an ap- carbon bond formation.

Following his doctoral stud- pointment as an Assistant

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

630

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

O

OH OMe

O

*

OMe

O

*

Me

OH OMe

Me

*

OH OMe

OH

*

O

h

a

*

OMe

g

*

b

c

Me

OH

Me

OH OMe

Me

*

O

*

f

O

Me

OH OMe

O

*

OH OMe

*

10

*

e

d

Me

Ph

Me

MeO

O

OH OMe

O

*

Me

Pathways a–h proceed in 1–10 steps without protecting group manipulations

Scheme 2 Synthesis of complex polyketides without protecting group manipulations

R⁴

OR¹

O

OR¹OH

Me

(RO)_n

regioselective

cross-coupling

R¹O

H⁺

O

X

propargylation

Ti

R³

H

with aldehydes,

nitriles, imines,

terminal alkynes,

or alkenes

Met

•

R²

Me

13

11

5

12

R⁴

OR¹OH

OH

OR¹OH

R³

OR¹OH

HN

R⁴

R³

R²

Me

R²

Me

R²

(alkyne + imine)

Me

16

14

15

(alkyne + aldehyde)

(alkyne + olefin)

OR¹OH

O

R³

R²

Me

R²

Me

18

17

(alkyne + nitrile)

(alkyne + terminal alkyne)

Scheme 3 Titanium alkoxide mediated cross-coupling of tris-homopropargylic alcohols with p-electrophiles

(3) To avoid the requirement of hydroxy group oxidation reochemical flexibility at every chiral center of 12, as well

state manipulations, often coupled to complex protecting as provide a convenient branch point for convergent syn-

group strategies, we targeted the preparation of aldehydes thesis of ene-1,5-diols (12 → 14), ene-1,5-amino alcohols

from alkenes rather than primary alcohols.

(12 → 15), stereodefined trisubstituted alkenes (12 → 16),

a,b-unsaturated ketones (12 → 17), and 1,3-dienes (12 →

18).

At the core of our design was the application of alkoxide-

directed, titanium-mediated, cross-coupling reactions of

functionalized p-systems. As illustrated in Scheme 3, We have demonstrated previously the utility of penta-2,3-

combination of this flexible fragment union process with diene-based allenylmetal reagents for the diastereoselec-

well-known propargylation reactions would allow for ste- tive propargylation of chiral aldehydes.¹⁸Based on the

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

631

pioneering work of Marshall,¹⁹we have defined reaction Alkyne–Aldehyde Cross-Coupling. Coupling of the

conditions for the selective preparation of all stereoiso- syn-anti tris-homopropargylic alcohol 28 with the simple

mers of homopropargylic alcohol 12.

chiral aldehyde ent-23 proceeds with high levels of site

selectivity, consistent with our previous studies. In short,

formation of the titanium–alkyne complex, followed by

addition of the chiral aldehyde and protonation of the pre-

sumed intermediate oxatitanacyclopentene provides ene-

1,5-diol 29. Although diastereoselection was not ideal

(ds 2:1), these initial studies demonstrated that we could

achieve high levels of site selectivity (≥20:1) in the func-

tionalization of alkyne 28.

We have also reported titanium alkoxide mediated C–C

bond-forming processes for the coupling of homopropar-

gylic alcohols 12 with aldehydes²⁰and terminal alkynes.²¹

These studies revealed that regioselection in the alkyne

functionalization process is a complex function of: (1) rel-

ative stereochemistry, (2) pairing of absolute stereochem-

istry of each coupling partner, and (3) the presence and

position of a tethered alkoxide on the internal alkyne. In-

terestingly, we found that with each stereoisomeric series Alkyne–Nitrile Cross-Coupling. Although one has the

studied (internal alkynes containing syn-syn, syn-anti, potential of adding a variety of polarized p-bonds to the

anti-syn, and anti-anti stereotriads), highest site-selectivi- preformed metal–alkyne complex of 28, we observed

ties in cross-coupling reactions with chiral aldehydes some limitations. For example, nitrile–alkyne cross-cou-

were observed with tris-homopropargylic alcohol con- pling proceeds to deliver the enone 30 as a single regio-

taining substrates (19–22; Scheme 4). Detailed experi- isomer, but does so with poor efficiency (35% yield).

mental procedures and comprehensive data regarding Nevertheless, this process represents a potential pathway

regioselection as a function of stereochemistry and posi- for alkoxide-directed hydroacylation²²of an internal

tion of tethered hydroxy group are available.^20b

alkyne and presents an interesting branch point in the

pathway.

Alkyne–Alkyne Cross-Coupling. Whereas the efficien-

cy of nitrile–alkyne coupling is a barrier for application in

the context of synthesis, alkyne–alkyne cross-coupling re-

actions provide an efficient convergent route to substitut-

ed 1,3-dienes embedded within the polyketide skeleton.

Deprotonation of the tris-homopropargylic alcohol 28,

followed by formation of the titanium–alkyne complex,

addition of a terminal alkyne 31, and protonation of the

presumed metallacyclopentadiene provides the trisubsti-

tuted 1,3-diene 32 (rr 10:1), as a single stereoisomer. In

this case, high site- and stereoselectivity is observed in the

functionalization of both p-systems.

OH OR

Me

O

OTBDPS

*

+

H

Me

23

stereoisomer:^x

19; syn-syn (R = PMB)

20; syn-anti (R = Bn)

21; anti-syn (R = PMB)

22; anti-anti (R = Bn)

titanium alkoxide mediated

cross-coupling

Me

HO

OH OR

OH OTBDPS

+

OTBDPS

*

Alkyne–Imine Cross-Coupling. Enabling the conver-

gent synthesis of stereodefined unsaturated 1,5-amino al-

cohols, alkyne–imine cross-coupling²³provides a unique

process for functionalization of 28. Formation of the

chiral titanium–imine complex derived from 33, followed

by addition of the lithium alkoxide of 28, and protonation

of the presumed azatitanacyclopentene affords the chiral

allylic amine 34 in 69% yield (rr ≥ 20:1; dr ≥ 15:1).

Alkyne–Alkyne, Alkyne–Allene and Alkyne–Alkene

Cross-Coupling. Interestingly, minor modification of the

substitution and/or nature of the p-system used in the

functionalization of alkyne 28 can deliver products that

contain structural motifs that deviate from the common

methylation patterns seen in natural products of

polyketide biosynthetic origin. For example, cross-

coupling of alkyne 28 with the chiral alkyne 35 or allene

37 provides stereodefined dienes 36 and 38, each bearing

a 1,3,5,8-tetramethylation pattern.²⁴Similarly, titanium-

mediated cross-coupling of internal alkyne 28 with the

chiral homoallylic alcohol 39 provides the diol 40 (rs

≥ 20:1, ds ≥ 15:1), a structure bearing a 1,3,5,6,8-penta-

methylation pattern.²⁵

Me

B

Me

A

a^x

regioselectivity (A : B)

8 : 1

18 : 1

20 : 1

16 : 1

24; syn-syn (R = PMB)

25; syn-anti (R = Bn)

26; anti-syn (R = PMB)

27; anti-anti (R = Bn)

Scheme 4 Regioselective cross-coupling of internal alkynes and al-

dehydes for polypropionate assembly. Reaction conditions: (i) n-Bu-

Li, toluene, –78 °C, (ii) ClTi(Oi-Pr)₃, cyclopentylmagnesium

chloride, –78 to –40 °C, (iii) aldehyde, BF₃·OEt₂, –78 °C.

Step 1: Flexibility in the Titanium-Mediated Frag-

ment Union Process

To explore the versatility of titanium-mediated cross-

coupling processes between chiral internal alkynes and di-

verse p-electrophiles we examined the reaction of tris-ho-

mopropargylic alcohol 28 with a variety of coupling

partners. The results of these initial studies are illustrated

in Scheme 5.

The sum of these experiments demonstrates that titanium

alkoxide based cross-coupling reactions of stereodefined

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

632

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

O

OTBDPS

ent-23

OH OMe

OH OTBDPS

H

Me

a

Me

O

49%

29

rr ≥ 20:1

dr = 2:1

OH OMe

i-PrCN

Me

b

35%

Me

O

30

rr ≥ 20:1

Ph

O

OH OMe

O

31

Me

c

78%

Me

32

rr = 10:1

Ph

N

Ph

MeO

OMe

33

Ph

OH OMe

Me

OH OMe

HN

H

d

69%

Me

34

rr ≥ 20:1

dr ≥ 15:1

28

Me

OTBDPS

OH OMe

Me

35

e

66%

Me

OTBDPS

36

rr = 14:1

Me

37

OH

•

OH OMe

Me

f

58%

Me

OH

38

rr ≥ 20:1

E/Z = 3:1

Me Me

39

OH

OH OMe

Me

g

57%

Me

OH

40

rr ≥ 20:1

dr ≥ 15:1

Scheme 5 Titanium alkoxide mediated cross-coupling of tris-homopropargylic alcohols with diverse p–electrophiles. Reaction conditions: (a)

(i) n-BuLi, Ti(Oi-Pr)₄, toluene, (ii) cyclopentylmagnesium chloride, –78 to –30 °C, (iii) BF₃·OEt₂, ent-23, –78 to –30 °C; (b) (i) n-BuLi, toluene,

Ti(Oi-Pr)₄, (ii) cyclopentylmagnesium chloride, –78 to –40 °C, (iii) i-PrCN, –40 to –10 °C; (c) (i) n-BuLi, toluene, Ti(Oi-Pr)₄, (ii) cyclopentyl-

magnesium chloride, –78 to –30 °C, (iii) 31, –78 to –20 °C; (d) (i) 33, Ti(Oi-Pr)₄, Et₂O, (ii) cyclopentylmagnesium chloride, –78 to –30 °C, (iii)

lithium alkoxide of 28, Et₂O, –30 °C to r.t.; (e) (i) n-BuLi, toluene, Ti(Oi-Pr)₄, (ii) cyclopentylmagnesium chloride, –78 to –30 °C, (iii) 35, –78

to –20 °C; (f) (i) n-BuLi, toluene, Ti(Oi-Pr)₄, (ii) cyclopentylmagnesium chloride, –78 to –30 °C, (iii) lithium alkoxide of 37, –78 to 0 °C; (g)

(i) n-BuLi, toluene, Ti(Oi-Pr)₄, (ii) cyclopentylmagnesium chloride, –78 to –30 °C, (iii) lithium alkoxide of 39, –78 to –20 °C.

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

633

tris-homopropargylic alcohol 28 with a variety of substi- diversification through a parallel sequence of reactions to

tuted p-systems provides a convenient and convergent install building block diversity. Ideally, this functionaliza-

route to diverse, highly functionalized acyclic systems. In tion would provide a means to append structural motifs

all cross-coupling reactions described, site selectivity is that are commonly found in natural products of polyketide

≥10:1 with respect to both of the p-systems involved. In biosynthetic origin (a,b-unsaturated carbonyls, lactones,

the reactions of alkyne 28 with carbonyl electrophiles, ste- hemiketals, and spiroketals). Next, conversion into a set

reoselectivity varies, but high diastereoselection is possi- of new complex aldehydes 46 could be followed by a sec-

ble in the double asymmetric coupling reaction of 28 with ond branch point for the installation of additional ele-

chiral imine 33 (dr ≥ 15:1).

ments of structural diversity. Such a pathway was

envisioned to provide access to the extensively function-

alized and diverse set of compounds 47.

Step 2: Forward Synthetic Analysis

With a workable strategy in place for the synthesis of di-

verse polyketide architecture from a stereodefined inter-

Alkyne–Aldehyde Coupling

nal alkyne (i.e., Scheme 5), we sought to define a flexible As depicted in Scheme 7, all diastereomers of the required

pathway for the bidirectional elaboration of one of these tris-homopropargylic alcohol can be prepared via a

central acyclic polyketide scaffolds. With this goal in straightforward three-step sequence. Double asymmetric

mind, we aimed to: (1) increase molecular complexity, (2) propargylation²⁶of aldehyde 48, ent-48, or 23, followed

access structural diversity (judged by stereochemistry and by methylation and deprotection provides diastereoselec-

substitution), and (3) maximize step economy by mini- tive access to the anti-syn, anti-anti, syn-anti, and syn-syn

mizing the use of protecting group manipulations. isomeric tris-homopropargylic alcohols 28 and 49–51.

Scheme 6 illustrates the general strategy that was pursued

to accomplish these goals.

Each of the stereoisomerically pure alkynes 28 and 49–51

can be effectively coupled to either enantiomer of a b,g-

Pentynylation of chiral aldehyde 5 was anticipated to pro- unsaturated aldehyde, (R)-42 and (S)-42 (Scheme 8).

vide a stereochemically flexible route to the internal These reactions are uniformly regioselective, provide ac-

alkynes 41. Coupling of these with chiral aldehyde 42 cess to the desired polyketide backbone, and occur with

would deliver a stereodefined collection of allylic alco- exclusive chemoselectivity. Furthermore these examples

hols 43. Conversion of these addition products into alde- demonstrate the mild nature of the reaction conditions em-

hydes 44 would then be followed by modular ployed. In no case did we find evidence for racemization

OR¹

*

O

OR¹OR²

Me

OR¹OR²

OH

*

a

c

b

Me

*

H

*

introduction of

stereochemical

diversity

O

Me

Me Me

*

H

42

43

5

41

introduction of

stereochemical

diversity

OR¹OR²

O

*

OR¹OR²

OH

O

d

c

*

H

*

introduction of

building-block

diversity

*

Me

44

45

OR²

O

*

diverse structural

motifs introduced

through modules (d)

O

OR²

O

*

d

*

introduction of

building-block

diversity

H

Me

46

Me

47

diverse three-dimensional

structure based on

stereochemical diversity

a = pentynylation – introduction of stereochemical diversity (8 diastereomers)

b = cross coupling – introduction of stereochemical diversity (32 diastereomers)

c = selective functionalization to produce aldehyde

d = modules for the installation of building-block diversity

Scheme 6 Synthetic strategy for the development of a general synthetic pathway to complex and diverse polyketides

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

634

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

OBn

O

OH OMe

Me

OBn

O

OH OMe

Me

b

a

H

36%

34%

Me

ent-48

Me

48

Me

49

50

OBn

O

OR

O

OH OMe

Me

OH OMe

Me

c

d

H

52%

55%

Me

48

Me

28

23

51

R = TBDPS

OMs

TMS

Me

TMS

Me

H

Me

•

Me

52

53

ent-53

Me

Scheme 7 Preparation of stereoisomeric alkyne coupling partners. Reaction conditions: (a) (1) Pd(PPh₃)₄, 52, THF, Et₂Zn, 0 °C to r.t., 60%,

ds 9:1, (2) NaH, MeI, DMF, 95%, (3) BBr₃, CH₂Cl₂, –78 °C, 66%; (b) (1) TiCl₄, 53, CH₂Cl₂, –78 °C, 70%, ds 5:1, (2) NaH, MeI, DMF, 99%;

(3) BBr₃, CH₂Cl₂, –78 °C, 62%; (c) (1) TiCl₄, 53, CH₂Cl₂, –78 °C, 82%, ds 20:1, (2) NaH, MeI, DMF, 95%, (3) BBr₃, CH₂Cl₂, –78 °C, 67%;

(d) (1) TiCl₄, ent-53, CH₂Cl₂, –78 °C, 75%, ds 15:1, (2) NaH, MeI, DMF, 99%, (3) TBAF, THF, 79%.

