Total syntheses of bryostatins: Synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment

FULL PAPER

DOI: 10.1002/chem.201002932

Total Syntheses of Bryostatins: Synthesis of Two Ring-Expanded Bryostatin

Analogues and the Development of a New-Generation Strategy to Access the

C7–C27 Fragment

Barry M. Trost,* Hanbiao Yang, and Guangbin Dong^[a]

Abstract: Herein, we report the synthe-

sis of novel ring-expanded bryostatin

analogues. By carefully modifying the

substrate, a selective and high-yielding

Ru-catalyzed tandem enyne coupling/

Michael addition was employed to con-

struct the northern fragment. Ring-

closing metathesis was utilized to form

the 31-membered ring macrocycle of

the analogue. These ring-expanded

bryostatin analogues possess anticancer

activity against several cancer cell lines.

Given the difficulty in forming the

C16–C17 olefin at a late stage, we also

describe our development of a new-

generation strategy to access the C7–

C27 fragment, containing both the ring

B and C subunits.

Keywords: bryostatins · domino re-

actions · metathesis · palladium ·

ruthenium

Introduction

of the Julia olefination reaction, the two exo-cyclic a,b-unsa-

turated enoates had to be masked and revealed after macro-

cyclization, resulting in lengthy syntheses (>40 steps in the

longest linear chain and >70 steps in total).

In previous papers, we have described our development of

chemoselective and atom-economical methods for the ste-

reoselective assembly of the bryostatin ring A, B, and C sub-

units (Scheme 1). Consequently, efforts have been made to-

wards the total synthesis of the bryostatins by taking advant-

age of these methods.^[1]Herein, we report a full account of

our synthesis and biological evaluation of two novel ring-ex-

panded bryostatin analogues by using ring-closing metathe-

sis (RCM) as the macrocyclization method. Given the diffi-

culty in forming the C16–C17 olefin in the late stages of the

synthesis, we also describe the development of a new-gener-

ation strategy to access the C7–C27 fragment containing the

ring B and C subunits.

In our two preceding articles, we described our efforts to

develop atom-economic transformations for the synthesis of

the ring A, B, and C subunits of the bryostatins. Importantly,

a high degree of stereocontrol of the geometry of the exocy-

clic methyl enoate was achieved, which is mechanism based.

However, utilization of these methodologies for the total

synthesis of bryostatins necessitates a more chemoselective

strategy for the macrocycle synthesis due to the sensitive

nature of exocyclic methyl enoates towards both acids and

bases. The impressive progress of strategies for performing

RCM reactions in organic synthesis and the mildness of the

reaction conditions prompted us to evaluate its use for our

bryostatin total synthesis (Scheme 2).^[7]

Results and Discussion

We envisioned that the 26-membered macrocycle in 1

could be formed by an RCM reaction from diene precursor

10, which can be synthesized from two fragments, 11 and 12

by esterification. Southern fragment 12, containing the ring

C subunit could be accessed from dihydropyran 5.^[8]North-

ern fragment 11 could be prepared from protected polyol

13, and synthesis of ring B in 13 would ultimately come

from a Ru-catalyzed tandem alkyne–enone coupling/Mi-

chael addition reaction^[9]between alkene 14 and alkyne 7.

The feasibility of this transformation has been previously es-

tablished in a model system [Eq. (1)], albeit with a low yield

and diastereoselectivity likely caused by the lability of the

cyclopentanone ketal and the presence of two terminal ole-

fins in 6. We anticipated that the nature of the protecting

groups in alkene partner 14 would have an impact on the

outcome of the Ru-catalyzed tandem coupling reaction.

Thus, alkene 14a, with a more robust acetonide moiety, was

chosen as the initial coupling partner.

Synthesis of two ring-expanded bryostatin analogues:

Retrosynthetic analysis: The 26-membered macrolactone em-

bedded in the bryostatins presents a significant synthetic

challenge.^[2]All three previously reported total syntheses

relied upon a Julia olefination to unite a southern and

northern hemisphere followed by a macrolactonization to

close the macrocycle.^[3–6]However, due to the basic nature

[a] Dr. B. M. Trost, Dr. H. Yang, Dr. G. Dong

Department of Chemistry

Stanford University

Stanford, CA 94305 (USA)

Fax : (+01)650-725-0002

E-mail: bmtrost@stanford.edu

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.201002932.

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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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cal assignment of the newly

formed C5-hydroxyl group

(bryostatin numbering) was

based upon similar precedent

reported by Evans et al.^[13]Sub-

sequent hydroxyl-directed anti-

reduction^[14](Me₄NBH

ACHTUNGTRENNUNG(OAc)₃,

AcOH/CH₃CN, À358C) set the

C3 stereochemistry with excel-

lent yield (96%) and diastereo-

selectivity (ꢀ15:1).

To proceed, the C3 and C5

hydroxyl groups were protected

as an acetonide, and the TBS

group was removed with tri-

AHCTUNGTERGeNNUN thylamine–HF. Upon oxida-

tion of the resultant neopentyl

alcohol, the stage was set for

allylACTHNUGTRNEUNGation of aldehyde 22. A va-

riety of allylation reagents, such

as allylmagnesium chloride, al-

lylzinc bromide, and B-allyl-9-

BBN, gave a complex mixture

due to the sensitivity of the al-

dehyde, although tetraallyl

tin^[15]gave no reaction. On the

Scheme 1. Stereoselective assembly of the bryostatin ring A, B, and C subunits.

other hand, indium-mediated

allylation^[16]with allyl iodide

(DMF, room temperature) pro-

vided a satisfactory 78% yield of the corresponding secon-

dary alcohols as a 1:1 diastereomeric mixture at C9. The dia-

stereoselectivity of this process is inconsequential as this ste-

reocenter is subsequently obliterated. Interestingly, replac-

ing allyl iodide with allyl bromide gave no reaction, even

with the aid of sonication. Subsequent oxidation (Dess–

Martin periodinane, NaHCO₃, CH₂Cl₂) resulted in b,g-

enone 14a.

Synthesis of the northern C1–C16 fragment: Our synthesis of

With enone 14a in hand, the Ru-catalyzed tandem cou-

pling reaction of 7 with 14a was then investigated [Eq. (2)].

Unfortunately, the reaction provided a complex mixture and

none of the desired coupling product was obtained. Never-

theless, we were able to identify an apparent signal at

6.69 ppm (CDCl₃, dt, J=10.5, 17.0 Hz) in the crude

¹H NMR spectrum, which indicated the formation of a

trans-a,b-unsaturated ester during the reaction.

This result was in striking contrast to our preliminary

model studies. We hypothesize that coordination of the C3-

oxygen in 14a with the cationic Ru species activated it to-

14a (Scheme 3) commenced with (R)-pantolactone, which

was converted to alcohol 15 in five steps [exhaustive reduc-

tion with lithium aluminum hydride (LAH), selective pro-

tection of the C7 and C9 alcohols as a 4-methoxylbenzalde-

hyde acetal, TEMPO-catalyzed oxidation^[10]of the C5 alco-

hol, Wittig olefination, and diisobutylaluminum hydride

(DIBAL-H) reduction] following a procedure by White

et al. and Mukaiyama et al.^[11,12]tert-Butyl silyl (TBS) pro-

tection of 15, followed by hydroboration/oxidation furnished

the desired alcohol in high yield (90% overall). Oxidation

of alcohol 16 was best accomplished by using TEMPO-cata-

lyzed oxidation with bleach. The crude aldehyde was used

without purification in the [TiACHTNUTRGNEUNG(OiPr)₂Cl₂]-mediated Mu-

kaiyama aldol reaction with bis(trimethylsilyl) dienol ether

17 to give secondary alcohol 18 in 68% yield over two steps

as a ꢀ10:1 diastereomeric mixture at C5. The stereochemi-

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Chem. Eur. J. 2011, 17, 9789 – 9805

Synthesis of Bryostatins

FULL PAPER

wards b-alkoxy elimination

(Scheme 4). The C5-oxygen

could consequently be depro-

tected and then participate in

Scheme 4. The b-alkoxy elimination of

14a.

other reactions, such as the for-

mation of a hemiketal. If this

hypothesis is correct, removal

of the ester group should mini-

mize the b-alkoxy-elimination

pathway.

To this end, the synthesis of a

new b,g-enone 14b was pursued

(Scheme 5). Methyl ester 20

was converted into alcohol 24

Scheme 2. Retrosynthetic analysis of the bryostatins.

through

a

straightforward

transformation

three-step

(LAH reduction, deprotection

of the TBS ether, and selective protection of the C1-hydrox-

yl group with TBDPSCl). The b,g-enone was installed in

three steps as previously described (Dess–Martin oxidation,

indium-mediated allylation, and Dess–Martin oxidation) to

furnish 14b.

To our delight, treatment of 14b and alkyne 7 with

[CpRuACTHNUGTRENNU(G CH₃CN)₃]ACHTUNGTERN[NUGN PF₆] under the optimized conditions

(0.4m in acetone, 40 h) gave the desired dihydropyran 25, al-

though the in low yield [21%; Eq. (3)].

Scheme 3. Synthesis of compound 14a. i) Tributylsilyl triflate (TBSOTf),

Et₃N; ii) 9-borabicyclo

ACHTUNGTRENNUNG

A

ACHTUNGTRENNUNG

iPr)₂Cl₂], PhCH₃, À788C; v) (CH₃)₄NBH(OAc)₃, AcOH/CH₃CN, À358C;

N

Scheme 5. Synthesis of 14b. i) LAH, THF; ii) Et₃N·3HF, THF; iii) t-butyl-

diphenylsilyl chloride (TBDPSCl), DMF; iv) Dess–Martin Oxidation;

v) allyl iodide, In, DMF; vi) Dess–Martin Oxidation.

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9791

B. M. Trost et al.

It is likely that the problem was caused by the acid sensi-

tivity of the acetonide in 14a and b, which could be en-

hanced by the presence of the C9 ketone moiety. For exam-

ple, the deprotected C5 alcohol could undergo cyclization to

form a hemi-ketal. To overcome this issue, a new enone 14c

was proposed (Scheme 6). Both the lactone and the TBDPS

ether moieties in 14c were expected to be stable under the

reaction conditions. Furthermore, the lactone would protect

both the C5-hydroxyl group and the C1-ester moiety, thus

minimizing protecting group manipulations.

Scheme 6. A new enone substrate.

The synthesis of enone 14c is outlined in Scheme 7. Start-

ing from diol 19, the two hydroxyl groups at C3 and C5

were differentiated by lactonization, which was best ach-

Scheme 8. Synthesis of the C1–C16 fragment. i) [CpRu

(10 mol%; Cp=cyclopentadienyl), acetone, RT; ii) N-bromosuccinimide

(NBS), DMF; iii) BF₃·OEt₂, CH₂Cl₂, HS(CH₂)₃SH, 08C; iv) PPTS,

CH₃OH, CH(OCH₃)₃, reflux; v) triethylsilyl chloride (TESCl), 4-dime-

ACHTUNGTREN(NUG CH₃CN)₃]ACHTUNGTRENNUNG[PF₆]

AHCTUNGTRENNUNG

thylaminopyridine (DMAP) then pyridine, Ac₂O; vi) PPTS, CH₃OH;

vii) DMSO, (COCl)₂, Et₃N, CH₂Cl₂, À788C to RT; viii) Ph₃PCH₃Br,

nBuLi; ix) (CH₃)₃SnOH, 1,1-dichloroethene (DCE), 1408C, microwave;

x) [PdACHTNUGTRNEG(UN PPh₃)₄], CO, DMF/CH₃OH, 858C.

1

the incorporation of two PMB groups in the H NMR spec-

trum (500 MHz, C₆D₆) suggested a successful coupling. This

was later confirmed by ¹³C NMR spectroscopy and elemen-

tal analysis. Assignment of the d=5.38 ppm signal (belong-

ing to the vinylsilane proton) as the cis-isomer was based on

previous model studies and later confirmed by 2D NMR ex-

periments on late stage compounds. Furthermore, we were

able to reduce the enone/alkyne ratio to 2.2:1 and recover

1.2 equivalents of 14c, and up to 5.5 g of 30 was synthesized.

Thwarted by acid-mediated protodesilylation of the vinylsi-

lane moiety, compound 30 was brominated with NBS in

DMF and then deprotected by using BF₃·Et₂O and 1,3-pro-

panedithiol in CH₂Cl₂at 08C to give diol 31. The shift of the

vinyl proton resonance from 5.38 to 6.04 ppm, disappear-

Scheme 7. Synthesis of 14c. i) 26 (10 mol%), hexane, reflux; ii) TBDPSCl,

imidazole, DMF, 508C; iii) AcOH/H₂O (4:1); iv) Dess–Martin oxidation;

v) allyl iodide, In, DMF, RT; vi) Dess–Martin oxidation.

ieved with the Otera catalyst (26).^[17]The use of PPTS gave

inferior results in terms of both yield and conversion. Pro-

tection of the C3 alcohol (TBDPSCl, DMF, imidazole) re-

quired heating (508C) as no reaction was observed at room

temperature. The primary TBS ether in lactone 28 was se-

lectively deprotected with aqueous acetic acid (80%, 4:1 v/

v) to give alcohol 29 in good yield (69–80%). The b,g-enone

functionality was installed as previously described without

incident to give the desired enone 14c in good overall yield

(56% over three steps).

With enone 14c in hand, the crucial Ru-catalyzed tandem

coupling was investigated (Scheme 8). To our delight, the re-

action went smoothly, delivering tetrahydropyran 30 in 56%

yield as a 9:1 cis/trans diastereomeric mixture. The appear-

ance of a singlet at 5.45 (minor) and 5.38 ppm (major) and

1

ance of both PMB groups in the H NMR spectrum, and ap-

pearance of a broad peak at 3436 cm^À1in the IR spectrum

support the structural assignment. Furthermore, the incorpo-

ration of a bromine atom into the molecule was confirmed

by mass spectrometry. Diol 31 was subsequently subjected

to a tandem methanolysis/ketalization reaction with PPTS in

refluxing CH₃OH/CH

ACHTUGNRTEN(NUGN OCH₃)₃to afford methyl ketal 32, in

which both rings A and B are installed.^[18]The assignment of

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Synthesis of Bryostatins

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the stereochemistry of the C9

methyl ketal was based on a

similar precedent in the litera-

ture.^[4a]

At this point, the remaining

task was to acetylate the C7 hy-

droxyl group, hydrolyze the C1

methyl ester, and install a ter-

minal olefin at C16. To this

end, the C7 hydroxyl group was

selectively acetylated in two

steps involving the temporary

protection of the C16 hydroxyl

as a TES ether, one-pot acetyla-

tion of the C7 hydroxyl moiety,

and deprotection of the C16 hy-

droxyl group to give compound

33. The resultant alcohol was

then oxidized (Moffatt–Swern

oxidation)

and

olefinated

Scheme 9. Synthesis of C17–C27 fragment 40. i) Et₃N·HF, THF, RT; ii) Dess–Martin Oxidation; iii) see Table 1;

iv) AcOH/H₂O (3:1), RT; vi) TESCl, Et₃N, DMF, À308C.

(Wittig olefination) to afford

terminal alkene 34 in 63%

yield over two steps. Surprising-

ly, saponification of the methyl

ester in compound 34 was troublesome; for example, the

use of LiOH in aqueous THF or nPrSLi in HMPA^[19]gave a

complex mixture. It was eventually found that the use of

(CH₃)₃SnOH^[20]resulted in acid 35 in 45–64% yield together

with 10–15% of recovered methyl ester 34. A large excess

of (CH₃)₃SnOH (15 equiv) and heating under microwave

conditions were required to achieve high conversion. Pd-cat-

(CH₃)₂] (Petasis reagent)^[23]as the olefination reagent solved

ACHTUNGTRENNUNG

the problem, and terminal alkene 39 was obtained in 58%

yield (70% based on recovered starting material, Table 1,

entry 7). Under the reaction conditions, a byproduct derived

from olefination of one of the ester groups was also ob-

served (5–10% yield). Cleavage of the acetonide with 75%

aqueous acetic acid, followed by selective protection of the

C26 hydroxyl with a TES group furnished fully functional-

ized southern fragment 40 in 52% yield over two steps.

The stereochemistry in tetrahydropyran 40 was confirmed

by ROESY experiments (Scheme 10). The selectivity for the

mono-TES protection was predicted according to literature

precedent^[4a]and confirmed by 2D NMR experiments.

alyzed carbonylation^[21]of acid 35 with [Pd

ACHTUNTRGNEUNG(PPh₃)₄] in DMF/

CH₃OH furnished the requisite a,b-unsaturated methyl

ester 36 in 55% yield. Note that both acids 35 and 36 could

be used as the RCM precursor. Moreover, the use of vinyl

bromide 35 as an RCM precursor could be advantageous be-

cause in principle it allows late-stage diversification through

cross-coupling reactions to provide novel bryostatin ana-

logues.