OH OMe

OH

OH OMe

OH

O

Me

H

Me Me

Me

(R)-42

54

58

a

c

OH OMe

74%

75%

rr = 7:1

rr = 10:1

Me

OH OMe

Me

OH OMe

Me

55

59

OH OMe

OH

OH OMe

OH

O

Me

50

Me

49

Me

H

Me Me

Me

(S)-42

56

60

b

d

OH OMe

74%

71%

rr = 10:1

rr = 12:1

Me

57

61

OH OMe

OH

OH OMe

OH

Me

(R)-42

66

62

g

e

OH OMe

76%

79%

rr = 6:1

rr = 7:1

Me

OH OMe

Me

OH OMe

Me

63

67

OH OMe

OH

OH OMe

OH

Me

51

Me

28

Me

(S)-42

64

68

h

f

OH OMe

72%

58%

rr = 5:1

rr = 6:1

Me

65

69

Scheme 8 Regioselective coupling of hydroxyalkynes 28 and 49–51 with b,g-unsaturated aldehydes 42 and ent-42. Reaction conditions: (a)

(i) alkyne, n-BuLi, Ti(Oi-Pr)₄, toluene, (ii) c-C₅H₉MgCl, –78 °C to –40°C, (iii) BF₃⋅OEt₂, aldehyde, –78 °C to –30 °C, ds 3:1; (b) same as above,

ds 3:1; (c) same as above, ds 2:1; (d) same as above, ds 2:1; (e) same as above, ds 2:1; (f) same as above, ds 2:1; (g) same as above, ds 2:1; (h)

same as above, ds 2:1.

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

635

of the potentially sensitive chiral b,g-unsaturated alde- Fortunately, we found that Horner–Wadsworth–Emmons

hyde 42.

(HWE) olefination, conducted by the procedure described

by Masamune and Roush²⁸(DBU, LiCl, MeCN) provided

a glimpse of success for the realization of a reaction pro-

cess to homologate the b-hydroxyaldehyde. Initially, we

were able to access 72 as the major product, yet this was

found along with a significant amount of starting aldehyde

and retro-aldol product (71/72/73 = 0.2:0.5:0.3; deter-

mined by ¹H NMR of the crude reaction mixture)

(Scheme 9, entry 1). Running the reaction at lower tem-

peratures (–40 to –10 °C) suppressed formation of the

retro-aldol product, but the reaction rate for the desired

HWE olefination dropped significantly. In this case, a

substantial amount of starting material could be isolated.

After significant experimentation, suitable conditions

were found to successfully functionalize the sensitive b-

hydroxy aldehyde (71 → 72). Key to this success was the

use of N,N-diisopropylethylamine as base, and maintain-

ing a temperature of –10 °C throughout the reaction.

Consistent with our earlier studies, these double asymmet-

ric alkyne–aldehyde coupling reactions proceed with Fel-

kin selectivity, yet do so with relatively low levels of

facial selectivity; in many of the cases, selectivity is on the

order of 2–3:1. Although this level of diastereoselection

leaves significant room for improvement, at this point, we

remained focused on the development of the pathway and

did not shift attention toward enhancing levels of facial

selectivity in this cross-coupling reaction. Rather, simple

flash column chromatography could typically be used to

deliver pure samples of each diastereomer.

Homologation of the Diene

With the collection of dienes in hand 54–69, we selected

a single isomer 62 to probe subsequent functionalization

reactions. As illustrated in Scheme 9, regioselective dihy-

droxylation of the less sterically congested trisubstituted Based on the functionality present in 71, and the flexibil-

alkene can be achieved with the Sharpless asymmetric di- ity of the Horner–Wadsworth–Emmons olefination, a va-

hydroxylation reaction.²⁷Although use of either AD-mix- riety of structural motifs common to natural products of

a or AD-mix-b provided similar levels of site selectivity, polyketide biosynthetic origin can be readily installed

best results were obtained with super AD-mix-b (62 → (Scheme 10). For example, a,b-unsaturated esters 74 can

70; 69%; rr ≥ 20:1). Interestingly, attempts to use standard be

introduced

by

direct

HWE

of

71

dihydroxylation conditions (OsO₄, NMO, acetone, H₂O) [(MeO)₂P(O)CH₂CO₂Me, DIPEA, LiCl, MeCN, –10 °C,

led only to products of bisfunctionalization.

58%]. Alternatively, a sequence of HWE olefination, fol-

lowed by chemoselective dissolving metal reduction²⁹and

acid promoted cyclization (average yield/step = 58%) de-

fines a convenient pathway to saturated lactones 75.

Selective oxidative cleavage of tetraol 70 delivers the sen-

sitive b-hydroxy aldehyde 71. Initial attempts to function-

alize 71 via olefination processes were not highly

effective due to the propensity of the aldehyde to undergo Methyl hemiketals are accessible by a similar homologa-

retro-aldol-based fragmentation (Scheme 9).

tion procedure. For example, HWE olefination of 71

[(MeO)₂P(O)CH₂C(O)Me, DIPEA, LiCl, MeCN, –10 °C,

OH OMe

OH

OH OMe

OH OH

"Super AD-Mix"

Me

69%

(rs ≥ 20:1)

Me OH

Me

OH

62

70

OH OMe

OH

O

OH OMe

O

Pb(OAc)₄

olefination

H

EtOAc, 0 °C

Me

71

Me

71

O

conditions

for olefination

ratio of products*

entry

OH OMe

OH

Me

(71:72:73)

DBU, LiCl, MeCN

(MeO)₂P(O)CH₂C(O)Me,

–40 to 0 °C

1

2

0.2 : 0.5 : 0.3

0.6 : 0.4 : 0

Me

72

DBU, LiCl, MeCN

(MeO)₂P(O)CH₂C(O)Me,

–40 to –10 °C

OH OMe

O

H

DIPEA, LiCl, MeCN

(MeO)₂P(O)CH₂C(O)Me,

–10 °C

Me

73

Me

3

0 : 0.9 : 0.1

* Ratio of products determined by ¹H-NMR integration of the crude reaction mixture.

Scheme 9 Optimization of the Horner–Wadsworth–Emmons reaction of the b-hydroxy aldehyde 71

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

636

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

OH OMe

OH

O

H

Me

71

Me

a

c

b

Me

O

MeO

OH OMe

OH

O

OH OMe

O

OH OMe

O

H

OMe

Me

75

Me

74

76

d

e

f

O

OH OMe

O

OH OMe

O

OH OMe

H

Me

78

Me

77

79

Scheme 10 A simple branched reaction pathway from the complex b-hydroxy aldehyde 71. Reaction conditions: (a) DIPEA, LiCl,

(MeO)₂P(O)CH₂CO₂Me, MeCN, –10 °C, 58% (2 steps); (b) (1) DIPEA, LiCl, (MeO)₂P(O)CH₂CO₂Me, MeCN, –10 °C, 58% (2 steps) (2) Mg,

MeOH, (3) CSA, CH₂Cl₂, 57% (2 steps); (c) (1) DIPEA, LiCl, (MeO)₂P(O)CH₂C(O)Me, MeCN, –10 °C, 50% (2 steps); (2) [CuH(PPh₃)]₆, ben-

zene, (3) PPTS, MeOH, 37% (2 steps); (d) (1) KHMDS, 18-crown-6, (CF₃CH₂O)₂P(O)CH₂CO₂Me, THF, –78 °C, (2) CSA, CH₂Cl₂, 43% (3

steps); (e) (1) DIPEA, LiCl, (MeO)₂P(O)CH₂CO₂Me, MeCN, –10 °C, 58% (2 steps), (2) Rh[(nbd)(dppb)]BF₄, H₂(52 bar), CH₂Cl₂, 62%; (f)

(1) DIPEA, LiCl, (MeO)₂P(O)CH₂C(O)(CH₂)₄OTES, MeCN, –10 °C, 51% (2 steps) (2) [CuH(PPh₃)]₆, benzene, (3) CSA, MeOH–CH₂Cl₂, 56%

(2 steps).

50%], followed by chemoselective conjugate reduction present in known polyketide-derived natural products.

with Stryker’s reagent ([CuH(PPh₃)]₆, benzene),³⁰and Importantly, in all cases 74–79, these stereodefined com-

acid-catalyzed cyclization of the crude reduction product plex species were prepared in six steps or less from alkyne

(PPTS, MeOH; average yield/step = 61%) provides 76.

28, without the need for protecting group manipulations.

Unsaturated lactones such as 77 can be prepared simply

by application of Still’s modification of the HWE³¹

[(CF₃CH₂O)₂P(O)CH₂CO₂Me, KHMDS, 18-crown-6,

THF, –78 °C], followed by acid-promoted cyclization

(CSA, CH₂Cl₂; average yield/step = 66%). Alternatively,

HWE reaction of 71, to afford 74 (described previously),

Homologation of the Primary Alcohol

The collection of polyketide-like molecules 74–79 pre-

pared from alkyne–aldehyde coupling, followed by HWE

and functionalization (Scheme 11), all contain a single

primary hydroxy group. As such, the potential exists to in-

corporate additional chemoselective operations as a

means to further enhance molecular complexity and struc-

tural diversity in the collection of polyketide-like mole-

cules produced from this pathway.

followed

by

hydroxy-directed

hydrogenation

(Rh[(nbd)(dppb)]BF₄, H₂(52 bar), CH₂Cl₂)³²provides 78

in 62% yield. In this case the saturated lactone, containing

a central deoxypropionate motif, is accessed through a

process that reduces each alkene and promotes cycliza-

tion.

For example, Dess–Martin oxidation of 75 provides the

chiral aldehyde 80, which, upon chemoselective function-

alization can be elaborated to a number of new synthetic

polyketides (Scheme 11). Wittig homologation of 80 pro-

vides the a,b-unsaturated esters 81 or 82 in 62% and 68%

yield, respectively. Installation of a Z-diene, a structural

motif found in the potent anticancer agents disco-

dermolide and dictyostatin, can also be achieved. As

depicted, allylation of 80 [4,4,5,5-tetramethyl-2-[(E)-3-

(trimethylsilyl)allyl]-1,3,2-dioxaborolane, toluene, 4 Å

MS], followed by base induced Peterson elimination (KH,

THF),³³and final acidification (CSA, CH₂Cl₂) provides

diene 83 in 46% yield over three steps.

Finally, spiroketals, structural motifs found in a large va-

riety of polyketides that possess anticancer and antibiotic

activities, can be installed by a similarly simple sequence

of transformations. For example, HWE of 71

[(MeO)₂P(O)CH₂C(O)(CH₂)₄OTES,

DIPEA,

LiCl,

MeCN, –10 °C; 51%], followed by conjugate reduction

([CuH(PPh₃)]₆, benzene), and acid-promoted cyclization

(CSA, MeOH–CH₂Cl₂; average yield/step = 75%), pro-

vides the complex spirocyclic polyketide 79.

Overall, the sequence of simple functionalization reac-

tions described provides a means to convert the pro-

pionate-like diene 62 into a collection of complex

molecules that possess a variety of structural motifs

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

637

Me

O

MeO

OH OMe

OH

O

OH OMe

O

H

OH OMe

O

H

OMe

Me

74

Me

O

75

76

O

OH OMe

O

OH OMe

O

OH OMe

H

Me

77

Me

78

79

O

OH OMe

O

OMe

O

H

Dess–Martin periodinane

H

Me

80

Me

75

80

c

a

b

O

OMe

O

OH OMe

O

OMe

O

H

R²O

R¹

Me

83

Me

84

Me

81; R¹= H, R²= Me

82; R¹= Me, R²= Et

Scheme 11 Subsequent functionalization of complex aldehyde 80. Reaction conditions: (a) R¹= H, R²= Me, Ph₃PCHCO₂Me, CH₂Cl₂, 62%

(2 steps), R¹= Me, R²= Et, Ph₃PC(Me)CO₂Et, CH₂Cl₂, 68% (2 steps); (b) (1) TMS-allyl pinacol borane, 4 Å MS, toluene, (2) KH, THF, (3)

CSA, CH₂Cl₂, 46% (4 steps); (c) (E)-(R,R)-DIPT-crotylboronate, 4 Å MS, toluene, –78 °C to r.t., 89% (dr = 4:1, 2 steps).

Alternatively, extension of the polypropionate backbone tion of a diene product derived from alkyne–aldehyde

can be accomplished by reaction of 80 with well-known coupling, provided a sensitive b-hydroxy aldehyde. This

crotylmetal reagents. For example, treatment with a diiso- intermediate was employed in chain-elongation process-

propyl tartrate modified (E)-crotylboronate³⁴provides the es, without the need for protecting group manipulations,

product of mismatched double asymmetric crotylation 84 by applying a variety of Horner–Wadsworth–Emmons re-

in 89% yield (dr 4:1).

action conditions (C9 → E1–E6).

(3) Subsequent chain elongation accomplished from ad-

vanced intermediates by selective functionalization of the

remaining primary free hydroxy. Conversion into a new

densely functionalized aldehyde provides an opportunity

to employ a wealth of well-known bond-construction pro-

cesses to further extend the growing polyketide backbone

(E4 → F1–F4).

This pathway is notable for its high step economy, provid-

ing complex and diverse products 74–84 in ten steps or

less (longest linear sequence) from a simple alkyne, while

avoiding the use of a single protecting group manipula-

tion. This extensive minimization of standard protecting

group manipulations is rare to synthetic sequences com-

Conclusion

We have developed a synthesis strategy for the generation

of complex and diverse polyketides from a tris-homopro-

pargylic alcohol and defined a highly branched synthetic

network for diversity oriented synthesis (Figure 2). This

pathway can be characterized by:

(1) Initial titanium-mediated fragment union between a

simple alkyne (28; B3, Figure 2) and a diverse array of

functionalized p-systems (including aldehydes, imines,

terminal alkynes, alkenes, and allenes; B3 → D1–D7).

(2) Selective oxidation of the coupled product to a com- monly employed to access such architectures, and repre-

plex aldehyde for subsequent homologation. In the proof- sents an important characteristic of the pathway

of-concept example provided, site-selective alkene oxida- described.

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

638

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

primary

hydroxy-based

chemoselective

homologation

(2–4 steps)

alkene-based

chemoselective

homologation

(3–5 steps)

aldehyde to

alkyne

(3 steps)

titanium-mediated

cross-coupling

(1 step)

C1

C2

C3

C4

C5

E1

C6

C7

E2

B1

B4

F1

C8

B2

B3

E3

A

C9

F2

C10

C11

D1

E4

D2

F3

E5

D3

E6

C12

F4

D4

C13

D5

C14

C15

D6

C16

D7

O

OH OMe

OH

OH OMe

OH

OH OMe

OH OTBDPS

Me

OH OMe

OH

OMe

=

E1

=

D1

D2

C1

C2

C9

Me

O

OR

O

Me

O

=

A

O

OMe

O

*

H

OH OMe

OH

OH OMe

F1

=

OH OMe

O

Me

EtO

Me

C10

Me

=

Me

OH OMe

H

Me

O

=

E2

E3

E4

OH OMe

Me

O

OH OMe

Ph

Me

B1

C3

C4

C5

C6

C11

C12

C13

C14

OH OMe

O

OH OMe

O

H

MeO

Me

F2

=

D3

OH OMe

O

H

OH OMe

Me

=

OH OMe

Ph

Me

O

Me

B2

B3

=

OMe

O

OH OMe

HN

OH OMe

Me

=

D4

D5

OMe

O

Ph

OH OMe

O

H

Me

F3

=

Me

OH OMe

Me

OH OMe

OH

OH OMe

OH

Me

=

O

Me

OTBDPS

Me

O

OH OMe

O

H

=

OH OMe

Me

E5

E6

O

OMe

O

H

=

D6

D7

C7

C8

=

C15

C16

=

F4

=

Me

O

MeO

OH OMe

Me

OH

=

B4

Me

OH OMe

Me

OH OMe

O

H

Me

Figure 2 A divergent pathway for the synthesis of stereochemically and structurally complex polyketides

ment. ¹H NMR chemical shifts are relative to residual CHCl₃(d =

7.26). ¹³C NMR data was recorded at 126 MHz or 101 MHz using

a Bruker AM-500, a Bruker Avance DPX-500 or a Bruker AM-400

instrument. ¹³C NMR chemical shifts are reported relative to the

central line of CDCl₃(d = 77.0). IR spectra were recorded using a

Midac Spectrometer M-series. LRMS was performed on a Waters

Micromass ZQ instrument using electrospray ionization (EI). Opti-

cal rotations were measured on a Perkin Elmer Model 341 polarim-

eter using a 1-mL capacity microcell with a 10-cm path length.