Synthesis of the southern C17–C27 fragment: The synthesis

commenced with tetrahydropyran 3, which was prepared in

5 or 6 steps from terminal alkyne 8 and ynoate 9 (see Refer-

ence [1c]). Removal of the C17 TBS ether in 3 was best ef-

fected by using Et₃N·3HF in THF (60–77% yield, ꢀ10% of

3 recovered; Scheme 9). An excess of reagents (15 equiv

Et₃N·3HF) and a long reaction time (12 h) were necessary

to achieve reasonable conversion of 3.^[22]Other deprotection

methods, such as TBAF, TBAF buffered with acetic acid,

HF in pyridine, and aqueous HF in acetonitrile, gave inferi-

or results. After oxidation of the C17 hydroxyl group to the

corresponding aldehyde, the stage was set for the introduc-

tion of a double bond at C17. This transformation turned

out to be non-trivial, and almost all of the classical olefina-

tion methods failed (see Table 1), likely due to the neopen-

tyl nature of the aldehyde and sensitivity of the dihydropyr-

an core towards bases. Eventually, employment of [Cp₂Ti-

Scheme 10. Key ROESY correlations observed for 40.

Investigation of the ring-closing metathesis approach: With

acid 36 and alcohol 40 in hand, the stage was set for their

union. Initial efforts with 1-ethyl-3-(3-dimethylaminopro-

pyl)carbodiimide hydrochloride (EDCl) as the coupling re-

agent were plagued by the formation of two inseparable

products in a 1:1 ratio, one of which was later identified as

the desired ester 42. No effort was made to identify the

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B. M. Trost et al.

Table 1. Olefination of 38.

product could be a dimer: the double bond at C16 disap-

peared whereas the one at C17 remained intact. Based upon

these observations, a possible explanation for the failure of

the RCM reaction is outlined in Scheme 12. Both terminal

Conditions

Observation

Yield

[%]

1

2

3

Ph₃P=CH₂, À30–08C

unkown byproduct

mainly 38

decomposition of 38

0

trace

0

CH₂I₂, Zn, Me₃Al, 258C

CH₂I₂, Zn, PbI₂, TiCl₄,

0–258C

4

5

[TMSCH₂CeCl₂], THF, À788C

only 38

38+decomposition

0

CH₂I₂, Zn, Me₃Al, BF₃·OEt₂, 258C

6

7

38+decomposition

0

G

(CH₃)₂]

39+a byproduct from

58

ester olefination

other product. The most satisfactory results were obtained

by employing 2-methyl-6-nitrobenzoic anhydride (MNBA)

in the method developed by Shiina et al. (Scheme 11).^[24]

Ester 42 was isolated in around 60% yield with the majority

of the excess alcohol (40) recovered.^[25]In addition, under

the same esterification conditions, acid 35 was coupled with

alcohol 40 to give ester 41 in a similar yield.

Scheme 12. Unsuccessful RCM: a possible explanation.

Consequently, the RCM reaction of both esters 41 and 42

was investigated. Our initial attempts were carried out with

the Grubbs–Hoveyda catalyst 45^[26]or pseudohalide catalyst

46^[27]in either refluxing CH₂Cl₂or benzene. Unfortunately,

these reactions were sluggish. Prolonged heating (>12 h)

was required for the conversion of either 41 or 42, even in

refluxing benzene. Furthermore, the major isolated product

was much more polar than the corresponding starting mate-

rials. ¹H NMR analysis supported the fact that the polar

double bonds at C16 and C17 are deactivated towards Ru–

alkylidene formation due to unfavorable steric and electron-

ic factors. At elevated temperature, the Ru–alkylidene selec-

tively initiated attack on the C16 double bond. Since the

C17 double bond has very low reactivity, presumably due to

steric congestion, intermediate 43 preferred to react with an-

other molecule of 42 to form a dimer even at a very low

substrate concentrations (ꢀ0.0005m). Concurrently, a simi-

lar observation was reported by Thomas and co-workers

during their investigation of an RCM approach to the bryo-

AHCTUNGTRENNUNG

cursor would have a dramatic impact on the efficiency of

the RCM reaction. The X-ray crystal structure of bryosta-

tin 1 (Figure 1)^[2a]clearly shows that the C3 OH group helps

to organize the macrocycle by serving as a hydrogen bond-

À

ing acceptor for the C19 lactol hydroxyl group (O···H O

bond length of 2.71 ꢁ) and donors for both the C5 and C11

À

pyran oxygens (O···H O bond length of 3.00 and 2.84 ꢁ, re-

spectively). If this holds true for the immediate RCM pre-

cursor, one would expect that a free hydroxyl group at C3 in

either 41 or 42 would facilitate the RCM reaction by bring-

ing the two terminal olefins together. Therefore, deprotec-

tion of the TBDPS ether at C3 was undertaken [Eq. (4)].

Unfortunately, only a complex mixture was obtained under

the three reaction conditions attempted (TBAF, HF in pyri-

dine, and NH₄F in CH₃OH). To circumvent this problem, it

Scheme 11. Synthesis of 41 and 42. i) Et₃N, DMAP, MNBA, CH₂Cl₂then

40.

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Synthesis of Bryostatins

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Figure 1. X-ray crystal structure of bryostatin 1 from reference [2a].

was decided to remove the TBDPS group at an earlier stage

in the synthesis.

Treatment of vinyl bromide 34 with TBAF led to smooth

deprotection of the C3 TBDPS ether to give alcohol 47 in

Scheme 13. i) Tetra-n-butylammonium (TBAF),

fluoride

THF;

ii) (CH₃)₃SnOH, DCE, 1408C, microwave; iii) [PdAHCUTNGTENR(NUNG PPh₃)₄], CO, DMF/

CH₃OH, 858C; iv) TESOTf, 2,6-lutidine, CH₂Cl₂, 08C; v) Et₃N, DMAP,

MNBA then 40; vi) PPTS, THF/H₂O; vii) Grubbs–Hoveyda catalyst (45).

82% yield (Scheme 13). In contrast to the hydrolysis of

methyl ester 34 (Scheme 8, 45–50% yield with 15 equiva-

lents of (CH₃)₃SnOH, 1408C, microwave, 1.5 h), the saponi-

fication of 47 was much simpler. Under the identical condi-

tions, the reaction went to completion in 40 min to deliver

hydroxy acid 48 in 86% yield. Presumably, the hydrolysis of

the C1 methyl ester was facilitated by pre-coordination (or

complexation) of the C3 hydroxyl group with

(CH₃)₃SnOH.^[29]Next, carbonylation of the vinyl bromide

moiety followed by selective protection of the C3 hydroxyl

group (TESOTf, CH₂Cl₂, 08C) converted 49 into acid 50,

which was subsequently acylated with alcohol 40 to give

ester 51. Removal of the TES groups at C3 and C26 with

PPTS in aqueous THF provided diol 52, the structure of

which was fully determined by COSY, ROESY, HSQC, and

HMBC experiments.

that the resulting ruthenium alkylidene 55 would cyclize

onto the C16 double bond to form macrocycle 53

(Scheme 14).

Unfortunately, when compound 52 was subjected to RCM

reactions in the presence of the Grubbs–Hoveyda catalyst

(45), no reaction was observed in refluxing CH₂Cl₂and heat-

ing to reflux in benzene only led to decomposition. It is evi-

dent from these studies that the low reactivity of the double

bond at C17 is the source of the problem. Thus, we decided

to initiate the ruthenium alkylidene formation onto the C17

double bond through relay ring-closing metathesis

(RRCM).^[30]If this could be accomplished, it was anticipated

Scheme 14. Relay ring-closing metathesis: a possible solution.

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B. M. Trost et al.