Overall, we believe that this study represents a step to-

ward the realization of a broad network of reaction pro-

cesses that could be employed in the efficient synthesis of

large collections of complex and diverse polyketide-like

molecules. Such accomplishments are required to investi-

gate the broad medical potential of polyketide-based ar-

chitecture, unbound by the laborious and serendipitous

process of natural product isolation, or the limitations of

combinatorial biosynthesis.³⁵

Chromatographic purifications were performed using 60 Å, 35–75

mm particle size silica gel from Silicycle. All compounds purified

by chromatography were sufficiently pure for use in subsequent ex-

periments, unless indicated otherwise. Semi-preparative HPLC nor-

mal phase separations were performed using a HPLC system

composed of two Dynamax SD-1 pumps, a Rheodyne injector and

a Shimadzu RID-10A refractive index detector or a Dynamax UV-

1 Absorbance detector at 254 nm.

All reactions were conducted in flame-dried glassware under nitro-

gen using anhydrous solvents. Toluene was dried by distillation

over Na/benzophenone ketyl. CH₂Cl₂and Et₂O were used after

passing through activated alumina columns. MeCN, EtOAc, and

THF were purchased from Aldrich Chemical Company in Sure/Seal

containers and were used as received. All chiral aldehydes were ob-

tained from a Dess–Martin periodinane oxidation of the corre-

sponding primary alcohol and were used without purification

except where indicated. All other commercially available reagents

were used as received.

9-(tert-Butyldiphenylsiloxy)-3-methoxy-2,4,6,8-tetramethyl-

non-5-ene-1,7-diols 29a and 29b

To a soln of alkyne 28 (102.3 mg, 0.601 mmol) in toluene (6.0 mL)

at r.t. was added sequentially 2.5 M n-BuLi in hexanes (240 mL,

0.601 mmol) and Ti(Oi-Pr)₄(360 mL, 1.202 mmol) and the mixture

¹H NMR data was recorded at 500 MHz or 400 MHz using a Bruker

AM-500, a Bruker Avance DPX-500 or a Bruker AM-400 instru-

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

639

was cooled to –78 °C. At –78 °C the pale yellow mixture was treat-

ed with 2.0 M cyclopentylmagnesium chloride in Et₂O (1.2 mL,

2.404 mmol), it was allowed to warm to –40 °C over 35 min and

then stirred at –40 °C for 1 h before it was recooled to –78 °C. At

–78 °C BF₃·OEt₂(150 mL, 1.202 mmol) was added and the mixture

was stirred for 15 min before the addition of aldehyde ent-23 (1.8

mL, 1.803 mmol, 1.0 M in toluene) dropwise via syringe. The mix-

ture was allowed to warm to –30 °C over 1.5 h and it was quenched

by the addition of sat. NH₄Cl (5 mL) and diluted with Et₂O (5 mL).

The reaction was allowed to quench for 1 h and was extracted with

Et₂O (2 × 20 mL). The combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. Chromatography [silica gel,

50 mL, 30% EtOAc–hexanes (100 mL) and EtOAc (100 mL)] gave

29a and 29b (147.4 mg, 49%); 31:1 mixture of regioisomers; 2:1

mixture of diastereomers. Further purification by normal-phase

HPLC (UV detection, gradient of 30% EtOAc–hexanes to 80%

EtOAc–hexanes over 20 min) provided characterization samples of

29a and 29b.

mL, 0.27 mmol) was added dropwise down the side of the flask and

the reaction was allowed to warm to –10 °C over 55 min. The reac-

tion was quenched with sat. NH₄Cl (2 mL), diluted with Et₂O (2

mL) and stirred for 1 h. The mixture was extracted with Et₂O

(2 × 20 mL). The combined organic extracts were dried (Na₂SO₄)

and concentrated in vacuo. Chromatography [silica gel, 15 mL,

30% EtOAc–hexanes (30 mL), 50% EtOAc–hexanes (30 mL), and

80% EtOAc–hexanes (30 mL)] gave 30 (7.6 mg, 35%) as a clear,

20

colorless oil; ≥20:1 mixture of regioisomers; [a]₅₈₉–9.0 (c 0.2,

CHCl₃).

IR (thin film, NaCl): 3466, 2969, 2932, 2876, 1666, 1461, 1381,

1236, 1119, 1088, 1046, 919, 734 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 6.48 (d, J = 9.8 Hz, 1 H), 3.71

(ddd, J = 10.1, 5.7, 3.8 Hz, 1 H), 3.62–3.56 (m, 1 H), 3.50 (s, 3 H),

3.30 (dddd, J = 6.9, 6.9, 6.9, 6.9 Hz, 1 H), 3.07 (t, J = 5.7 Hz, 1 H),

2.91–2.84 (m, 1 H), 2.58 (t, J = 5.4 Hz, 1 H), 1.81 (s, 3 H), 1.81–

1.78 (m, 1 H), 1.11 (d, J = 6.6 Hz, 3 H), 1.09 (d, J = 6.9 Hz, 3 H),

1.08 (d, J = 6.9 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 206.2, 143.8, 135.1, 90.3, 65.7,

(E)-(2S,3R,4S,7R,8S)-9-(tert-Butyldiphenylsiloxy)-3-methoxy-

2,4,6,8-tetramethylnon-5-ene-1,7-diol (29a)

61.7, 37.9, 36.9, 33.9, 19.6, 19.5, 15.3, 14.9, 11.9.

Clear, colorless oil; [a]₅₈₉²⁰–1.3 (c 5.2, CHCl₃).

LRMS (EI): m/z [M + Na]⁺calcd for C₁₄H₂₆NaO₃: 265.2; found:

265.1.

IR (thin film, NaCl): 3421, 2962, 2931, 2859, 1472, 1457, 1428,

1113, 1085, 1008, 824, 741, 703, 614 cm^–1

¹H NMR (500 MHz, CDCl₃): d = 7.64–7.62 (m, 4 H), 7.43–7.38 (m,

6 H), 5.31 (ddd, J = 10.1, 1.3, 1.3 Hz, 1 H), 4.14 (s, 1 H), 3.68 (ddd,

J = 10.7, 3.8, 3.8 Hz, 1 H), 3.64 (d, J = 5.4 Hz, 2 H), 3.46–3.42 (m,

1 H), 3.42 (s, 3 H), 2.90 (dd, J = 6.9, 4.7 Hz, 1 H), 2.82 (t, J = 5.4

Hz, 1 H), 2.71–2.64 (m, 1 H), 2.55 (s, 1 H), 1.88–1.82 (m, 1 H),

1.77–1.71 (m, 1 H), 1.52 (d, J = 1.3 Hz, 3 H), 1.08 (s, 9 H), 1.01 (d,

J = 6.6 Hz, 3 H), 1.00 (d, J = 7.3 Hz, 3 H), 0.90 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.6, 135.5 134.8, 133.3, 133.1,

129.8, 129.7, 128.6, 127.7, 91.9, 77.8, 67.9, 65.5, 61.7, 37.8, 37.2,

35.9, 26.8, 19.2, 16.5, 15.5, 13.3, 10.4.

(5E,7E)-(2S,3R,4S)-3-Methoxy-2,4,6-trimethyl-8-[(2R,4S,5R)-

5-methyl-2-phenyl-1,3-dioxan-4-yl]octa-5,7-dien-1-ol (32)

To a soln of alkyne 28 (14.9 mg, 0.087 mmol) in toluene (870 mL)

was added sequentially 2.5 M n-BuLi in hexanes (35 mL, 0.087

mmol) and Ti(Oi-Pr)₄(52 mL, 0.175 mmol). The resulting pale yel-

low mixture was cooled to –78 °C and was treated with 2 M cyclo-

pentylmagnesium chloride in Et₂O (175 mL, 0.351 mmol) dropwise

via syringe. The reaction was allowed to warm to –40 °C over 45

min and it was stirred at –40 °C for 1.25 h and then recooled to –78

°C. To the resulting dark brown soln terminal alkyne 31 (614 mL,

0.061 mmol, 0.1 M in toluene) was added and the reaction was al-

lowed to warm to –20 °C over 2 h. The reaction was quenched with

sat. NH₄Cl (2 mL) and diluted with Et₂O (2 mL) and stirred for 1 h.

The biphasic mixture was extracted with Et₂O (2 × 20 mL). The

combined organic extracts were dried (Na₂SO₄) and concentrated in

vacuo. Chromatography [silica gel, 20 mL, 30% EtOAc–hexanes

(50 mL) and EtOAc (50 mL)] gave 32 (18 mg, 78%) as a clear, col-

orless oil; 10:1 mixture of regioisomers. Further purification by nor-

mal-phase HPLC (UV detection (254nm), gradient of 20% EtOAc–

hexanes to 50% EtOAc–hexanes over 30 min) provided a character-

ization sample of 32; [a]₅₈₉²⁰–4.2 (c 0.3, CHCl₃).

LRMS (EI): m/z [M + Na]⁺calcd for C₃₀H₄₆NaO₄Si: 521.3; found:

521.2.

(E)-(2S,3R,4S,7S,8S)-9-(tert-Butyldiphenylsiloxy)-3-methoxy-

2,4,6,8-tetramethylnon-5-ene-1,7-diol (29b)

Clear, colorless oil; [a]₅₈₉²⁰+8.8 (c 2.3, CHCl₃).

IR (thin film, NaCl): 3421, 2962, 2931, 2859, 1457, 1438, 1112,

1086, 1008, 824, 741, 703 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 7.68 (d, J = 6.6 Hz, 4 H), 7.47–

7.38 (m, 6 H), 5.23 (d, J = 10.1 Hz, 1 H), 4.01 (s, 1 H), 3.90 (d,

J = 8.8 Hz, 1 H), 3.76 (m, 2 H), 3.66 (dd, J = 10.1, 8.5 Hz, 1 H), 3.54

(dd, J = 11.0, 5.4 Hz, 1 H), 3.49 (s, 3 H), 2.97 (dd, J = 6.6, 5.0 Hz,

1 H), 2.88 (s, 1 H), 2.75–2.68 (m, 1 H), 1.97–1.89 (m, 1 H), 1.87–

1.81 (m, 1 H), 1.65 (d, J = 0.9 Hz, 3 H), 1.06 (s, 9 H), 1.04 (d,

J = 6.9 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 0.61 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.6, 135.3, 132.8, 132.7, 131.4,

129.9, 127.8, 91.7, 84.0, 69.6, 65.7, 61.8, 37.7, 37.2, 35.9, 26.8,

19.1, 16.8, 16.2, 15.6, 13.5, 11.2.

IR (thin film, NaCl): 3447, 2966, 2932, 2360, 2337, 1734, 1456,

1274, 1114, 1027 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 7.52–7.49 (m, 2 H), 7.38–7.30 (m,

3 H), 6.31 (dd, J = 15.5, 7.6 Hz, 1 H), 5.60 (dd, J = 15.5, 7.6 Hz, 1

H), 5.55 (s, 1 H), 5.34 (d, J = 10.1 Hz, 1 H), 4.18 (dd, J = 11.7, 5.0

Hz, 1 H), 3.92 (dd J = 9.8, 7.9 Hz, 1 H), 3.74–3.68 (m, 1 H), 3.58–

3.47 (m, 2 H), 3.47 (s, 3 H), 2.96 (dd, J = 6.3, 5.4 Hz, 1 H), 2.82–

2.76 (m, 2 H), 1.98–1.91 (m, 1 H), 1.76 (s, 3 H), 1.05 (d, J = 6.6 Hz,

3 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 138.5, 138.4, 136.8, 132.3, 128.9,

128.3, 128.2, 126.2, 125.0, 101.3, 91.6, 84.9, 73.1, 65.7, 61.8, 37.4,

36.4, 34.5, 16.1, 15.5, 12.7, 12.5.

LRMS (EI): m/z [M + Na]⁺calcd for C₃₀H₄₆NaO₄Si: 521.3; found:

521.4.

(E)-(6S,7R,8S)-9-Hydroxy-7-methoxy-2,4,6,8-tetramethylnon-

4-en-3-one (30)

LRMS (EI): m/z [M + Na]⁺calcd for C₂₃H₃₄NaO₄: 397.3; found:

To a soln of internal alkyne 28 (15.3 mg, 0.09 mmol) in toluene (900

mL) was added sequentially 2.5 M n-BuLi in hexanes (36 mL, 0.09

mmol) and Ti(Oi-Pr)₄(33 mL, 0.112 mmol). The resulting pale yel-

low mixture was cooled to –78 °C and was treated with 1.9 M cy-

clopentylmagnesium chloride in Et₂O (118 mL, 0.225 mmol). This

soln was allowed to warm to –40 °C over 45 min and it was stirred

at –40 °C for 1 h. To the resulting dark brown mixture i-PrCN (24

397.3.

(E)-(2S,3R,4S,7S)-3-Methoxy-7-{[(S)-2-methoxy-1-phenyleth-

yl]amino}-2,4,6-trimethyl-7-phenylhept-5-en-1-ol (34)

To a soln of imine 33 (60.8 mg, 0.254 mmol) in Et₂O (1.5 mL, 0.17

M) at r.t. was added Ti(Oi-Pr)₄(68.1 mL, 0.229 mmol) and the re-

sulting mixture was cooled to –78 °C before the addition of 2 M cy-

Synthesis 2008, No. 4, 627–648 © Thieme Stuttgart · New York

640

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

clopentylmagnesium chloride in Et₂O (229 mL, 0.458 mmol). The

reaction was allowed to stir with warming to –30 °C over 45 min

and then it was stirred at –30 °C for 3 h. To the resulting dark brown

soln was added, via canula, the lithium alkoxide of the tris-

homopropargyl alcohol 28 [generated through the reaction of 2.5 M

n-BuLi in hexanes (51 mL, 0.127 mmol) with 28 (21.6 mg, 0.127

mmol) in Et₂O (420 mL, 0.3 M)]. The resulting mixture was allowed

to warm from –30 °C to r.t. over 2 h and allowed to stir at r.t. for 1

h before quenching with sat. NH₄Cl. The mixture was diluted with

Et₂O (5 mL) and it was stirred at r.t. for 1 h. The mixture was ex-

tracted with Et₂O (2 × 20 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo. The residue was

subjected to chromatography [silica gel, 25 mL, 30% EtOAc–hex-

anes (25 mL), 50% EtOAc–hexanes (25 mL), 80% EtOAc–hexanes

(25 mL), and EtOAc (50 mL)] to give 34 (27.3 mg, 69%) as a clear,

LRMS (EI): m/z [M + Na]⁺calcd for C₃₁H₄₆NaO₃Si: 517.3; found:

517.6.