An RRCM Strategy: Although direct installation of a relay

moiety onto the southern fragment through Takai olefina-

tion^[31][Eq. (5)] or olefin cross-metathesis^[32][Eq. (6)] was

difficult, this problem was solved with a two-step procedure:

initial Takai olefination of aldehyde 38 with iodoform,^[33]fol-

lowed by a Negishi cross-coupling^[34]gave compound 60

(Scheme 15). The quality of the CrCl₂utilized was crucial

With polyolefin 64 in hand, the RRCM reaction was next

investigated (Table 2). To avoid the undesired dimerization,

the solution of 64 was added dropwise through a syringe

pump to a solution of the Grubbs–Hoveyda catalyst (45;

18 mol%) in benzene at 508C and then the bath tempera-

ture was raised to 808C. The starting material disappeared

within one hour (Table 2, entry 1). However, no RRCM

product was observed. Surprisingly, the direct RCM prod-

ucts were isolated as a mixture of 1:1 E/Z isomers (66 and

67) in a very high yield (80%). The assignment of the direct

RCM products was supported by high-resolution mass spec-

trometry and 2D NMR experiments. Changing the order of

addition (adding 45 to a solution of 64 in benzene) gave the

same product ratio. However, employing second generation

Grubbs catalyst 65 and running the reaction in refluxing tol-

uene improved the product ratio of 66/67 to 1:2.3 favoring

the E-isomer (Table 2, entry 2).^[36]

Scheme 15. Synthesis of precursor 64 for relay ring-closing metathesis.

i) CrCl₂, CHI₃, THF, RT (BRSM=based on recovered starting material);

ii) 61, [PdACHTUNGTRENNUNG(PPh₃)₄], THF; iii) AcOH/H₂O (4:1); iv) TESCl, DMF, Et₃N,

08C to RT; v) 50, MNBA, DMAP, Et₃N, CH₂Cl₂.

for the Takai olefination reaction, and a high chromium

loading (ꢀ15 equiv) was necessary for full conversion of the

starting material.^[35]The yield (26%, 47% based on recov-

ered starting material) was moderate, perhaps due to the

steric congestion around the aldehyde. Subsequent deprotec-

tion (80% aqueous AcOH) followed by selective TES pro-

tection (TESCl, DMF, Et₃N, 0 8C to RT) converted 62 into

mono-TES ether 63, which was then acetylated with north-

ern fragment 50 to give RRCM precursor 64 in 51% yield.

Treatment of the mixture of macrocycles 66 and 67 with

PPTS in anhydrous MeOH cleanly removed both TES

groups (Scheme 17). At this stage, diols 68 and 69 were sep-

arated by preparative TLC, and their structures were deter-

mined by IR, HRMS, ¹H, ¹³C, and 2D NMR experiments.

Note that in the presence of water the global deprotection

only resulted in a complex mixture; however, treatment of

this mixture with PPTS in dry MeOH provided the same

mixture (68 and 69) as above. We rationalize that this inter-

esting phenomena was probably caused by the rapid tauto-

merization of the C9 hemiketal (Scheme 18).

1

The structure of compound 64 was determined by H, ¹³C,

and 2D NMR experiments. In particular, the observed

ROESY correlations confirmed our previous stereochemical

assignments for rings A, B, and C (Scheme 16).

Biological evaluation of the new ring-expanded bryostatin

analogues: Compounds 68 and 69 contain all of the func-

tionality present in the bryostatins except that they have an

unusual 31-membered macrolactone ring. As almost all pre-

vious efforts to synthesize bryostatin analogues have been

centered on the 26-membered macrocycle backbone, we en-

visioned that these “ring-expanded bryostatins” could serve

as a family of new analogues to further probe the structure–

activity relationships (SARs) of the bryostatins. To this end,

macrocycles 68 and 69 and acyclic compound 52 were tested

against several cancer cell lines (Table 3). Interestingly,

whereas acyclic compound 52 is completely inactive, 31-

membered lactones 68 and 69 exhibit activities against a

range of cancer cell lines, including SKBR3 (a breast cancer

cell line), SKOV3 (an ovarian cancer cell line), and NCI-

Scheme 16. Key ROESY correlations observed for 64.

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Synthesis of Bryostatins

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Table 2. Relay ring-closing metathesis studies of compound 64.

Conditions

Results

1

2

Hoveyda catalyst 45 (18 mol%), benzene, 50–808C, N₂sparging

second generation Grubbs catalyst 65 (ꢀ20 mol%), toluene, reflux, N₂sparging

80% yield (66/67, 1:1)

small scale reaction, clean by TLC and NMR (66/ 67, 1:2.3)

Table 3. Biological activities of bryostatin analogues.^[a]

Sample

SKBR3

SKOV3

NCI-ADR

[nm]

68

69

560

52

840

66

1100

123

[a] The numbers are the half maximal inhibitory concentrations (IC₅₀) for

68 and 69 in cell growth inhibition assays. SKBR3: a breast cancer cell

line. SKOV3: an ovarian cancer cell line. NCI-ADR: a breast cancer cell

line with multi-drug resistant pumps.

macrocyclic RCM or RRCM strategy. Indeed, previous syn-

theses have noted the difficulties in forming this double

bond,^[4]which led us to conceive a new strategy for the in-

stallation of this sterically hindered trans alkene at an earlier

stage.

We envisioned that enyne fragment 70 could serve as a

linchpin to allow us to “glue” all of the subunits together

(Scheme 19). The function of fragment 70 is three-fold:

Scheme 17. Final deprotection of 66 and 67. i) PPTS, CH₃OH; ii) PPTS,

THF/H₂O (3:1); iii)PPTS, CH₃OH.

Scheme 18.

Scheme 19. Linchpin: fragment 70.

ADR (a breast cancer cell line with added multi-drug resist-

ant pumps). Remarkably, analogue 69 was effective at nm

levels against all three cell lines, most notably with respect

to NCI-ADR for which the IC₅₀value was as low as

123 nm.^[37]

1) the homopropargyl alcohol moiety could permit the use

of a Ru-catalyzed tandem enyne coupling/Michael addition

to construct bryostatin ring B; 2) it provides the C16–17

olefin directly; and 3) the TBS protected primary alcohol

could serve as a masked terminal alkyne, so that fragment

70 could also provide a link to build bryostatin ring C

Development of a new-generation strategy to access the C7–

C27 fragment: We have disclosed the synthetic challenges to

installing the C16–C17 olefin at a late stage through either a

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9797

B. M. Trost et al.

through Pd-catalyzed alkyne–alkyne coupling and then 6-

endo-dig cyclization.

racemic homopropargyl alcohol 70 in 68% yield. Dess–

Martin oxidation^[42]of the allylic alcohol followed by CBS-

reduction^[43]of corresponding ketone 77 afforded 70 in

90% ee and 90% yield over two steps. Homopropargyl

ketone 77 proved to be quite unstable and extremely sensi-

tive to acids;^[44]hence, after aqueous workup, it was directly

subjected to the subsequent reduction without any purifica-

tion.

As substrates with an allylic alcohol moiety have not pre-

viously been examined in the Ru-catalyzed enyne coupling/

Michael addition reaction and it is known that allylic alco-

hols are able to participate in various Ru-catalyzed transfor-

mations, such as redox isomerizations,^[38]the issue of chemo-

selectivity needed to be investigated prior to use of enyne

70 as the substrate. On the other hand, the Pd-catalyzed

alkyne–alkyne coupling and 6-endo-dig cyclization have also

not been previously tested on complex substrates. Therefore,

it was necessary to build a model system to address these

chemoselectivity issues. Consequently, compound 71, with

the C7–C27 bryostatin skeleton, as well as the ring B and C

entities, was designed as the model target molecule

(Scheme 20).

A Weinreb-amide route to ketone 77 was also explored,

since it could potentially shorten the synthesis by one step

(Scheme 22). Weinreb-amide 78 was synthesized in 56%

Scheme 22. A Weinreb–amide route. i) Ba(OH)₂, THF/H₂O; ii) 1-trime-

thylsilylprop-1-yne, nBuLi, tetramethylethylenediamine (TMEDA), Et₂O,

08C to RT.

yield through Horner–Wadsworth–Emmons (HWE) olefina-

tion^[45]of aldehyde 74. Although subsequent allenyl lithium

addition was able to provide desired ketone 77, the impurity

in the crude (compound 77 cannot be purified by chroma-

tography) did not permit the CBS reduction, especially on a

large scale. Therefore, this route was abandoned.

The other fragment, b,g-unsaturated ketone 73, was pre-

pared according to our previously published procedure.^[9]

With both alkene 73 and alkyne 70 in hand, the conditions

for the Ru-catalyzed tandem alkene–alkyne coupling/Mi-

chael addition were next examined (Scheme 23). The

Scheme 20. Retrosynthetic analysis of compound 71.

Scheme 21. Asymmetric synthesis of fragment 70. i) 75, Me₂Zn, Et₂O,

À788C then NaHSO₄; ii) 1-trimethylsilyl-3-bromoprop-1-yne, In/InF₃,

668C; iii) Dess–Martin periodinane (DMP), NaHCO₃; iv) (S)-Corey–

Bakshi–Shibata catalyst ((S)-CBS; 5 mol%), catecholborane, CH₂Cl₂,

À788C.

Scheme 23. Synthesis of 79. i) [CpRu

CH₂Cl₂, 08C to RT then HF·pyridine.

ACHTUTGNREN(UNG CH₃CN)₃]CAHTUNGTREN[NNGU PF₆], (10 mol%),

[CpRuACTHNUGTRENN(GU CH₃CN)₃]ACHTUGNTREN[NUNG PF₆] complex (10 mol%) was employed

as the catalyst, and three equivalents of alkene 73 were used

to ensure good conversion. As the initial cyclization product

was difficult to separate from the starting materials, the TBS

group was subsequently removed with HF in pyridine to

give primary alcohol 79, which could be easily purified. We

found that the solvent plays an important role in the prod-

uct conversion. Under the original reaction conditions, in

which acetone was used, tetrahydropyran 79 was only isolat-

ed in 32% yield;^[46]however, upon switching to CH₂Cl₂, a

much higher conversion and a much cleaner reaction was

Enantioselective synthesis of TMS-alkyne 70 is described

in Scheme 21. Aldehyde 74^[39]was treated with cis-2-ethoxy-

vinyl lithium 75 and Me₂Zn followed by an acidic aqueous

workup, providing a,b-unsaturated aldehyde 76 in 97%

yield.^[40]NaHSO₄was selected as a mild acid source; if HCl

(1 n) was used, a much lower yield (51%) was observed.

Following a protocol described by Loh et al.,^[41]treatment of

aldehyde 76 with indium metal, TMS-propargyl bromide

and a catalytic amount of InF₃in refluxing THF afforded

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Chem. Eur. J. 2011, 17, 9789 – 9805

Synthesis of Bryostatins

FULL PAPER

observed, with an isolated yield of 62% over two steps,

almost doubling that of the reaction in acetone. We rational-

ize that as CH₂Cl₂is a much less coordinating solvent than

remained intact under the reaction conditions, which dem-

onstrates excellent chemoselectivity for the Pd-catalyzed

alkyne–alkyne coupling reaction.

acetone, it enhances the reactivity of [CpRuACHTUNGRTENN(UG CH₃CN)₃]ACHTUGNTREN[NUGN PF₆].

The diastereoselectivity ratio (d.r.) for this cyclization was

around 6.7:1 (determined by integration of peaks in the

¹H NMR spectrum; d_major=2.91 and d_minor=2.80 ppm), favor-

ing the cis-isomer.

Advancement of compound 79 to terminal alkyne 72 was

achieved in two steps. Dess–Martin oxidation of the primary

alcohol, followed by Ohira–Bestmann alkynylation^[47]of the

corresponding aldehyde provided alkyne 72 in 79% yield

over two steps (Scheme 24).

A metal-catalyzed 6-endo-dig cyclization of enyne 82 was

next required to construct ring C of bryostatin (Table 4). As

shown in our previous paper (see Reference [1c]), this cycli-

zation could be very challenging because a number of possi-

ble byproducts can be formed. For example, if the alkyne is

substituted with a bulky group, such as a tBu group, forma-

tion of the 5-exo addition product would be competitive. In

addition, acids can catalyze the isomerization of the external

olefin of the 6-endo-dig product, giving the other geometric

isomer (Scheme 25).^[48]Moreover, the secondary alcohol

could attack the ester, instead of the alkyne, to give the 6-

Scheme 24. Synthesis of alkyne 72. i) DMP, NaHCO₃, CH₂Cl₂, 08C to RT;

ii) 81, K₂CO₃, MeOH.

The stage was now set to test the Pd-catalyzed alkyne–

alkyne coupling reaction. Acceptor alkyne 9 was synthesized

in six steps from commercially available d-galactonic acid-

1,4-lactone (see Reference [1c]). The coupling between al-

kynes 72 and compound 9 proceeded well by using Pd-

A

(10 mol%)/tris(2,6-dimethoxyphenyl)phosphine

(TDMPP) as the catalyst [Eq. (7)]; enyne 82 was isolated in

73% yield. The primary alcohol, vinylsilane, and trans olefin

Scheme 25. Bronsted acid catalyzed olefin isomerization.

Table 4. The 6-endo-dig cyclization of enyne 82.

Conditions

Results

6-endo

1

2

3

A

₂A

(71+83)/5-exo (84) ꢀ1:1

G

E

71/83/84 1.5:0.5:1 (ꢀ10% 82 + ꢀ30% 85)

53% yield (71/83/84 5.1:1:1.3)

N

CHTUNGTRENNUNG

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9799

B. M. Trost et al.

membered lactone. Given these concerns, we decided to re-

visit this 6-endo-dig cyclization issue.

Conclusion

With the goal of achieving good regio- and chemoselectiv-

ity, the conditions for this 6-endo-dig cyclization were opti-

mized and a number of catalysts were surveyed (Table 4). If

enyne 82 was subjected to the previously optimized condi-

By taking advantage of two tandem methods, Ru-catalyzed

enyne coupling/Michael addition and Pd-catalyzed diyne

coupling/6-endo cyclization, we were able to furnish fully

functionalized northern and southern fragments of bryosta-

tins. An esterification/olefin metathesis strategy has been in-

vestigated to unite the two fragments and to advance them

to the natural products. Although formation of the C16–C17

olefin through olefin metathesis was unsuccessful, we were

able to synthesize two new bryostatin analogues with a ring-

expanded backbone. These analogues retain almost all the

functionalities in the bryostatins, as well as their biological

activities against several cancer cell lines, including NCI-

ADR (the cell line containing multi-drug resistant pumps).

To overcome this “olefination problem”, a new strategy

was developed to install the C16–C17 olefin at an earlier

stage. Enyne 70 was designed and synthesized to serve as a

“linchpin” to connect both the northern and southern parts

together. To test this strategy, model substrate 71, containing

the C7–C27 carbon skeleton and rings B and C of the bryo-

tions ([PdCl₂ACHTUNGTRENNUNG(CH₃CN)₂] (17 mol%), TDMPP (10 mol%),

THF, RT), the products from 6-endo (71+83) and 5-exo

(84) cyclization pathways were isolated in a ratio of around

1:1 (Table 4, entry 1). A slightly better 6-endo/5-exo ratio

(around 2:1) was observed by using Pd

ACHTUNGRTEN(NGNU OAc)₂/TDMPP/Pd-

ACHTUNGTRENNUNG

however, this reaction gave incomplete conversion and lac-

tone 85 was formed in around a 30% yield (Table 4,

entry 2). Eventually, the most satisfactory result was found

⁺A[SbF₆]^Àas

when using cationic gold(I) complex [AuACTHNUTRGNENUG(PPh₃)] CHTUNGTRENNUGN

the catalyst in CH₃CN (Table 4, entry 3).^[49]The product

ratio of 71/83/84 was enhanced to 5.1:1:1.3, which is equal to

around 5:1 6-endo/5-exo regioselectivity. NaHCO₃was em-

ployed as a buffer to minimize the acid-catalyzed olefin iso-

merization. The only drawback to these conditions was that

the reaction proceeded relatively slowly (53% yield over

4 days). If the Au-catalyzed reaction was conducted in

CH₂Cl₂, a much higher rate was observed; however the reac-

tion became messy and many unidentified byproducts were

formed. The structure of the final model-study product 71

AHCTUNGTREGsNNUN tatins, was synthesized in only six steps. During this study,

several chemoselectivity issues were addressed, including

the functional group tolerance of the Ru-catalyzed tandem

alkene–alkyne coupling/Michael addition reaction and the

Pd-catalyzed alkyne–alkyne coupling. Moreover, a cationic

gold complex was found to be a superior catalyst for the

challenging 6-endo-dig cyclization. Therefore, our ring-ex-

panded analogue synthesis, along with the new linchpin

strategy described in this article, should provide key support

for our subsequent accomplishment of the total synthesis of

bryostatins.

1

was confirmed by H NMR, IR, HRMS, and 2D NMR ex-

periments.