(2E,5E)-(7S,8R,9S)-8-Methoxy-2,5,7,9-tetramethyldeca-2,5-di-

ene-1,10-diol (38)

To a soln of internal alkyne 28 (79.6 mg, 0.467 mmol) in toluene

(4.7 mL) was added sequentially 2.5 M n-BuLi in hexanes (188 mL,

0.467 mmol) and Ti(Oi-Pr)₄(210 mL, 0.701 mmol). The resulting

pale yellow mixture was cooled to –78 °C and was treated with 2 M

cyclopentylmagnesium chloride in Et₂O (700 mL, 1.40 mmol). This

soln was allowed to warm to –30 °C over 1 h and stirred at –30 °C

for 1 h before recooling to –78 °C. In a separate flask the allene 37

(27.5 mg, 0.327 mmol) in toluene (820 mL) at –78 °C was treated

with 2.5 M n-BuLi in hexanes (130 mL, 0.327 mmol) and stirred for

15 min while warming to –30 °C. The resulting soln was transferred

via canula to the cooled (–78 °C) soln of the titanium–alkyne com-

plex. The mixture was allowed to stir with warming to 0 °C over 130

min and it was quenched with sat. NH₄Cl (5 mL), diluted with Et₂O

(5 mL), and stirred for 1 h. The mixture was extracted with Et₂O

(2 × 20 mL) and the combined organic extracts were dried (Na₂SO₄)

and concentrated in vacuo. Chromatography [silica gel, 50 mL,

30% EtOAc–hexanes (100 mL) and EtOAc (100 mL)] gave 38

(69.5 mg, 58%) as a clear, colorless oil; 20:1 mixture of regioiso-

mers; ratio E/Z 3:1. Further purification by normal-phase HPLC (RI

detection, isocratic at 70% EtOAc–hexanes) provided a character-

ization sample of 38; [a]₅₈₉²⁰–15.1 (c 1.1, CHCl₃).

20

colorless oil; 20:1 mixture of regioisomers; dr 15:1; [a]₅₈₉+22.7

(c 0.9, CHCl₃).

IR (thin film, NaCl): 3443, 2963, 2926, 2877, 1453, 1114, 701 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 7.42–7.18 (m, 10 H), 5.17 (d,

J = 10.1 Hz, 1 H), 4.00 (s, 1 H), 3.90 (t, J = 6.6 Hz, 1 H), 3.82 (ddd,

J = 8.5, 4.4, 4.4 Hz, 1 H), 3.66–3.60 (m, 1 H), 3.52 (s, 3 H), 3.45 (d,

J = 6.9 Hz, 2 H), 3.36 (s, 3 H), 2.98 (dd, J = 7.3, 4.4 Hz, 1 H), 2.87

(t, J = 5.7 Hz, 1 H), 2.80–2.72 (m, 1 H), 2.36 (s, 1 H), 1.97–1.91 (m,

1 H), 1.45 (s, 3 H), 1.15 (d, J = 7.3 Hz, 3 H), 1.06 (d, J = 6.6 Hz, 3

H).

¹³C NMR (126 MHz, CDCl₃): d = 142.8, 140.6, 134.5, 131.9, 128.3,

128.0, 127.6, 127.3, 126.8, 126.5, 91.9, 78.1, 65.4, 65.4, 61.9, 59.0,

58.8, 37.6, 36.5, 16.8, 15.8, 11.6.

IR (thin film, NaCl): 3381, 2966, 2932, 2361, 2340, 1717, 1457,

1086, 1026 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.41 (dddd, J = 7.6, 7.6, 1.3, 1.3

Hz, 1 H), 5.02 (ddd, J = 9.8, 1.3, 1.3 Hz, 1 H), 4.03 (d, J = 4.4 Hz,

2 H), 3.73–3.68 (m, 1 H), 3.56–3.50 (m, 1 H), 3.46 (s, 3 H), 2.93

(dd, J = 6.6, 5.4 Hz, 1 H), 2.85 (t, J = 5.0 Hz, 1 H), 2.72–2.61 (m, 3

H), 1.83–1.78 (m, 1 H), 1.68 (s, 3 H), 1.61 (d, J = 1.3 Hz, 3 H), 1.48

(t, J = 4.4 Hz, 1 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3

H).

¹³C NMR (126 MHz, CDCl₃): d = 136.1, 133.4, 128.3, 123.8, 91.8,

68.9, 65.9, 61.5, 37.7, 37.1, 35.9, 16.6, 16.4, 15.5, 13.7.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₅H₂₈NaO₃: 279.2; found:

279.2.

LRMS (EI): m/z [M + H]⁺calcd for C₂₆H₃₈NO₃: 412.3; found:

412.5.

(5E,7E)-(2S,3R,4S,9R)-10-(tert-Butyldiphenylsiloxy)-3-meth-

oxy-2,4,6,9-tetramethyldeca-5,7-dien-1-ol (36)

To a soln of alkyne 28 (18 mg, 0.106 mmol) in toluene (1.1 mL) was

added sequentially 2.5 M n-BuLi in hexanes (42 mL, 0.106 mmol)

and Ti(Oi-Pr)₄(63 mL, 0.212 mmol). The resulting pale yellow mix-

ture was cooled to –78 °C and was treated with 2 M cyclopentyl-

magnesium chloride in Et₂O (210 mL, 0.424 mmol) dropwise via

syringe. The reaction was allowed to warm to –40 °C (45 min) and

stirred for 1.25 h at –40 °C; it was then recooled to –78 °C. To the

resulting dark brown soln terminal alkyne 35 (850 mL, 0.085 mmol,

0.1 M in toluene) was added and the reaction was allowed to warm

to –20 °C over 2 h. The reaction was quenched with sat. NH₄Cl (2

mL) and diluted with Et₂O (2 mL) and stirred for 1 h. The biphasic

mixture was extracted with Et₂O (2 × 20 mL). The combined organ-

ic extracts were dried (Na₂SO₄), and concentrated in vacuo. Chro-

matography [silica gel, 20 mL, 30% EtOAc–hexanes (50 mL) and

EtOAc (50 mL)] gave 36 (27.7 mg, 66%) as a clear, colorless oil;

mixture of regioisomers 14:1 . Further purification by normal-phase

HPLC (UV detection, gradient of 10% EtOAc–hexanes to 50%

EtOAc–hexanes over 30 min) provided a characterization sample of

36; [a]₅₈₉²⁰–4.6 (c 2.9, CHCl₃).

(E)-(2S,3R,4S,7R,9R)-3-Methoxy-2,4,6,7,9-pentamethyldec-5-

ene-1,10-diol (40)

To a soln of internal alkyne 28 (48.9 mg, 0.287 mmol) in toluene

(2.9 mL) was added sequentially 2.5 M n-BuLi in hexanes (115 mL,

0.287 mmol) and Ti(Oi-Pr)₄(130 mL, 0.431 mmol). The resulting

pale yellow mixture was cooled to –78 °C and was treated with 2 M

cyclopentylmagnesium chloride in Et₂O (430 mL, 0.861 mmol).

This soln was allowed to warm to –30 °C over 1 h and was stirred

at –30 °C for 1 h before recooling to –78 °C. In a separate flask the

alkene 39 (14.4 mg, 0.144 mmol) in toluene (240 mL) at –78 °C was

treated with 2.5 M n-BuLi in hexanes (60 mL, 0.144 mmol) and

stirred for 15 min while warming to –30 °C. The resulting soln was

transferred via canula to the cooled (–78 °C) soln of the titanium–

alkyne complex. The mixture was allowed to stir with warming to

–20 °C over 70 min and then it was stirred at –20 °C for 2 h. The

reaction was quenched with sat. NH₄Cl (5 mL), diluted with Et₂O (5

mL) and stirred for 1 h. The mixture was extracted with Et₂O

(2 × 20 mL) and the combined organic extracts were dried (Na₂SO₄)

and concentrated in vacuo. Chromatography [silica gel, 50 mL,

30% EtOAc–hexanes (100 mL) and EtOAc (100 mL)] gave 40

(22.4 mg, 57%) as a clear colorless oil; 20:1 mixture of regioiso-

mers; dr 15:1. Further purification by normal-phase HPLC (RI

detection, isocratic at 70% EtOAc–hexanes) provided a character-

ization sample of 40; [a]₅₈₉²⁰–0.8 (c 1.1, CHCl₃).

IR (thin film, NaCl): 3432, 2961, 2931, 2858, 1589, 1428, 1112,

965, 824, 702 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 7.68–7.65 (m, 4 H), 7.42–7.35 (m,

6 H), 6.04 (d, J = 15.8 Hz, 1 H), 5.52 (dd, J = 15.8, 7.3 Hz, 1 H),

5.21 (d, J = 9.5 Hz, 1 H), 3.74 (ddd, J = 11.0, 4.4, 4.4 Hz, 1 H),

3.58–3.49 (m, 3 H), 3.49 (s, 3 H), 2.96 (dd, J = 6.6, 5.0 Hz, 1 H),

2.82–2.75 (m, 2 H), 2.48–2.42 (m, 1 H), 1.82–1.77 (m, 1 H), 1.72

(d, J = 1.3 Hz, 3 H), 1.10–1.03 (m, 18 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.6, 134.4, 134.0, 134.0, 133.8,

132.9, 130.6, 129.5, 127.6, 91.9, 68.7, 65.7, 61.8, 39.4, 37.3, 36.3,

26.8, 19.3, 16.8, 16.4, 15.6, 12.7.

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

641

IR (thin film, NaCl): 3364, 2962, 2927, 2873, 2361, 2337, 1489,

1261, 1084, 1024, 800 cm^–1.

J = 1.3 Hz, 3 H), 1.54 (d, J = 1.3 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 3 H),

0.90 (d, J = 6.9 Hz, 3 H), 0.88 (d, J = 7.8 Hz, 3 H).

¹H NMR (500 MHz, CDCl₃): d = 5.03 (d, J = 9.5 Hz, 1 H), 3.74–

3.70 (m, 1 H), 3.57–3.48 (m, 2 H), 3.48 (s, 3 H), 3.44–3.39 (m, 1 H),

2.92 (dd, J = 6.6, 5.0 Hz, 1 H), 2.82 (s, 1 H), 2.68–2.61 (m, 1 H),

2.22–2.15 (m, 1 H), 1.84–1.77 (m, 1 H), 1.61–1.54 (m, 1 H), 1.54

(s, 3 H), 1.34–1.14 (m, 3 H), 1.04 (d, J = 7.3 Hz, 3 H), 0.99 (d,

J = 6.6 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 136.2, 130.2, 129.6, 127.7, 87.7,

82.5, 66.0, 60.3, 37.5, 36.4, 34.3, 25.7, 18.3, 17.8, 17.3, 12.0, 11.5.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.7.

(E)-(2S,3S,4S,7R,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (55)

¹³C NMR (126 MHz, CDCl₃): d = 138.9, 127.6, 92.1, 68.1, 65.9,

61.7, 40.2, 38.4, 37.3, 35.8, 33.5, 19.5, 17.1, 16.4, 15.5, 12.6.

Clear, colorless oil; [a]₅₈₉²⁰+4.6 (c 1.2, CHCl₃).

LRMS (EI): m/z [M + Na]⁺calcd for C₁₆H₃₂O₃Na: 295.2; found:

295.2.

IR (thin film, NaCl): 3376, 2964, 2926, 2870, 1576, 1473, 1378,

1261, 1089, 1028, 933, 797 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.42 (dd, J = 9.4, 1.3 Hz, 1 H),

4.95 (dt, J = 9.8, 1.3 Hz, 1 H), 3.63 (dd, J = 10.4, 6.6 Hz, 1 H), 3.55

(d, J = 9.1 Hz, 1 H), 3.50 (dd, J = 10.4, 5.0 Hz, 1 H), 3.41 (s, 3 H),

3.09 (dd, J = 5.7, 4.7 Hz, 1 H), 2.73–2.68 (m, 1 H), 2.56–2.51 (m, 1

H), 1.88–1.84 (m, 1 H), 1.79 (s, 1 H), 1.73 (d, J = 1.3 Hz, 3 H), 1.67

(d, J = 1.3 Hz, 3 H), 1.64 (d, J = 1.6 Hz, 3 H), 0.98 (d, J = 6.9 Hz, 3

H), 0.94 (d, J = 6.9 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 134.9, 134.7, 131.8, 127.3, 87.2,

82.7, 66.3, 60.5, 37.9, 36.8, 34.9, 26.0, 18.3, 18.1, 17.4, 11.8, 11.0.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.7.

(R)-2,4-Dimethylpent-3-enal [(R)-42]; Typical Procedure

To a soln of (R)-2,4-dimethylpent-3-en-1-ol (390 mg, 3.4 mmol) in

anhyd CH₂Cl₂(22 mL) at 0 °C was added Dess–Martin periodinane

(2.9 g, 6.8 mmol) and the mixture was stirred vigorously for 10 min

to effect dissolution. To this cloudy mixture at 0 °C was added drop-

wise via addition funnel CH₂Cl₂saturated with H₂O over 2 h. At this

time the reaction was complete by TLC and the mixture was con-

centrated in vacuo to a volume of ca. 2 mL. The slurry was suspend-

ed in 50% Et₂O–hexanes (30 mL), washed with sat. NaHCO₃/10%

Na₂S₂O₃soln (1:1, 50 mL) and brine, dried (Na₂SO₄), and concen-

trated in vacuo. The resulting oil (380 mg, quant.) was used without

purification in the subsequent step.

¹H NMR (500 MHz, CDCl₃): d = 9.49 (d, J = 1.9 Hz, 1 H), 4.95 (dt,

J = 9.1, 1.6 Hz, 1 H), 3.28–3.20 (m, 1 H), 1.78 (d, J = 0.9 Hz, 3 H),

1.70 (d, J = 0.9 Hz, 3 H), 1.15 (d, J = 6.9 Hz, 3 H).

(E)-(2S,3S,4S,7R,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (56)

Clear, colorless oil; [a]₅₈₉²⁰+24.9 (c 0.5, CHCl₃).

¹³C NMR (126 MHz, CDCl₃): d = 201.6, 137.1, 120.6, 46.5, 25.8,

18.4, 14.1

IR (thin film, NaCl): 3387, 2967, 2928, 2872, 1455, 1376, 1091,

1027, 933 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.44 (d, J = 9.5 Hz, 1 H), 4.89 (dt,

J = 9.8, 1.6 Hz, 1 H), 3.76 (dd, J = 7.9, 3.4 Hz, 1 H), 3.60–3.49 (m,

2 H), 3.44 (s, 3 H), 3.09 (dd, J = 5.0, 5.0 Hz, 1 H), 2.71–2.64 (m, 1

H), 2.60–2.52 (m, 1 H), 1.90–1.84 (m, 2 H), 1.63 (d, J = 1.3 Hz, 3

H), 1.62 (d, J = 1.6 Hz, 3 H), 1.58 (d, J = 1.3 Hz, 3 H), 1.48 (d,

J = 3.5 Hz, 1 H), 1.00 (d, J = 6.9 Hz, 3 H), 0.99 (d, J = 6.6 Hz, 3 H),

0.95 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 136.5, 130.7, 129.8, 127.5, 87.8,

82.4, 66.2, 60.5, 37.9, 36.5, 34.6, 25.8, 18.4, 17.8, 17.2, 12.3, 11.9.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃Na: 307.2; found:

307.2.

3-Methoxy-2,4,6,8,10-pentamethylundeca-5,9-diene-1,7-diols

54 and 55; Typical Procedure

To a soln of the tris-homopropargyl alcohol 49 (98.5 mg, 0.58

mmol) in toluene (5.8 mL, 0.1 M) at r.t., 2.5 M n-BuLi in hexanes

(232 mL, 0.58 mmol) and Ti(Oi-Pr)₄(345 mL, 1.16 mmol) were add-

ed sequentially. The resulting light yellow, clear soln was cooled to

–78 °C and treated with 1.9 M cyclopentylmagnesium chloride in

Et₂O(1.22 mL, 2.31 mmol) dropwise via syringe. The resulting mix-

ture was allowed to warm to –40 °C over 35 min and stirred at –40

°C for 1 h and then re-cooled to –78 °C. The dark brown mixture

was treated with BF₃·OEt₂(147 mL, 1.16 mmol) and allowed to stir

for 15 min before the addition of the freshly prepared aldehyde (R)-

42 (1.7 mL, 1.74 mmol, 1.0 M in toluene) dropwise via syringe. The

reaction was allowed to warm to –30 °C (1.5 h), quenched with sat.

NH₄Cl (5 mL), diluted with Et₂O (5 mL), and stirred at r.t. for 1 h.

The biphasic mixture was extracted with Et₂O (2 × 20 mL) and the

organic extracts were dried (Na₂SO₄) and concentrated in vacuo.

Chromatography [silica gel, 50 mL, 30% EtOAc–hexanes (100 mL)

and 100% EtOAc (100 mL)] gave 54 and 55 (121.7 mg, 74%); 7:1

mixture of regioisomers; major regioisomer dr 2:1. Further purifica-

tion by chromatography [silica gel, 40 mL, 30% EtOAc–hexanes

(10 mL), 50% EtOAc–hexanes (80 mL), and 80% EtOAc–hexanes

(80 mL); gave the diastereomeric diols 54 and 55.

(E)-(2S,3S,4S,7S,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (57)

Clear, colorless oil; [a]₅₈₉²⁰–3.2 (c 0.6, CHCl₃).

IR (thin film, NaCl): 3376, 2964, 2926, 2870, 1576, 1473, 1378,

1261, 1089, 1028, 933 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.41 (d, J = 10.1 Hz, 1 H), 4.95

(dt, J = 10.1, 1.2 Hz, 1 H), 3.62–3.54 (m, 2 H), 3.55 (d, J = 9.5 Hz,

1 H), 3.43 (s, 3 H), 3.11 (dd, J = 5.4, 5.4 Hz, 1 H), 2.75–2.71 (m, 1

H), 2.54–2.49 (m, 1 H), 1.95–1.89 (m, 2 H), 1.77 (s, 1 H), 1.73 (d,

J = 1.3 Hz, 3 H), 1.67 (d, J = 1.3 Hz, 3 H), 1.64 (d, J = 1.3 Hz, 3 H),

0.95 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 0.76 (d, J = 6.9

Hz, 3 H).

(E)-(2S,3S,4S,7S,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (54)

¹³C NMR (126 MHz, CDCl₃): d = 134.8, 134.8, 131.4, 127.4, 87.5,

82.6, 66.3, 60.4, 37.6, 36.9, 34.7, 26.0, 18.3, 18.1, 17.4, 11.8, 11.1.

Clear, colorless oil; [a]₅₈₉²⁰–4.2 (c 1.6, CHCl₃).

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.2.

IR (thin film, NaCl): 3389, 2965, 2926, 2872, 1435, 1376, 1261,

1089, 1027, 932, 796 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.32 (d, J = 9.8 Hz, 1 H), 4.81 (dt

J = 9.8, 1.3 Hz, 1 H), 3.69 (d, J = 8.2 Hz, 1 H), 3.57 (dd, J = 10.7,

6.9 Hz, 1 H), 3.46 (dd, J = 10.7, 5.4 Hz, 1 H), 3.41 (s, 3 H), 3.06 (dd,

J = 4.7, 4.7 Hz, 1 H), 2.64–2.58 (m, 1 H), 2.53–2.47 (m, 1 H), 2.37

(s, 1 H), 1.94–1.88 (m, 1 H), 1.60 (d, J = 1.0 Hz, 3 H), 1.57 (d,

(E)-(2R,3S,4S,7S,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (58)

Clear, colorless oil; [a]₅₈₉²⁰–5.1 (c 0.6, CHCl₃).

642

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

IR (thin film, NaCl): 3430, 2965, 2927, 2872, 1452, 1376, 1096,

1029, 984 cm^–1.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.3.

¹H NMR (500 MHz, CDCl₃): d = 5.32 (d, J = 9.8 Hz, 1 H), 4.86 (dt,

J = 9.5, 1.3 Hz, 1 H), 3.75 (d, J = 7.6 Hz, 1 H), 3.63 (dd, J = 10.7,

3.8 Hz, 1 H), 3.59 (dd, J = 10.7, 5.9 Hz, 1 H), 3.49 (s, 3 H), 2.97 (dd,

J = 7.6, 3.8 Hz, 1 H), 2.68–2.62 (m, 1 H), 2.56–2.50 (m, 1 H), 1.80–

1.74 (m, 1 H), 1.63 (d, J = 1.3 Hz, 3 H), 1.59 (d, J = 0.9 Hz, 3 H),

1.54 (d, J = 1.3 Hz, 3 H), 0.96 (d, J = 6.6 Hz, 6 H), 0.89 (d, J = 6.9

Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 136.6, 130.6, 128.1, 127.6, 91.3,

82.1, 66.6, 61.5, 38.2, 36.4, 35.2, 25.7, 18.0, 17.8, 17.0, 15.0, 12.0.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.3.

(E)-(2S,3R,4S,7S,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (62)

Clear, colorless oil; [a]₅₈₉²⁰–27.8 (c 0.5, CHCl₃).

IR (thin film, NaCl): 3393, 2963, 2928, 2871, 1457, 1375, 1094,

1023, 935 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.16 (d, J = 9.8 Hz, 1 H), 4.86 (dt,

J = 9.8, 1.3 Hz, 1 H), 3.75–3.68 (m, 2 H), 3.52–3.48 (m, 1 H), 3.46

(s, 3 H), 2.92 (dd, J = 7.3, 4.7 Hz, 1 H), 2.79 (dd, J = 5.9, 5.0 Hz, 1

H), 2.67–2.61 (m, 1 H), 2.55–2.49 (m, 1 H), 1.80–1.74 (m, 1 H),

1.62 (d, J = 1.3 Hz, 3 H), 1.58 (d, J = 1.3 Hz, 3 H), 1.55 (d, J = 1.3

Hz, 3 H), 1.46 (d, J = 3.8 Hz, 1 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.94

(d, J = 6.6 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H).

(E)-(2R,3S,4S,7R,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (59)

¹³C NMR (126 MHz, CDCl₃): d = 135.9, 130.9, 129.8, 127.4, 91.9,

81.7, 65.6, 61.8, 37.3, 36.5, 35.9, 25.8, 17.9, 16.7, 16.3, 15.7, 12.4.

Clear, colorless oil; [a]₅₈₉²⁰+42.1 (c 0.6, CHCl₃).

IR (thin film, NaCl): 3429, 2966, 2927, 2871, 1452, 1376, 1096,

1029, 984 cm^–1.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.7.

¹H NMR (500 MHz, CDCl₃): d = 5.39 (d, J = 9.7 Hz, 1 H), 4.93 (d,

J = 9.7 Hz, 1 H), 3.64–3.52 (m, 3 H), 3.49 (s, 3 H), 2.97 (dd, J = 7.8,

3.8 Hz, 1 H), 2.74–2.68 (m, 1 H), 2.56–2.49 (m, 1 H), 2.10 (s, 1 H),

1.74 (s, 3 H), 1.74–1.70 (m, 1 H), 1.68 (s, 3 H), 1.63 (s, 3 H), 1.06

(d, J = 6.9 Hz, 3 H), 0.87 (d, J = 7.3 Hz, 3 H), 0.77 (d, J = 6.9 Hz, 3

H).

(E)-(2S,3R,4S,7R,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (63)

Clear, colorless oil; [a]₅₈₉²⁰+32.3 (c 1.0, CHCl₃).

IR (thin film, NaCl): 3382, 2962, 2928, 2871, 1460, 1388, 1094,

1024 cm^–1.

¹³C NMR (126 MHz, CDCl₃): d = 135.1, 135.1, 130.6, 127.4, 91.3,

¹H NMR (500 MHz, CDCl₃): d = 5.24 (d, J = 9.8 Hz, 1 H), 4.93 (d,

J = 9.8 Hz, 1 H), 3.75–3.69 (m, 1 H), 3.53–3.47 (m, 1 H), 3.46 (s, 3

H), 2.92 (dd, J = 6.6, 5.0 Hz, 1 H), 2.81 (t, J = 5.4 Hz, 1 H), 2.73–

2.67 (m, 1 H), 2.56–2.50 (m, 1 H), 1.79 (d, J = 1.6 Hz, 1 H), 1.79–

1.73 (m, 1 H), 1.74 (d, J = 0.9 Hz, 3 H), 1.67 (d, J = 0.9 Hz, 3 H),

1.63 (d, J = 1.3 Hz, 3 H), 1.03 (d, J = 7.3 Hz, 3 H), 1.02 (d, J = 6.9

Hz, 3 H), 0.73 (d, J = 6.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.3, 134.6, 132.5, 127.1, 91.9,

82.7, 61.7, 65.7, 37.3, 36.9, 36.0, 26.0, 18.4, 17.4, 16.1, 15.6, 11.0.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

82.9, 66.8, 61.4, 38.3, 36.7, 35.4, 26.0, 18.3, 18.0, 17.4, 14.9, 10.8.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.3.

(E)-(2R,3S,4S,7R,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (60)

Clear, colorless oil; [a]₅₈₉²⁰+53.9 (c 0.8, CHCl₃).

IR (thin film, NaCl): 3435, 2966, 2927, 2871, 1452, 1376, 1096,

1029, 984 cm^–1.

307.2.

¹H NMR (500 MHz, CDCl₃): d = 5.35 (d, J = 9.8 Hz, 1 H), 4.85 (dt,

J = 9.8, 1.3 Hz, 1 H), 3.72 (d, J = 8.5 Hz, 1 H), 3.61 (dd, J = 10.7,

4.1 Hz, 1 H), 3.58 (dd, J = 10.7, 5.9 Hz, 1 H), 3.49 (s, 3 H), 2.95 (dd,

J = 8.5, 3.2 Hz, 1 H), 2.65–2.59 (m, 1 H), 2.56–2.50 (m, 1 H), 1.74–

1.68 (m, 1 H), 1.62 (d, J = 0.9 Hz, 3 H), 1.59 (d, J = 1.3 Hz, 3 H),

1.54 (d, J = 1.3 Hz, 3 H), 1.03 (d, J = 6.9 Hz, 3 H), 0.98 (d, J = 6.6

Hz, 3 H), 0.80 (d, J = 6.9 Hz, 3 H).

(E)-(2S,3R,4S,7R,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (64)

Clear, colorless oil; [a]₅₈₉²⁰+2.6 (c 1.2, CHCl₃).

IR (thin film, NaCl): 3418, 2964, 2928, 2873, 1669, 1457, 1376,

1085, 1023, 803 cm^–1.

¹³C NMR (126 MHz, CDCl₃): d = 136.9, 130.5, 128.7, 127.5, 91.0,

¹H NMR (500 MHz, CDCl₃): d = 5.13 (d, J = 10.4 Hz, 1 H), 4.77

(dt, J = 9.8, 1.3 Hz, 1 H), 3.72 (dd, J = 11.0, 3.2 Hz, 1 H), 3.67 (d,

J = 8.5 Hz, 1 H), 3.46 (s, 3 H), 3.44 (dd, J = 11.0, 5.0 Hz, 1 H), 2.88

(dd, J = 7.6, 4.4 Hz, 1 H), 2.67–2.61 (m, 1 H), 2.56–2.50 (m, 1 H),

1.75–1.70 (m, 1 H), 1.59 (d, J = 1.3 Hz, 3 H), 1.58 (d, J = 1.3 Hz, 3

H), 1.54 (d, J = 1.3 Hz, 3 H), 1.53 (s, 1 H), 1.05 (d, J = 7.3 Hz, 3 H),

1.01 (d, J = 6.6 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 136.3, 130.8, 130.8, 127.3, 92.2,

82.7, 65.4, 61.9, 36.9, 36.5, 36.1, 25.9, 17.8, 17.4, 16.7, 15.8, 11.5.

LRMS (EI): m/z [M + H]⁺calcd for C₁₇H₃₃O₃: 285.2; found: 285.2.

82.9, 66.9, 61.4, 38.4, 36.4, 35.1, 25.8, 18.0, 17.8, 17.5, 14.6, 11.4.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.3.

(E)-(2R,3S,4S,7S,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (61)

Clear, colorless oil; [a]₅₈₉²⁰–7.9 (c 0.4, CHCl₃).

IR (thin film, NaCl): 3420, 2966, 2928, 2871, 1452, 1376, 1097,

1030, 984 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.39 (d, J = 9.5 Hz, 1 H), 4.95 (d,

J = 9.5 Hz, 1 H), 3.65 (dd, J = 10.4, 3.8 Hz, 1 H), 3.59 (dd, J = 10.7,

5.4 Hz, 1 H), 3.56 (d, J = 9.1 Hz, 1 H), 3.48 (s, 3 H), 2.98 (dd,

J = 7.6, 3.8 Hz, 1 H), 2.75–2.69 (m, 1 H), 2.54–2.49 (m, 1 H), 1.99

(s, 1 H), 1.84–1.79 (m, 1 H), 1.73 (s, 3 H), 1.67 (s, 3 H), 1.63 (s, 3

H), 1.01 (d, J = 6.9 Hz, 3 H), 0.89 (d, J = 7.6 Hz, 3 H), 0.77 (d,

J = 6.9 Hz, 3 H).

(E)-(2S,3R,4S,7S,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (65)

Clear, colorless oil; [a]₅₈₉²⁰–4.2 (c 0.6, CHCl₃).

IR (thin film, NaCl): 3388, 2966, 2928, 2872, 1457, 1375, 1091,

1027 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.23 (dd, J = 9.2, 1.3 Hz, 1 H),

4.94 (dt, J = 9.8, 1.3 Hz, 1 H), 3.73 (dt, J = 11.0, 3.5 Hz, 1 H), 3.55–

3.52 (m, 2 H), 3.49 (s, 3 H), 2.97 (dd, J = 6.6, 5.1 Hz, 1 H), 2.83 (t,

J = 5.7 Hz, 1 H), 2.74–2.69 (m, 1 H), 2.55–2.49 (m, 1 H), 1.86–1.80

¹³C NMR (126 MHz, CDCl₃): d = 135.2, 134.8, 129.9, 127.3, 91.1,

82.5, 66.6, 61.4, 37.9, 36.9, 35.3, 26.0, 18.3, 17.9, 17.5, 15.1, 11.1.

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

643

(m, 1 H), 1.78 (d, J = 1.6 Hz, 1 H), 1.76 (d, J = 1.3 Hz, 3 H), 1.73

(d, J = 1.3 Hz, 3 H), 1.66 (d, J = 1.3 Hz, 3 H), 1.04 (d, J = 7.3 Hz, 3

H), 0.99 (d, J = 6.6 Hz, 3 H), 0.78 (d, J = 6.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.1, 134.5, 131.7, 126.9, 91.7,

82.3, 65.8, 61.8, 37.2, 36.9, 35.9, 26.0, 18.3, 17.5, 16.2, 15.6, 11.3.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.2.