The exact reason why the cationic gold catalyst gave

much higher regio- and chemoselectivity is unclear. We ra-

tionalize that the higher chemoselectivity could be attribut-

ed to goldꢂs unique affinity for alkynes,^[50]and the higher re-

gioselectivity may relate to the ionic nature and linear struc-

ture of the Au^Icatalyst. As shown in Scheme 26, when Au

Experimental Section

All reactions were run under a nitrogen atmosphere unless otherwise in-

dicated. Anhydrous solvents were transferred through an oven-dried sy-

ringe or cannula. Flasks were flame-dried under vacuum and cooled

under a stream of nitrogen or argon. Tetrahydrofuran (THF), dimethoxy-

ethane (DME), benzene, pyridine, diisopropylamine, triethylamine, diiso-

propylethylamine, dimethylsulfoxide, acetonitrile, hexane, toluene, dieth-

yl ether, and dichloromethane were purified with a Solv–Tek solvent pu-

rification system by passing through a column of activated alumina. Ace-

tone was distilled from calcium sulfate. Methanol was distilled from mag-

nesium methoxide.

Where indicted, solvents were degassed through freezing in liquid nitro-

gen and thawing under high vacuum. The above cycle was repeated three

times, unless otherwise indicated. Analytical thin layer chromatography

(TLC) was carried out by using 0.2 mm commercial silica gel plates (DC–

Fertigplatten Krieselgel 60 F₂₅₄). Melting points were determined on a

Thomas–Hoover melting point apparatus in open capillaries and are un-

corrected. Infrared spectra were recorded on a Perkin–Elmer 1420 spec-

trophotometer. Absorbance frequencies are reported in reciprocal centi-

meters (cm^À1). Proton nuclear magnetic resonance (¹H NMR) spectra

were recorded by using a Varian UI-600 (600 MHz), Varian UI-500

(500 MHz), or Varian MERC-400 (400 MHz) spectrometer. Chemical

shifts are reported in parts per million (ppm) downfield from tetrame-

thylsilane (TMS) or in ppm relative to the singlet at 7.26 ppm for chloro-

form. Coupling constants are reported in Hertz (Hz). The following ab-

breviations are used: s (singlet), d (doublet), t (triplet), q (quartet), and

Scheme 26. 5-exo vs. 6-endo addition.

binds to the alkyne, the steric interaction between the sub-

stituted tBu-like group and the [AuACTHNUTRGNEUNG(PPh₃)] cation and adja-

cent [SbF₆] anion would largely disfavor the 5-exo addition,

because this interaction would become much worse in inter-

mediate 90 than in 91. Hence, the 6-endo pathway is pre-

ferred.

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Chem. Eur. J. 2011, 17, 9789 – 9805

Synthesis of Bryostatins

FULL PAPER

m (multiplet). Carbon-13 nuclear magnetic resonance (¹³C NMR) spectra

were recorded by using a Varian UI-600 (150 MHz), Varian UI-500

(125 MHz), or Varian MERC-400 (100 MHz) spectrometer. Chemical

shifts are reported in parts per million (ppm) relative to the center line

of the triplet at 77.1 ppm for deuterochloroform. ¹³C NMR spectra were

routinely run with broadband decoupling. Optical rotation data was ob-

tained with a Jasco DIP-360 digital polarimeter at the sodium D line

(589 nm) in the solvent and concentration indicated.

1.5, 17.7 Hz, 1H), 4.82 (dd, J=1.5, 10.8 Hz, 1H), 4.13 (ddt, J=2.8, 5.5,

12.7 Hz, 1H), 3.91 (ddd, J=1.2, 8.4, 10.5 Hz, 1H), 3.76 (dd, J=1.8,

15.8 Hz, 1H), 3.48 (dq, J=6.0, 8.4 Hz, 1H), 3.32 (s, 3H), 3.31 (s, 3H),

2.47 (ddd, J=2.2, 11.8, 14.8 Hz, 1H), 1.61 (s, 3H), 1.48 (ddd, J=2.1, 10.0,

12.2 Hz, 1H), 1.37–1.31 (m, 1H), 1.36 (s, 3H), 1.35 (s, 3H), 1.23 (s, 3H),

1.22 (s, 3H), 1.08 ppm (d, J=6.0 Hz, 3H); ¹³C NMR (125 MHz, C₆D₆):

d=168.5, 166.4, 153.2, 146.6, 117.5, 108.8, 107.9, 103.0, 78.5, 77.2, 72.2,

68.8, 51.2, 50.7, 47.0, 38.6, 33.3, 27.5, 27.4, 24.3, 23.0, 20.8, 17.0 ppm; IR

(neat film): n˜ =3076, 2996, 2931, 1746, 1719, 1664, 1460, 1433, 1370, 1230,

1157, 1094, 1048, 1021, 994 cm^À1; HRMS calcd for C₂₂H₃₂O₇⁺: 408.2148

[MÀCH₄O]⁺; found: 408.2129.

Synthesis of compound 30: Acetone (freshly distilled over calcium sul-

fate, 3 mL) was added to a mixture of alkene 14c (2.09 g, 3.33 mmol) and

alkyne 7 (0.442 g, 1.51 mmol) in a V-shaped vial with a septum. The mix-

ture was stirred at room temperature for 5 min to ensure formation of a

homogeneous solution and the septum was quickly removed to allow the

Synthesis of compound 40:

Acetonide cleavage: Compound 39 (40 mg, 0.09 mmol) in aqueous acetic

acid (75% (v/v); 7 mL) was stirred at room temperature for 6 h. The con-

tents were poured into ice-cooled saturated aqueous Na/K tartrate, neu-

tralized with saturated aqueous Na₂CO₃, and extracted three times with

EtOAc. The combined organic extracts were dried over Na₂SO₄, filtered,

and concentrated. The residue was purified by flash column chromatogra-

phy on silica gel with Et₂O/petroleum ether (50%) followed by CH₃OH/

CH₂Cl₂(6%) to give a triol (34 mg) contaminated with a small amount

(<10%) of an impurity. R_f=0.18 (6% CH₃OH/CH₂Cl₂); [a]²_D⁴=À11.1

(c=0.55 in CH₂Cl₂); ¹H NMR (500 MHz, C₆D₆): d=6.43 (dd, J=10.5,

14.0 Hz, 1H), 6.34 (d, J=1.5 Hz, 1H), 5.54 (s, 1H), 4.94–4.89 (m, 2H),

4.33 (t, J=10.6 Hz,1H), 4.07 (dd, J=2.1, 13.8 Hz, 1H), 3.77–3.73 (m,

1H), 3.44 (q, J=6.2 Hz, 1H), 3.32 (s, 3H), 2.33 (t, J=13.7 Hz, 1H), 1.80–

1.74 (m, 1H), 1.67–1.61 (m, 1H), 1.61 (s, 3H), 1.28 (s, 3H), 1.23 (s, 3H),

1.05 ppm (d, J=6.1 Hz, 3H); ¹³C NMR (125 MHz, C₆D₆): d=168.8,

166.8, 152.2, 145.4, 120.3, 110.8, 100.1, 73.8, 72.8, 71.3, 67.1, 50.9, 45.7,

39.6, 23.0, 21.8, 21.0, 20.2, 19.5 ppm; IR (neat film): n˜ =3438 (br), 3076,

1743, 1721, 1683, 1635, 1437, 1410, 1369, 1234, 1152, 1080, 1031, 1017,

745, 728 cm^À1; HRMS calcd for C₁₄H₂₁O₈: 317.1236 [MÀC₅H₉]⁺; found:

317.1240.

addition of [CpRuACHTUNGTRENNUNG(CNCH₃)₃]ACHTUNGTREN[NGUN PF₆] (65 mg, 0.15 mmol). The reaction was

stirred at room temperature for 40 h and the solvent removed under re-

duced pressure. The residue was purified by flash column chromatogra-

phy on silica gel with EtOAc/petroleum ether (10%, 12.5%, 15%,

17.5%, and 20%) to give 30 as a pale yellow foam (0.81 g, 56%, 9:1 d.r.

determined by integrating peaks at 5.38 and 5.36 ppm). Significant

amounts of both alkene 14c and alkyne 7 were recovered as an insepara-

ble mixture (1.02 g, 14c/7, 7:1). R_f=0.37 (20% EtOAc/petroleum ether);

[a]²_D³=À35.5 (c=0.6 in CH₂Cl₂); ¹H NMR (500 MHz, C₆D₆): d=7.66–

7.61 (m, 4H), 7.23–7.17 (m, 10H), 6.80 (d, J=8.6 Hz, 2H), 6.74 (d, J=

8.6 Hz, 2H), 5.38 (s, 1H), 4.50 (d, J=11.6 Hz, 1H), 4.38–4.35 (m, 3H),

4.22–4.16 (m, 1H), 4.03 (dd, J=1.7, 10.3 Hz, 1H), 3.81–3.75 (m, 1H),

3.69–3.63 (m, 2H), 3.53 (dd, J=5.2, 10.0 Hz, 1H), 3.41 (dd, J=5.3,

10.0 Hz, 1H), 3.29 (s, 3H), 3.27 (s, 3H), 3.07 (dd, J=7.0, 17.3 Hz, 1H),

2.66 (d, J=13.2 Hz, 1H), 2.40 (dd, J=5.2, 17.3 Hz, 1H), 2.34 (dd, J=5.2,

16.5 Hz, 1H), 2.29 (d, J=12.6 Hz, 1H), 2.21 (dd, J=5.6, 16.4 Hz, 1H),

2.09 (q, J=12.3 Hz, 2H), 1.56–1.30 (m, 4H), 1.13 (s, 3H), 1.08 (s, 9H),

1.04 (s, 3H), 0.17 ppm (s, 9H); ¹³C NMR (125 MHz, C₆D₆): d=210.9,

168.9, 159.7, 153.7, 136.0, 135.9, 133.9, 133.7, 131.4, 131.0, 130.3, 130.2,

129.6, 129.3, 128.3, 128.1, 127.9, 123,6, 114.0, 80.1, 77.7, 75.3, 73.3, 73.0,

72.7, 65.7, 54.8, 54.7, 52.8, 45.6, 45.3, 39.6, 38.9, 38.3, 37.4, 26.9, 21.5, 20.4,

19.2, 0.4 ppm; IR (neat film): n˜ =3075, 3042, 1742, 1705, 1609, 1585, 1510,

1484, 1427, 1386, 1361, 1303, 1245, 1170, 1108, 1091, 1033, 839, 818, 739,

702 cm^À1; elemental analysis calcd (%) for C₅₄H₇₂O₉Si₂: C 70.40, H 7.88;

found: C 70.21, H 7.80.

TES protection: Et₃N (0.12 mL, 0.86 mmol) and then TESCl (16.3 mL,

0.097 mmol) were added to a solution of the triol formed above (34 mg,

0.088 mmol) in DMF (2.5 mL) at À308C. The reaction was stirred at

À308C for 30 min and the contents were poured into saturated aqueous

NaHCO₃. The mixture was extracted with EtOAc. The combined organic

extracts were dried over Na₂SO₄, filtered, and concentrated. The residue

was purified by flash column chromatography on silica gel with EtOAc/

petroleum ether (20% and 30%) to give 40 (23 mg, 52% over the two

steps). R_f=0.52 (40% EtOAc/petroleum ether); [a]²_D²=À7.5 (c=0.75 in

Synthesis of compound 32: A solution of diol 31 (0.62 g, 0.9 mmol) and

pyridinium p-toluenesulfonate (99 mg, 0.39 mmol) in CH₃OH (15 mL)

and trimethyl orthoformate (0.75 mL) was heated at reflux for 2 h. The

contents were cooled to room temperature, poured into saturated aque-

ous NaHCO₃, and extracted with EtOAc. The combined organic extracts

were dried over Na₂SO₄, filtered, and concentrated. The residue was pu-

rified by flash column chromatography on silica gel with EtOAc/petrole-

um ether (30%, 40%, and 50%) to give 32 as a clear colorless oil

(0.47 g, 71%). R_f=0.50 (50% EtOAc/petroleum ether); [a]²_D³=À30.5

(c=1.4 in CH₂Cl₂); ¹H NMR (500 MHz, C₆D₆): d=7.82–7.77 (m, 4H),

7.24–7.20 (m, 6H), 5.83 (t, J=2.1 Hz, 1H), 4.54–4.49 (m, 1H), 3.73–3.69

(m, 1H), 3.43–3.31 (m, 3H), 3.33 (s, 3H), 3.14–3.10 (m, 1H), 2.83 (s, 3H),

2.71–2.62 (m, 3H), 2.01–1.94 (m, 3H), 1.83–1.75 (m, 1H), 1.67–1.49 (m,

4H), 1.18–1.15 (m, 2H), 1.16 (s, 9H), 1.06 (s, 3H), 0.9 ppm (s, 3H);

¹³C NMR (125 MHz, C₆D₆): d=171.6, 140.3, 136.3, 134.4, 134.2, 130.1,

128.3, 104.0, 100.8, 77.3, 74.4, 70.4, 69.4, 66.2, 65.8, 51.2, 48.0, 44.4, 43.4,

43.2, 42.0, 38.8, 36.5, 32.7, 27.1, 20.9, 19.5, 15.8 ppm; IR (neat film): n˜ =

3446, 3073, 3047, 1734, 1632, 1588, 1472, 1428, 1388, 1357, 1260, 1105,

953, 821, 736, 701 cm^À1; HRMS calcd for C₃₇H₅₃BrNaO₈Si: 755.2591

[M+Na]⁺; found: 755.2592.

1

CH₂Cl₂); H NMR (500 MHz, C₆D₆): d=6.41–6.36 (m, 1H), 6.36 (s, 1H),

5.55 (s, 1H), 4.88 (d, J=18.1 Hz, 1H), 4.87 (d, J=11.6 Hz, 1H), 4.52 (t,

J=10.3 Hz, 1H), 4.20 (dd, J=2.3, 13.9 Hz, 1H), 3.82–3.79 (brm, 1H),

3.57 (s, 1H), 3.51 (quin, J=6.1 Hz, 1H), 3.30 (s, 3H), 2.65 (brd, J=

4.8 Hz, 1H), 2.40 (ddd, J=2.0, 11.6, 13.6 Hz, 1H), 1.72–1.67 (m, 1H),

1.60–1.54 (m, 1H), 1.59 (s, 3H), 1.27 (s, 3H), 1.16 (s, 3H), 1.05 (d, J=

6.1 Hz, 3H), 0.95 (t, J=7.9 Hz, 9H), 0.53 ppm (q, J=7.9 Hz, 6H);

¹³C NMR (125 MHz, C₆D₆): d=168.6, 166.5, 152.0, 145.2, 120.4, 111.4,

99.6, 74.0, 72.0, 67.3, 50.7, 45.7, 39.8, 32.0, 22.4, 22.1, 21.0, 20.0, 7.1,

5.2 ppm; IR (neat film): 3408 (br), 3082, 1741, 1718, 1662, 1434, 1369,

1230, 1174, 1155, 1086, 1030 cm^À1; HRMS calcd for C₂₅H₄₂O₇: 482.2700

[MÀH₂O]⁺; found: 482.2698.

Synthesis of compound 48: A mixture of 47 (40 mg, 0.075 mmol) and tri-

methyltin hydroxide (135 mg, 0.75 mmol) in CH₂Cl₂(3.2 mL) in a sealed

vial was heated with a microwave at 1408C for 40 min. The mixture was

cooled to room temperature and directly purified by flash column chro-

matography on silica gel with EtOAc/petroleum ether (40%) followed

by CH₃OH/CH₂Cl₂(6% and 12%) to give 48 (32 mg, 82%). R_f=0.42

(8% CH₃OH/CH₂Cl₂); [a]²_D³=+75.0 (c=0.3 in CH₂Cl₂); ¹H NMR

(500 MHz, C₆D₆): d=6.02 (s, 1H), 5.82 (ddd, J=5.0, 11.0, 17.5 Hz, 1H),

5.51 (dd, J=4.5, 11.3 Hz, 1H), 5.26 (d, J=17.0 Hz, 1H), 5.01 (d, J=

11.0 Hz, 1H), 4.31 (t, J=9.0 Hz, 1H), 3.86–3.82 (m, 1H), 3.74–3.69 (m,

1H), 3.58–3.53 (m, 1H), 3.05 (s, 1H), 3.04 (s, 3H), 2.94 (d, J=13.0 Hz,

1H), 2.35–2.13 (m, 4H), 1.77–1.64 (m, 4H), 1.70 (s, 3H), 1.43 (q, J=

12.5 Hz, 1H), 1.36–1.30 (m, 1H), 1.30–1.23 (m, 1H), 1.10 (s, 3H),

1.04 ppm (s, 3H); ¹³C NMR (125 MHz, C₆D₆): d=170.1, 140.6, 138.7,

114.8, 104.1, 100.6, 77.4, 74.5, 73.9, 65.3, 64.9, 48.3, 42.4, 42.3, 42.1, 41.8,

Synthesis of compound 39: Dimethyltitanocene (75; Petasis reagent) in

THF (0.52m, 5.3 mL, 2.76 mmol) was added to a solution of aldehyde 38

(0.33 g, 0.75 mmol) in THF (1.3 mL) in a pressure tube at room tempera-

ture. The tube was sealed and the reaction was heated at 908C for 2.5 h.