IR (thin film, NaCl): 3386, 2966, 2927, 2872, 1457, 1419, 1375,

1091, 1027 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.15 (dd, J = 9.7, 0.9 Hz, 1 H),

4.93 (dt, J = 9.8, 1.6 Hz, 1 H), 3.59–3.50 (m, 3 H), 3.45 (s, 3 H),

3.08 (dd, J = 8.8, 2.5 Hz, 1 H), 2.65–2.60 (m, 1 H), 2.55–2.50 (m,

1 H), 1.79–1.74 (m, 1 H), 1.72 (d, J = 1.3 Hz, 3 H), 1.66 (d, J = 1.3

Hz, 3 H), 1.63 (d, J = 1.3 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.81

(d, J = 6.9 Hz, 3 H), 0.74 (d, J = 6.9 Hz, 3 H).

(E)-(2S,3S,4R,7S,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (66)

¹³C NMR (126 MHz, CDCl₃): d = 135.1, 134.4, 132.1, 127.2, 86.6,

82.7, 66.4, 61.2, 38.4, 36.9, 36.0, 26.0, 18.3, 17.6, 17.3, 10.9, 10.3.

Clear, colorless oil; [a]₅₈₉²⁰–33.0 (c 1.0, CHCl₃).

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

IR (thin film, NaCl): 3396, 2966, 2928, 2872, 1457, 1375, 1091,

1027 cm^–1.

307.2.

(E)-(2S,3R,4S,7S,8S,9R)-3-Methoxy-2,4,6,8,10-pentamethylun-

dec-5-ene-1,7,9,10-tetraol (70)

¹H NMR (500 MHz, CDCl₃): d = 5.08 (d, J = 9.8 Hz, 1 H), 4.79 (dt,

J = 9.8, 1.3 Hz, 1 H), 3.67 (dd, J = 8.5, 3.5 Hz, 1 H), 3.59–3.53 (m,

2 H), 3.47 (s, 3 H), 3.07 (dd, J = 9.5, 2.2 Hz, 1 H), 2.59–2.50 (m, 1

H), 1.82–1.75 (m, 1 H), 1.61 (d, J = 1.3 Hz, 3 H), 1.59 (d, J = 1.3

Hz, 3 H), 1.56 (d, J = 1.3 Hz, 3 H), 1.43 (d, J = 3.5 Hz, 1 H), 1.03

(d, J = 6.6 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H), 0.76 (d, J = 6.9 Hz,

3 H).

¹³C NMR (126 MHz, CDCl₃): d = 136.0, 130.7, 130.6, 127.3, 86.7,

82.8, 66.4, 61.3, 38.2, 36.5, 36.0, 25.8, 17.9, 17.8, 17.5, 11.4, 10.1.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.2.

To a soln of diene 62 (406 mg, 1.43 mmol) in t-BuOH (7.1 mL) the

following were added sequentially: (DHQD)₂PHAL (55.7 mg,

0.072 mmol), methanesulfonamide (136.0 mg, 1.43 mmol), K₂CO₃

(593.0 mg, 4.29 mmol), and K₃Fe(CN)₆(1.41 g, 4.29 mmol). To the

resulting suspension H₂O (7.1 mL) was added followed by OsO₄

(205 mL, 2% soln in H₂O, 0.014 mmol). The resulting biphasic mix-

ture was stirred for 24 h at r.t. and quenched with solid Na₂SO₃and

stirred at r.t. for 1 h. The mixture was diluted with EtOAc (200 mL),

washed with 1 M KHSO₄(20 mL), sat. NaHCO₃(20 mL), and brine

(20 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. The

residue was passed through a plug of silica gel (30 mL) eluting with

EtOAc (40 mL) and 10% MeOH–EtOAc (60 mL) to yield tetraol 70

(314 mg, 69%); 2:1 mixture of diastereomers. The mixture was used

in subsequent reactions without further purification.

(E)-(2S,3S,4R,7R,8R)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (67)

Clear, colorless oil; [a]₅₈₉²⁰+12.8 (c 1.2, CHCl₃).

¹³C NMR (126 MHz, CDCl₃): d = 134.6, 127.9, 91.9, 81.2, 80.9,

72.9, 65.5, 61.8, 37.3, 36.0, 35.6, 30.8, 25.2, 16.5, 15.2, 14.1, 5.9.

IR (thin film, NaCl): 3386, 2963, 2926, 2873, 1457, 1375, 1262,

1091, 1027, 933 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.15 (d, J = 9.8 Hz, 1 H), 4.94 (dt,

J = 9.5, 1.3 Hz, 1 H), 3.58–3.55 (m, 2 H), 3.52 (d, J = 8.8 Hz, 1 H),

3.47 (s, 3 H), 3.11 (dd, J = 9.1, 2.5 Hz, 1 H), 2.67–2.62 (m, 1 H),

2.53–2.49 (m, 1 H), 1.90–1.85 (m, 1 H), 1.76 (s, 1 H), 1.73 (d,

J = 1.3 Hz, 3 H), 1.67 (d, J = 1.3 Hz, 3 H), 1.63 (d, J = 1.3 Hz, 3 H),

1.02 (d, J = 6.6 Hz, 3 H), 0.84 (d, J = 6.9 Hz, 3 H), 0.77 (d, J = 6.6

Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.0, 134.3, 131.6, 127.1, 86.6,

82.4, 66.5, 61.2, 38.3, 36.9, 35.9, 26.0, 18.3, 17.6, 17.5, 11.2, 10.6.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.7.

(3E,7E)-(5R,6S,9S,10R,11S)-6,12-Dihydroxy-10-methoxy-

5,7,9,11-tetramethyldodeca-3,7-dien-2-one (72)

To a soln of tetraol 70 (42.7 mg, 0.134 mmol) in EtOAc (540 mL) at

0 °C was added Pb(OAc)₄(62.4 mg, 0.141 mmol) in one portion.

The resulting mixture was allowed to stir for 5 min and was filtered

through a plug of silica gel (7 mL) eluting with EtOAc (3 × 10 mL).

The eluent was concentrated in vacuo to yield a clear colorless oil

(35 mg, 99%) and was used without purification in the subsequent

step. LiCl (6.8 mg, 0.161 mmol) was flame-dried in a 10-mL flask

equipped with a magnetic stir bar and was suspended in MeCN (140

mL) upon cooling. Dimethyl 2-oxopropylphosphonate (22 mL, 0.161

mmol) was added to the resulting suspension followed by DIPEA

(23 mL, 0.134 mmol) and the mixture was allowed to stir at r.t. for

30 min before cooling to –10 °C. The previously generated crude al-

dehyde in MeCN (1.3 mL) was added to the cooled reaction via sy-

ringe and the mixture was stirred at –10 °C for 16 h. The reaction

was quenched with 0.1 M HCl (1 mL), was extracted with Et₂O

(3 × 15 mL); the combined organic extracts were washed with sat.

NaHCO₃(10 mL) and brine (10 mL), dried (Na₂SO₄), and concen-

trated in vacuo. The residue was purified by chromatography [silica

gel, 30 mL, EtOAc (120 mL)] to give 72 (20.1 mg, 50%) as a clear,

colorless oil; [a]₅₈₉²⁰–7.5 (c 0.2, CHCl₃).

(E)-(2S,3S,4R,7R,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (68)

Clear, colorless oil; [a]₅₈₉²⁰+20.0 (c 0.8, CHCl₃).

IR (thin film, NaCl): 3395, 2967, 2927, 2871, 1457, 1374, 1090,

1027 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.09 (dt, J = 10.0, 0.9 Hz, 1 H),

4.86 (dt, J = 9.8, 1.3 Hz, 1 H), 3.72 (dd, J = 7.6, 3.5 Hz, 1 H), 3.60–

3.56 (m, 2 H), 3.47 (s, 3 H), 3.09 (dd, J = 9.1, 2.5 Hz, 1 H), 2.61–

2.50 (m, 2 H), 1.86–1.81 (m, 1 H), 1.64 (d, J = 1.3 Hz, 3 H), 1.59

(d, J = 1.6 Hz, 3 H), 1.56 (d, J = 1.3 Hz, 3 H), 1.45 (d, J = 3.8 Hz,

1 H), 0.98 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.6 Hz, 3 H), 0.83 (d,

J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 135.7, 130.9, 129.7, 127.5, 86.7,

81.9, 66.5, 61.2, 38.3, 36.5, 35.8, 25.7, 17.9, 17.6, 16.8, 12.2, 10.4.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₂NaO₃: 307.2; found:

307.2.

IR (thin film, NaCl): 3405, 2964, 2929, 2874, 2361, 2340, 1671,

1623, 1457, 1363, 1258, 1092, 1025, 982 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 6.67 (dd, J = 16.1, 7.9 Hz, 1 H),

6.05 (dd, J = 16.1, 0.9 Hz, 1 H), 5.28 (d, J = 9.8 Hz, 1 H), 3.89 (dd,

J = 6.9, 3.5 Hz, 1 H), 3.72 (ddd, J = 8.8, 5.0, 3.8 Hz, 1 H), 3.57–3.51

(m, 1 H), 3.49 (s, 3 H), 2.95 (dd, J = 6.6, 4.7 Hz, 1 H), 2.75 (t,

J = 5.0 Hz, 1 H), 2.72–2.65 (m, 1 H), 2.58–2.52 (m, 1 H), 2.22 (s, 3

H), 1.81–1.76 (m, 1 H), 1.61 (d, J = 1.3 Hz, 3 H), 1.56 (s, 1 H), 1.10

(d, J = 6.9 Hz, 3 H), 1.05 (d, J = 6.9 Hz, 3 H), 0.97 (d, J = 6.9 Hz, 3

H).

(E)-(2S,3S,4R,7S,8S)-3-Methoxy-2,4,6,8,10-pentamethylunde-

ca-5,9-diene-1,7-diol (69)

Clear, colorless oil; [a]₅₈₉²⁰–2.4 (c 0.5, CHCl₃).

644

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

¹³C NMR (126 MHz, CDCl₃): d = 198.5, 149.8, 135.1, 130.8, 130.5,

91.4, 80.1, 65.5, 61.8, 40.5, 37.3, 35.8, 26.8, 16.4, 15.6, 14.9, 12.2.

¹³C NMR (126 MHz, CDCl₃): d = 171.5, 129.5, 128.9, 91.9, 84.3,

65.4, 62.1, 37.2, 36.4, 28.4, 26.7, 26.1, 16.7, 15.8, 13.9, 12.4.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₀NaO₄: 321.2; found:

LRMS (EI): m/z [M + Na]⁺calcd for C₁₆H₂₈NaO₄: 307.2; found:

321.3.

307.2.

Methyl (2E,6E)-(4R,5S,8S,9R,10S)-5,11-Dihydroxy-9-methoxy-

4,6,8,10-tetramethylundeca-2,6-dienoate (74)

(E)-(2S,3R,4S)-3-Methoxy-6-[(2S,3R,6S)-6-methoxy-3,6-di-

methyl-tetrahydro-2H-pyran-2-yl)-2,4-dimethylhept-5-en-1-ol

(76)

To a soln of tetraol 70 (33.4 mg, 0.105 mmol) in EtOAc (420 mL) at

0 °C was added Pb(OAc)₄(48.8 mg, 0.110 mmol) in one portion.

The resulting mixture was allowed to stir for 5 min and was filtered

through a plug of silica gel (7 mL) eluting with EtOAc (3 × 10 mL).

The eluent was concentrated in vacuo to yield a clear colorless oil

(26 mg, 98%) and was used without purification in the subsequent

step. LiCl (5.3 mg, 0.126 mmol) was flame dried in a 10-mL flask

equipped with a magnetic stir bar and was suspended in MeCN (105

mL) upon cooling. Trimethyl phosphonoacetate (17 mL, 0.126

mmol) was added to the resulting suspension followed by DIPEA

(18 mL, 0.105 mmol) and the mixture was allowed to stir at r.t. for

30 min before cooling to 0 °C. The previously generated crude al-

dehyde in MeCN (1.1 mL) was added to the cooled reaction via sy-

ringe and the mixture was stirred at 0 °C for 20 h. The reaction was

quenched with 0.1 M HCl (1 mL), was extracted with Et₂O (3 × 15

mL); the combined organic extracts were washed with sat. NaHCO₃

(10 mL) and brine (10 mL), dried (Na₂SO₄), and concentrated in

vacuo. The residue was purified by chromatography [silica gel, 20

mL, 50% EtOAc–hexanes (50 mL), 80% EtOAc–hexanes (50 mL),

and EtOAc (50 mL)] to give 74 (19.1 mg, 58%) as a clear, colorless

oil; [a]₅₈₉²⁰–31.9 (c 0.2, CHCl₃).

In a glove box, [CuH(PPh₃)]₆(64.9 mg, 0.033 mmol) was added to

72 (26.7 mg, 0.090 mmol) in a 10-mL flask equipped with a mag-

netic stir bar. The resulting solids were dissolved in benzene (2.2

mL, containing 0.02% H₂O by volume, degassed using three itera-

tions of the freeze–pump–thaw method) and the rust colored soln

was stirred at r.t. for 16 h. The reaction vessel was opened to air to

quench and was allowed to stir exposed to the ambient atmosphere

for 2 h. The resulting brown turbid mixture was passed through a

short plug of silica gel (5 mL) eluting with EtOAc (20 mL) and the

eluent was concentrated in vacuo. The crude residue was resuspend-

ed in MeOH (900 mL) and was treated with 0.25 M PPTS in CH₂Cl₂

(36 mL, 0.009 mmol). The resulting mixture was stirred at r.t. for 24

h and was quenched with sat. NaHCO₃(1 mL). The mixture was ex-

tracted with EtOAc (2 × 30 mL) and the combined organic extracts

were dried (Na₂SO₄) and concentrated in vacuo. Purification of the

residue using chromatography (silica gel, 20 mL, 50% EtOAc–hex-

anes) gave 76 [10.4 mg, 37% (2 steps)] as a clear, colorless oil;

[a]₅₈₉²⁰–3.8 (c 1.0, CHCl₃).

IR (thin film, NaCl): 3420, 2963, 2933, 2875, 1717, 1457, 1378,

1226, 1118, 1088, 1054, 864 cm^–1.

IR (thin film, NaCl): 3426, 2968, 2935, 2879, 1720, 1453, 1385,

1275, 1113, 1027, 714 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.34 (dt, J = 9.8, 1.3 Hz, 1 H), 3.96

(app s, 1 H), 3.76 (ddd, J = 7.9, 4.4, 3.5 Hz, 1 H), 3.54–3.49 (m, 1

H), 3.50 (s, 3 H), 3.14 (s, 3 H), 2.96 (dd, J = 7.3, 4.7 Hz, 1 H), 2.92

(dd, J = 6.3, 4.7 Hz, 1 H), 2.72–2.66 (m, 1 H), 2.09–2.01 (m, 1 H),

1.89–1.78 (m, 2 H), 1.67–1.59 (m, 1 H), 1.54 (s, 3 H), 1.54–1.50 (m,

1 H), 1.44–1.39 (m, 1 H), 1.30 (s, 3 H), 1.07 (d, J = 6.9 Hz, 3 H),

1.03 (d, J = 6.9 Hz, 3 H), 0.70 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 132.8, 126.1, 98.2, 92.4, 73.8,

65.7, 61.8, 47.8, 37.2, 35.9, 29.9, 28.4, 26.3, 23.9, 16.6, 15.6, 14.0,

11.2.

¹H NMR (500 MHz, CDCl₃): d = 6.85 (dd, J = 15.9, 8.1 Hz, 1 H),

5.80 (dd, J = 15.9, 1.3 Hz, 1 H), 5.27 (d, J = 10.4 Hz, 1 H), 3.88 (dd,

J = 7.1, 3.5 Hz, 1 H), 3.76–3.71 (m, 1 H), 3.71 (s, 3 H), 3.57–3.50

(m, 1 H), 3.48 (s, 3 H), 2.95 (dd, J = 7.1, 4.8 Hz, 1 H), 2.80 (t,

J = 5.6 Hz, 1 H), 2.72–2.64 (m, 1 H), 2.57–2.50 (m, 1 H), 1.82–1.74

(m, 1 H), 1.60 (d, J = 1.3 Hz, 3 H), 1.58 (s, 1 H), 1.09 (d, J = 6.8 Hz,

3 H), 1.05 (d, J = 7.1 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 166.9, 151.1, 135.0, 130.7, 120.5,

91.6, 80.3, 65.6, 61.8, 51.5, 40.4, 37.3, 35.9, 16.3, 15.7, 14.8, 12.4.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₇H₃₀NaO₅: 337.2; found:

LRMS (EI): m/z [M + Na]⁺calcd for C₁₈H₃₄NaO₄: 337.2; found:

338.2.

337.3.

(5R,6S)-6-[(E)-(3S,4R,5S)-6-Hydroxy-4-methoxy-1,3,5-trimeth-

ylhex-1-enyl)-5-methyl-5,6-dihydro-2H-pyran-2-one (77)

(5R,6S)-6-[(E)-(3S,4R,5S)-6-Hydroxy-4-methoxy-1,3,5-trimeth-

ylhex-1-enyl)-5-methyl-tetrahydro-2H-pyran-2-one (75)

To a soln of 74 (167.1 mg, 0.531 mmol) in MeOH (4.4 mL) at r.t.

was added Mg turnings (129 mg, 5.3 mmol) and the mixture was

stirred vigorously for 1.5 h at which time it had become white and

cloudy with little remaining Mg solids. The mixture was diluted

with EtOAc (50 mL) and passed through a plug of silica gel (40 mL)

eluting with EtOAc (50 mL) and the eluent was concentrated in vac-

uo. The residue was resuspended in CH₂Cl₂(5.3 mL) at r.t. and CSA

(6.2 mg, 0.026 mmol) was added. The mixture was stirred at r.t. for

39 h and was loaded directly onto a chromatography column [silica

gel, 70 mL, 50% EtOAc–hexanes (70 mL), 80% EtOAc–hexanes

(70 mL), and EtOAc (100 mL)] to give 75 (86.1 mg, 57%) as a clear,

colorless oil; [a]₅₈₉²⁰–10.0 (c 0.5, CHCl₃).

To a soln of 70 (19.6 mg, 0.062 mmol) in EtOAc (250 mL) at 0 °C

was added Pb(OAc)₄(28.6 mg, 0.065 mmol) in one portion. The

mixture was stirred at 0 °C for 5 min and was filtered through a plug

of silica gel (5 mL) eluting with EtOAc (30 mL). The eluent was

concentrated in vacuo and was used in the subsequent reaction with-

out purification. Bis(2,2,2-trifluoroethyl) (methoxycarbonylmeth-

yl)phosphonate (52 mL, 0.246 mmol) was added to a soln of 18-

crown-6 (316.9 mg, 0.984 mmol, freshly recrystallized from

MeCN, 2:1 MeCN/18-crown-6 complex) in THF (1.2 mL) and the

mixture was cooled to –78 °C and treated with 0.6 M KN(TMS)₂in

toluene (330 mL, 0.197 mmol). The mixture was stirred for 20 min

at –78 °C before the addition of the freshly prepared aldehyde (620

mL, 0.1 M in THF). The reaction was stirred at –78 °C for 4 h and

was quenched with sat. NH₄Cl (2 mL), extracted with Et₂O (3 × 15

mL) and the combined organic extracts were dried (MgSO₄) and

concentrated in vacuo. The residue was passed through a plug of sil-

ica gel (10 mL) eluting with 80% EtOAc–hexanes to give the a,b-

unsaturated ester as a mixture. The mixture of a,b-unsaturated es-

ters (13.4 mg, 0.043 mmol) was dissolved in CH₂Cl₂(420 mL), treat-

ed with CSA (0.5 mg, 0.002 mmol) and allowed to stir at r.t. for 19

h. The reaction was loaded directly onto a column (silica gel, 20

mL, 80% EtOAc–hexanes) to give 77 as a clear colorless oil [7.4

IR (thin film, NaCl): 3421, 2966, 2933, 2875, 2831, 1692, 1461,

1242, 1093, 1017 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.47 (d, J = 10.1 Hz, 1 H), 4.66

(app s, 1 H), 3.76 (ddd, J = 11.0, 4.4, 4.4 Hz, 1 H), 3.54–3.49 (m, 1

H), 3.50 (s, 3 H), 2.98 (dd, J = 7.3, 4.4 Hz, 1 H), 2.79 (dd, J = 6.9,

4.4 Hz, 1 H), 2.78–2.70 (m, 1 H), 2.57 (dd, J = 8.2, 6.6 Hz, 1 H),

2.28–2.20 (m, 1 H), 2.14–2.05 (m, 1 H), 1.80–1.67 (m, 2 H), 1.62

(s, 3 H), 1.08 (d, J = 7.3 Hz, 3 H), 1.05 (d, J = 6.6 Hz, 3 H), 0.81 (d,

J = 7.3 Hz, 3 H).

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

645

mg, 43% (3 steps)]. The isolated product was contaminated with a

small amount of an inseparable impurity and was fully character-

ized following conversion into the corresponding TBDPS ether.

¹H NMR (500 MHz, CDCl₃): d = 7.00 (dd, J = 9.8, 6.3 Hz, 1 H),

6.00 (d, J = 9.5 Hz, 1 H), 5.61 (ddd, J = 10.1, 1.3, 1.3 Hz, 1 H), 4.78

(app s, 1 H), 3.76 (ddd, J = 10.7, 4.1, 4.1 Hz, 1 H), 3.54–3.45 (m, 1

H), 3.50 (s, 3 H), 2.99 (dd, J = 7.3, 4.4 Hz, 1 H), 2.82 (dd, J = 6.6,

4.1 Hz, 1 H), 2.80–2.72 (m, 1 H), 2.60–2.54 (m, 1 H), 1.80–1.74 (m,

1 H), 1.64 (s, 3 H), 1.08 (d, J = 6.9 Hz, 3 H), 1.06 (d, J = 6.9 Hz, 3

H), 0.87 (d, J = 7.3 Hz, 3 H).

0.96 (d, J = 6.9 Hz, 3 H), 0.93 (d, J = 6.6 Hz, 3 H), 0.89 (d, J = 6.9

Hz, 3 H), 0.89 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 171.8, 88.6, 87.5, 67.0, 61.4, 38.5,

38.1, 33.4, 32.8, 26.9, 26.7, 26.2, 15.7, 15.2, 15.1, 11.5.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₆H₃₀NaO₄: 309.2; found:

309.2.

(E,E)-(8R,9S,12S,13R,14S)-9,15-Dihydroxy-13-methoxy-

8,10,12,14-tetramethyl-1-(triethylsiloxy)pentadeca-6,10-diene-

5-one and (E)-(2S,3R,4S)-3-Methoxy-6-[(2S,3R)-3-methyl-1,7-

dioxaspiro[5.5]undec-2-yl]-2,4,6-trimethylhex-5-en-1-ol (79)

To a soln of 70 (25.5 mg, 0.08 mmol) in EtOAc (320 mL) at 0 °C

was added Pb(OAc)₄(37.3 mg, 0.084 mmol) in one portion. The

mixture was stirred at 0 °C for 5 min and was filtered through a plug

of silica gel (5 mL) eluting with EtOAc (30 mL). The eluent was

concentrated in vacuo and was used in the subsequent reaction with-

out purification. LiCl (4.1 mg, 0.096 mmol) was flame dried in a 10-

mL flask equipped with a magnetic stir bar and was suspended in

MeCN (100 mL) upon cooling. Dimethyl 6-(triethylsiloxy)-2-oxo-

hexylphosphonate (32.5 mg, 0.096 mmol) was added to the result-

ing suspension followed by DIPEA (14 mL, 0.08 mmol) and the

mixture was allowed to stir at r.t. for 30 min and then cooled to –20

°C. The previously generated crude aldehyde in MeCN (800 mL)

was added to the cooled reaction via syringe and the mixture was

stirred at –20 °C for 15.5 h. The reaction was quenched with sat.

NaHCO₃(1 mL) and extracted with EtOAc (4 × 15 mL). The com-

bined organic extracts were dried (Na₂SO₄) and concentrated in

vacuo. The residue was purified by chromatography [silica gel, 30

mL, 80% EtOAc–hexanes (120 mL)] to give the a,b-unsaturated ke-

tone (19.4 mg, 51%) as a clear, colorless oil.

¹³C NMR (126 MHz, CDCl₃): d = 164.3, 151.4, 129.7, 128.5, 119.9,

91.9, 81.8, 65.3, 61.9, 37.3, 36.3, 31.5, 16.6, 15.7, 13.6, 11.8.

(5R,6S)-6-[(E)-(3S,4R,5S)-6-(tert-Butyldiphenylsiloxy)-4-meth-

oxy-1,3,5-trimethylhex-1-enyl]-5-methyl-5,6-dihydro-2H-pyr-

an-2-one

To a soln of 77 (4.4 mg, 0.016 mmol) in CH₂Cl₂(150 mL) the fol-

lowing were added sequentially: 0.5 M Et₃N in CH₂Cl₂(40 mL,

0.019 mmol), 0.5 M TBDPSCl in CH₂Cl₂(34 mL, 0.017 mmol), and

0.002 M DMAP in CH₂Cl₂(60 mL, 0.002 mmol). The reaction ves-

sel was sealed under argon and was stirred at r.t. for 36 h. The crude

residue was loaded onto a plug of silica gel (10 mL) and eluted with

20% EtOAc–hexanes (20 mL) and 30% EtOAc–hexanes (20 mL) to

give the TBDPS ether of 77 (8.0 mg, 99%) as a clear, colorless oil.

Further purification by HPLC (UV detection (254 nm), 15% to 30%

EtOAc–hexanes over 25 min) provided an analytical sample.

[a]₅₈₉²⁰–31.5 (c 0.4, CHCl₃).

IR (thin film, NaCl): 2962, 2930, 2857, 2361, 2337, 1733, 1489,

1387, 1247, 1106, 823, 702 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 7.66–7.64 (m, 4 H), 7.42–7.33 (m,

6 H), 6.98 (dd, J = 9.4, 6.3 Hz, 1 H), 5.99 (d, J = 9.4 Hz, 1 H), 5.64

(d, J = 9.4 Hz, 1 H), 4.73 (app s, 1 H), 3.68–3.62 (m, 2 H), 3.36 (s,

3 H), 3.00 (dd, J = 6.0, 6.0 Hz, 1 H), 2.63–2.58 (m, 1 H), 2.53–2.47

(m, 1 H), 1.88–1.82 (m, 1 H), 1.52 (s, 3 H), 1.05 (m, 12 H), 0.96 (d,

J = 6.9 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 164.4, 151.5, 135.7, 133.9, 133.9,

130.7, 129.5, 127.9, 127.5, 119.9, 87.4, 82.0, 65.1, 61.2, 39.0, 34.9,

31.8, 26.9, 19.3, 15.6, 15.1, 13.4, 11.9.

[a]₅₈₉²⁰+8.0 (c 1.9, CHCl₃).

IR (thin film, NaCl): 3421, 2958, 2876, 2361, 2340, 1684, 1457,

1096, 1017, 744 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 6.68 (dd, J = 16.1, 8.2 Hz, 1 H),

6.06 (d, J = 16.1 Hz, 1 H), 5.26 (d, J = 9.8 Hz, 1 H), 3.87 (dd,

J = 6.9, 2.8 Hz, 1 H), 3.71 (ddd, J = 10.7, 4.1, 4.1 Hz, 1 H), 3.60 (dd,

J = 6.3, 6.3 Hz, 2 H), 3.56–3.50 (m, 1 H), 3.48 (s, 3 H), 2.94 (dd,

J = 6.9, 5.0 Hz, 1 H), 2.80 (t, J = 5.4 Hz, 1 H), 2.69–2.64 (m, 1 H),

2.56–2.50 (m, 3 H), 1.82–1.74 (m, 2 H), 1.68–1.60 (m, 2 H), 1.60

(s, 3 H), 1.59–1.50 (m, 2 H), 1.08 (d, J = 6.6 Hz, 3 H), 1.05 (d,

J = 6.9 Hz, 3 H), 0.94 (app t, J = 7.9 Hz, 12 H), 0.58 (q, J = 7.9 Hz,

6 H).

¹³C NMR (126 MHz, CDCl₃): d = 200.4, 148.6, 135.1, 130.7, 129.5,

91.4, 80.4, 65.4, 62.5, 61.7, 40.5, 39.8, 37.3, 35.8, 32.3, 20.6, 16.4,

15.6, 14.9, 12.2, 6.8, 4.4.

LRMS (EI): m/z [M + Na]⁺calcd for C₂₆H₅₀NaO₅Si: 493.3; found:

493.3.

LRMS (EI): m/z [M + Na]⁺calcd for C₃₂H₄₄NaO₄Si: 543.3; found:

543.5.

(5R,6S)-6-[(1S,3S,4R,5S)-6-Hydroxy-4-methoxy-1,3,5-trimeth-

ylhexyl]-5-methyl-tetrahydro-2H-pyran-2-one (78)

The a,b-unsaturated ester 74 (24.2 mg, 0.077 mmol) was dissolved

in degassed CH₂Cl₂(3.8 mL, degassed by bubbling through with

dry argon gas for 10 min), and was transferred to a glass sleeve for

the Parr hydrogenation apparatus containing Rh[(nbd)(dppb)]BF₄

(16.3 mg, 0.023 mmol). The mixture was placed under an atmo-

sphere of H₂(52 bar) and was allowed to react at r.t. for 6 h. The

crude mixture was filtered through a plug of silica gel eluting with

EtOAc and was concentrated to provide 78 (13.4 mg, 62%) as a

clear colorless oil; 19:1 mixture of isomers. An analytical sample

(dr >20:1) was obtained by HPLC purification (RI detector, 80%

EtOAc–hexanes, 8 mL/min).

[CuH(PPh₃)]₆(17.3 mg, 0.009 mmol) was added to the a,b-unsatur-

ated ketone (11.2 mg, 0.024 mmol) in a glove box. The resulting

solids were dissolved in benzene (600 mL, containing 0.02% H₂O by

volume, degassed using 3 iterations of the freeze–pump–thaw meth-

od) and the rust colored soln was stirred at r.t. for 11.5 h. The reac-

tion vessel was opened to air to quench and was allowed to stir

exposed to the ambient atmosphere for 1 h. The resulting brown tur-

bid mixture was passed through a short plug of silica gel (1 mL)

eluting with 10% EtOAc–hexanes (2 mL), 50% EtOAc–hexanes (2

mL), EtOAc (2 mL), and 10% MeOH–EtOAc (2 mL). The 50%

EtOAc–hexanes and EtOAc fractions were concentrated in vacuo.

The residue was dissolved in MeOH–CH₂Cl₂(1:1, 240 mL) at r.t.

and 0.25 M CSA in CH₂Cl₂(19 mL, 0.005 mmol) was added. The

mixture was stirred at r.t. for 1 h, was diluted with CH₂Cl₂(480 mL),

and allowed to stir for 20 h. The mixture was diluted with CH₂Cl₂

(10 mL), was quenched with sat. NaHCO₃(5 mL) and extracted

with CH₂Cl₂(3 × 10 mL). The combined organic extracts were

[a]₅₈₉²⁰+7.0 (c 0.7, CHCl₃).

IR (thin film, NaCl): 3447, 2965, 2932, 2878, 1734, 1457, 1381,

1248, 1098, 983 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 3.88 (dd, J = 10.1, 2.5 Hz, 1 H),

3.68 (ddd, J = 11.0, 6.9, 3.5 Hz, 1 H), 3.58 (ddd, J = 11.0, 8.2, 4.1

Hz, 1 H), 3.54 (s, 3 H), 3.01 (dd, J = 8.5, 2.8 Hz, 1 H), 2.91 (dd,

J = 7.9, 3.2 Hz, 1 H), 2.52 (dd, J = 8.5, 6.6 Hz, 1 H), 2.22–2.15 (m,

1 H), 2.11–2.01 (m, 2 H), 1.91–1.76 (m, 3 H), 1.71–1.59 (m, 2 H),

646

L. J. Perez, G. C. Micalizio

FEATURE ARTICLE

dried (Na₂SO₄) and concentrated in vacuo. Purification was

achieved by chromatography [silica gel, 10 mL, 10% EtOAc–hex-

anes (15 mL), 30% EtOAc–hexanes (30 mL), and 50% EtOAc–hex-

anes (30 mL)] to give 79 (4.5 mg, 56%) as a clear, colorless oil.

[a]₅₈₉²⁰–10.9 (c 0.4, CHCl₃).

IR (thin film, NaCl): 3447, 2935, 2870, 1473, 1086, 1004, 877 cm^–1.

¹H NMR (500 MHz, CDCl₃): d = 5.39 (dd, J = 10.1, 1.3 Hz, 1 H),

4.05 (app s, 1 H), 3.77 (dd, J = 11.0, 3.5 Hz, 1 H), 3.56–3.50 (m, 3

H), 3.50 (s, 3 H), 2.97 (dd, J = 6.9, 5.0 Hz, 1 H), 2.74–2.68 (m, 1 H),

2.12–2.04 (m, 1 H), 1.94–1.85 (m, 2 H), 1.85–1.78 (m, 1 H), 1.69–

1.64 (m, 1 H), 1.60–1.38 (m, 7 H), 1.55 (d, J = 1.0 Hz, 3 H), 1.07

(d, J = 6.9 Hz, 3 H), 1.03 (d, J = 6.6 Hz, 3 H), 0.70 (d, J = 6.9 Hz, 3

H).

¹³C NMR (126 MHz, CDCl₃): d = 133.0, 126.1, 95.8, 92.5, 72.7,

65.8, 61.8, 60.6, 37.2, 35.9, 35.8, 29.9, 28.8, 26.1, 25.4, 18.8, 16.6,

15.6, 13.9, 11.2.

action was complete by TLC and the mixture was concentrated in

vacuo to yield a thick white slurry (ca. 100 mL). This slurry was di-

luted with Et₂O (30 mL), quenched with sat. NaHCO₃–10%

Na₂S₂O₃(1:1, 20 mL), and extracted with Et₂O (20 mL). The Et₂O

extract was washed with brine (10 mL) and dried (Na₂SO₄). The

crude aldehyde (13.6 mg, quant.) was used without purification in

the subsequent reaction after azeotropic removal of H₂O by concen-

tration from benzene. The crude residue was resuspended in CH₂Cl₂

(250 mL) and was treated with [1-(ethoxycarbonyl)ethylidene]tri-

phenylphosphorane (21.4 mg, 0.064 mmol). The resulting mixture

was sealed under N₂and allowed to stir at r.t. for 24 h. The resulting

mixture was diluted with 10% EtOAc–hexanes and loaded directly

onto a column and chromatographed [silica gel, 25 mL, 30%

EtOAc–hexanes (70 mL) and 50% EtOAc–hexanes (70 mL)] to

give 82 (12.1 mg, 68%) as a clear, colorless oil.

[a]₅₈₉²⁰–13.6 (c 0.1, CHCl₃).

IR (thin film, NaCl): 2966, 2932, 2834, 1734, 1707, 1457, 1367,

1301, 1237, 1094, 1074 cm^–1.

LRMS (EI): m/z [M + Na]⁺calcd for C₂₀H₃₆NaO₄: 363.3; found:

¹H NMR (500 MHz, CDCl₃): d = 6.82 (dd, J = 9.8, 1.6 Hz, 1 H),

5.40 (dt, J = 10.1, 1.6 Hz, 1 H), 4.65 (app s, 1 H), 4.18 (dddd,

J = 9.8, 4.4, 2.8, 2.5 Hz, 2 H), 3.47 (s, 3 H), 2.88 (dd, J = 7.9, 3.5

Hz, 1 H), 2.69–2.64 (m, 1 H), 2.60–2.49 (m, 3 H), 2.25–2.19 (m, 1

H), 2.12–2.04 (m, 1 H), 1.78 (d, J = 1.6 Hz, 3 H), 1.76–1.70 (m, 1

H), 1.54 (d, J = 1.3 Hz, 3 H), 1.29 (t, J = 7.3 Hz, 3 H), 1.06 (d,

J = 6.9 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.87 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 171.5, 168.3, 143.5, 129.9, 129.5,

127.6, 89.6, 84.7, 61.6, 60.4, 36.8, 36.7, 28.7, 26.7, 26.1, 17.4, 16.8,

14.3, 13.8, 12.7, 12.6.

360.3.

Methyl (2E,7E)-(4S,5S,6S)-5-Methoxy-4,6-dimethyl-8-[(2S,3R)-

3-methyl-6-oxo-tetrahydro-2H-pyran-2-yl]nona-2,7-dienoate

(81)

To a soln of 75 (20.2 mg, 0.071 mmol) in CH₂Cl₂(470 mL) at 0 °C

was added Dess–Martin periodinane (60.2 mg, 0.142 mmol). To the

resulting vigorously stirred mixture was added CH₂Cl₂(890 mL, sat-

urated with H₂O) via syringe pump over 1 h. At this time the reac-

tion was complete by TLC and the mixture was concentrated in

vacuo to yield a thick white slurry (ca. 100 mL). This slurry was di-

luted with Et₂O (30 mL), quenched with sat. NaHCO₃–10%

Na₂S₂O₃(1:1, 20 mL), and extracted with Et₂O (20 mL). The Et₂O

was washed with brine (10 mL), and dried (Na₂SO₄). The crude al-

dehyde (20.0 mg, quant.) was used without purification in the sub-

sequent reaction after azeotropic removal of H₂O by concentration

from benzene. The crude residue was resuspended in CH₂Cl₂(180

mL) and was treated with methyl (triphenylphosphoranylidene)ace-

tate (30.8 mg, 0.092 mmol). The resulting mixture was sealed under

N₂and allowed to stir at r.t. for 24 h. The resulting mixture was di-

luted with 10% EtOAc–hexanes and loaded directly onto a column

and chromatographed [silica gel, 25 mL, 30% EtOAc–hexanes (70

mL) and 50% EtOAc–hexanes (70 mL)] to give 81 (14.9 mg, 62%)

as a clear, colorless oil.

LRMS (EI): m/z [M + Na]⁺calcd for C₂₁H₃₄NaO₅: 389.2; found:

389.3.

(5R,6S)-6-[(1E,8Z)-(3S,4S,5S)-4-Methoxy-1,3,5-trimethylnona-

1,6,8-trienyl]-5-methyl-tetrahydro-2H-pyran-2-one (83)

To a soln of 75 (20.3 mg, 0.071 mmol) in CH₂Cl₂(475 mL) at 0 °C

was added Dess–Martin periodinane (60.6 mg, 0.143 mmol). To the

resulting vigorously stirring mixture was added CH₂Cl₂(890 mL,

saturated with H₂O) via syringe pump over 1 h. At this time the re-

action was complete by TLC and the mixture was concentrated in

vacuo to yield a thick white slurry (ca. 100 mL). This slurry was di-

luted with Et₂O (30 mL), quenched with sat NaHCO₃–10% Na₂S₂O₃

(1:1, 20 mL) and extracted with Et₂O (20 mL). The Et₂O extract was

washed with brine (10 mL) and dried (Na₂SO₄). The crude aldehyde

(20.2 mg, quant.) was used without purification in the subsequent

reaction after azeotropic removal of H₂O by concentration from

benzene. Molecular sieves (4 Å powdered, 8.6 mg) were flame

dried in a 10-mL flask equipped with a stir bar and upon cooling 0.6

[a]₅₈₉²⁰–36.9 (c 0.6, CHCl₃).

IR (thin film, NaCl): 2966, 2933, 2875, 2831, 1725, 1738, 1461,

1241, 1093, 1074, 933.

¹H NMR (500 MHz, CDCl₃): d = 7.00 (dd, J = 15.8, 8.5 Hz, 1 H),

5.73 (d, J = 16.1 Hz, 1 H), 5.42 (d, J = 10.1 Hz, 1 H), 4.66 (app s, 1

H), 3.71 (s, 3 H), 3.48 (s, 3 H), 2.89 (dd, J = 8.8, 3.2 Hz, 1 H), 2.58

(dd, J = 8.2, 6.3 Hz, 2 H), 2.57–2.45 (m, 2 H), 2.31–2.24 (m, 1 H),

2.14–2.06 (m, 1 H), 1.76–1.69 (m, 1 H), 1.58 (s, 3 H), 1.13 (d,

J = 6.9 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.85 (d, J = 6.9 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 171.5, 166.9, 150.8, 129.8, 128.5,

121.2, 89.9, 84.3, 61.9, 51.4, 40.1, 36.9, 28.3, 26.6, 26.1, 17.6, 17.1,

13.9, 12.4.

M

4,4,5,5-tetramethyl-2-[(E)-3-(trimethylsilyl)allyl]-1,3,2-dioxa-

borolane in toluene (140 mL) was added. The freshly prepared alde-

hyde was added as a soln in toluene (720 mL, with a 300 mL wash)

and the reaction was heated to 60 °C for 21 h, was quenched with

1.5 M NaOH (2 mL), stirred vigorously for 20 min, and extracted

with Et₂O (3 × 15 mL). The combined organic extracts were dried

(Na₂SO₄) and concentrated in vacuo. Purification was achieved by

chromatography [silica gel, 20 mL, 30% EtOAc–hexanes (40 mL),

50% EtOAc–hexanes (40 mL), and 80% EtOAc–hexanes (40 mL)]

to give the TMS allylated product as a mixture of diastereomers

(16.7 mg, 59%). To a soln of KH (1.6 mg, 0.040 mmol, weighed out

neat in a glove box) in THF (400 mL) at –78 °C was added the fresh-

ly prepared TMS allylated product prepared above (16 mg, 0.040

mmol) as a soln in THF (400 mL, with a 400 mL wash). The mixture

was stirred with warming to 0 °C over 2 h, was stirred at 0 °C for 30

min and was quenched with anhyd MeOH (1 mL) and diluted with

H₂O (2 mL) and Et₂O (10 mL). The Et₂O layer was separated and

discarded and the aqueous layer was acidified with 1 M HCl (10

mL) and extracted with Et₂O (2 × 20 mL). The combined organic

LRMS (EI): m/z [M + Na]⁺calcd for C₁₉H₃₀NaO₅: 361.2; found:

361.3.

Ethyl (2E,7E)-(4S,5R,6S)-5-Methoxy-2,4,6-trimethyl-8-

[(2S,3R)-3-methyl-6-oxo-tetrahydro-2H-pyran-2-yl)nona-2,7-

dienoate (82)

To a soln of 75 (14 mg, 0.049 mmol) in CH₂Cl₂(330 mL) at 0 °C

was added Dess–Martin periodinane (41.6 mg, 0.098 mmol). To the

resulting vigorously stirring mixture was added CH₂Cl₂(610 mL,

saturated with H₂O) via syringe pump over 1 h. At this time the re-

FEATURE ARTICLE

Synthesis of Complex and Diverse Polyketides

647

extracts were washed with brine (10 mL), dried (MgSO₄), and con-

centrated in vacuo. The resulting residue was resuspended in

CH₂Cl₂(2.0 mL), treated with 0.1 M CSA in CH₂Cl₂(80 mL, 0.008

mmol), sealed under N₂and stirred for 18 h at r.t.. The mixture was

loaded directly onto column and chromatographed (silica gel, 30

mL, 50% EtOAc–hexanes) to give 83 (9.7 mg, 78%) as a clear, col-

orless oil; 19:1 mixture of isomers.

¹³C NMR (126 MHz, CDCl₃): d = 171.5, 142.6, 129.7, 129.4, 114.4,

91.9, 84.4, 74.0, 62.4, 41.8, 36.1, 35.7, 28.4, 26.7, 26.0, 16.8, 16.5,

14.1, 12.5, 11.3.

LRMS (EI): m/z [M + Na]⁺calcd for C₂₀H₃₄NaO₄: 361.2; found:

361.3.

[a]₅₈₉²⁰+10.0 (c 0.4, CHCl₃).

Acknowledgment

IR (thin film, NaCl): 2962, 2928, 2871, 1734, 1472, 1237, 1092,

1001, 668 cm^–1.

We gratefully acknowledge financial support of this work by the

American Cancer Society (RSG-06-117-01), the American Chemi-

cal Society (PRF-45334-G1), the Arnold and Mabel Beckman

Foundation, Boehringer Ingelheim, Eli Lilly & Co., and the Natio-

nal Institutes of Health – NIGMS (GM80266). The authors also

wish to thank Raul Navarro for assistance in the synthesis of 28 and

53. Finally, L.J.P. acknowledges support from Novartis in the form

of a graduate student fellowship.

¹H NMR (500 MHz, CDCl₃): d = 6.66 (ddd, J = 16.7, 11.0, 11.0 Hz,

1 H), 6.00 (t, J = 11.0 Hz, 1 H), 5.53 (t, J = 10.4 Hz, 1 H), 5.39 (dd,

J = 9.8, 1.3 Hz, 1 H), 5.15 (d, J = 17.0 Hz, 1 H), 5.03 (d, J = 10.4

Hz, 1 H), 4.64 (app s, 1 H), 3.48 (s, 3 H), 2.84 (dd, J = 8.5, 2.5 Hz,

1 H), 2.81–2.74 (m, 1 H), 2.61–2.50 (m, 3 H), 2.26–2.20 (m, 1 H),

2.10–2.02 (m, 1 H), 1.75–1.67 (m, 1 H), 1.53 (s, 3 H), 1.06 (d,

J = 7.3 Hz, 3 H), 1.01 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 7.3 Hz, 3 H).

¹³C NMR (126 MHz, CDCl₃): d = 171.6, 134.0, 132.6, 129.8, 129.7,

129.1, 116.9, 90.1, 84.7, 61.8, 36.9, 35.8, 28.7, 26.8, 26.1, 19.1,

17.0, 13.9, 12.7.

LRMS (EI): m/z [M + Na]⁺calcd for C₁₉H₃₀NaO₃: 329.2; found:

329.5.

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Article Doi

Titanium-mediated fragment union processes in complex molecule synthesis: Development of a branched reaction pathway of high step economy for the synthesis of complex and diverse polyketides

DOI: 10.1055/s-2008-1032160

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