The contents were cooled to room temperature and the solvent was re-

moved in vacuo. The residue was purified by flash column chromatogra-

phy on silica gel with Et₂O/petroleum ether (20%, 30%, and 40%) to

give olefin 39 (0.193 g, 58%). R_f=0.59 (20% EtOAc/petroleum ether);

[a]²_D⁴=+3.3 (c=0.5 in CH₂Cl₂); ¹H NMR (500 MHz, C₆D₆): d=6.43 (dd,

J=10.8, 17.7 Hz, 1H), 6.21 (t, J=1.0 Hz, 1H), 5.77 (s, 1H), 4.87 (dd, J=

Chem. Eur. J. 2011, 17, 9789 – 9805

ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

9801

B. M. Trost et al.

38.9, 36.9, 32.8, 20.8, 20.7, 17.0 ppm; IR (thin film): n˜ =3499 (br), 3077,

1735, 1434, 1365, 1245, 1159, 1129, 1060, 1021 cm^À1

fied by flash column chromatography on silica gel with EtOAc/petroleum

ether (5%, 10%, 15%, 20%, and 30%) to give 64 (23 mg, 51% yield).

R_f=0.63 (20% EtOAc/petroleum ether); [a]²_D³=+12.7 (c=0.3 in

CH₂Cl₂); ¹H NMR (600 MHz, C₆D₆): d=6.33 (s, 1H), 6.14 (d, J=

15.6 Hz, 1H), 6.01 (s, 1H), 5.90–5.80 (m, 2H), 5.55 (td, J=4.8, 11.4 Hz,

2H), 5.51 (s, 1H), 5.44 (dt, J=6.6, 16.2 Hz, 1H), 5.38 (d, J=17.4 Hz,

1H), 5.08 (dd, J=1.2, 15.6 Hz, 1H), 5.02 (d, J=10.8 Hz, 2H), 4.40 (quin,

J=4.8 Hz, 1H), 4.31 (d, J=13.8 Hz, 1H), 4.11 (d, J=13.8 Hz, 1H), 4.07

(t, J=10.8 Hz, 1H), 3.97 (quin, J=6.0 Hz, 1H), 3.88 (dd, J=2.4, 11.4 Hz,

1H), 3.80–3.74 (m, 2H), 3.46 (s, 3H), 3.33 (s, 3H), 3.15 (s, 3H), 2.99 (s,

1H), 2.81 (dd, J=4.2, 16.2 Hz, 1H), 2.60 (dd, J=7.2, 16.2 Hz, 1H), 2.40–

2.36 (m, 2H), 2.23 (dd, J=6.0, 15.6 Hz, 1H), 2.15–2.12 (m, 2H), 2.09–

2.04 (m, 2H), 1.99 (t, J=12.6 Hz, 1H), 1.91–1.76 (m, 4H), 1.71 (s, 3H),

1.63–1.59 (m, 1H), 1.60 (s, 3H), 1.57–1.48 (m, 2H), 1.42 (s, 3H), 1.37 (s,

3H), 1.33 (s, 3H), 1.21 (d, J=6.0 Hz, 3H), 1.20 (s, 3H), 1.10 (s, 3H),

1.07–1.01 (m, 18H), 0.69–0.63 ppm (m, 12H); ¹³CNMR (125 MHz, C₆D₆):

d=172.0, 169.9, 168.6, 166.6, 166.5, 157.7, 152.2, 138.9, 138.8, 136.9, 120.5,

115.1, 114.8, 114.6, 104.5, 99.5, 77.9, 74.9, 74.3, 73.7, 73.6, 68.7, 67.9, 66.3,

66.2, 50.8, 50.6, 48.3, 45.2, 44.2, 44.0, 43.3, 42.4, 39.4, 35.9, 35.0, 33.8, 32.8,

31.7, 30.4, 30.2, 29.3, 23.7, 22.3, 20.93, 20.90, 20.7, 18.6, 16.9, 7.21, 7.19,

5.5, 5.2 ppm; IR (thin film): n˜ =3508, 3077, 1744, 1718, 1655, 1462, 1435,

1368, 1233, 1152, 1112, 1080, 1027, 910, 874, 744, 726 cm^À1; HRMS calcd

for C₆₁H₁₀₆O₁₇Si₂N: 1180.6999 [M+NH₄]⁺; found: 1180.6974.

.

Synthesis of compound 60: A solution of 38 (470 mg, 1.06 mmol) and

CHI₃(2.53 g, 6.38 mmol) in THF (6 mL and 2ꢃ2 mL rinse) was added

through a cannula to a suspension of anhydrous CrCl₂(99.99% from Al-

drich, 2.0 g, 16.26 mmol) in freshly distilled THF (10 mL) at 08C. The ice

bath was removed and the brown suspension was stirred at room temper-

ature in the dark for 20 h before being poured into a brine/H₂O mixture

(1:1). The mixture was extracted with EtOAc. The combined organic ex-

tracts were concentrated in vacuo. The residue was purified by flash

column chromatography on silica gel with EtOAc/petroleum ether (5%,

10%, and 20%) to give vinyl iodide 60 (158 mg, 26%) and recovered al-

dehyde 38 (208 mg; 44% yield of 60 based on recovered starting materi-

al). R_f=0.35 (16% EtOAc/petroleum ether); [a]²_D³=À9.7 (c=0.9 in

CH₂Cl₂); ¹H NMR (500 MHz, C₆D₆): d=7.08 (d, J=15.0 Hz, 1H), 6.10

(s, 1H), 5.82 (s, 1H), 5.72 (d, J=15.0 Hz, 1H), 4.07 (dddd, J=2.5, 2.5,

5.0, 12.5 Hz, 1H), 3.81 (ddd, J=2.0, 8.5, 10.5 Hz, 1H), 3.49–3.43 (m, 2H),

3.36 (s, 3H), 3.26 (s, 3H), 2.49 (dd, J=12.0, 15.5 Hz, 1H), 1.75 (s, 3H),

1.354 (s, 3H), 1.352 (s, 3H), 1.34–1.28 (m, 3H), 1.24–1.18 (m, 2H), 1.07

(d, J=6 Hz, 3H), 1.04 (s, 3H), 0.99 ppm (s, 3H); ¹³C NMR (125 MHz,

C₆D₆): d=168.8, 166.3, 153.8, 153.2, 116.4, 107.9, 102.2, 78.3, 77.2, 73.0,

71.0, 68.7, 50.7, 50.6, 50.4, 38.3, 34.3, 27.5, 23.1, 22.6, 20.9, 17.0 ppm; IR

(neat film): n˜ =3072, 1745, 1719, 1662, 1596, 1433, 1380, 1367, 1227, 1165,

1095, 1042 cm^À1

found: 551.1165.

;

HRMS calcd for C₂₃H₃₅IO₈: 551.1142 [MÀCH₃]⁺;

Synthesis of compounds 66 and 67: The Hoveyda catalyst 65 (4.5 mg,

18 mol%) in benzene (2 mL) was added over 5 min through a syringe to

a solution of 64 (20 mg, 0.018 mmol) in benzene (8 mL) at 508C with N₂

sparging. The contents were stirred at 508C for 30 min before heating the

oil bath to 808C. Stirring was continued for 15 min at 808C. The contents

were then cooled to room temperature. The solvent was removed under

reduced pressure and the residue was purified by preparative TLC with

EtOAc/petroleum ether (16%) to give 66 and 67 (16 mg, 80% combined

yield) as a 1:1 mixture (as shown by integrating the peaks at 3.36 and

3.32 ppm in the ¹H NMR spectrum). HPLC: t_r=5.72 min and 7.07 min

(Alltech–Econosphere silica 3 micro column; 99:1 heptane/isopropanol;

254 nm; 1 mLmin^À1); ¹H NMR (500 MHz, C₆D₆): d=6.34–6.33 (m), 6.09

(s), 6.02–5.97 (m), 5.90–5.84 (m), 5.79–5.75 (m), 5.67–5.62 (m), 5.59–5.53

(m), 5.52 (s), 5.46 (s), 5.45–5.34 (m), 4.67–4.61 (m), 4.52 (t, J=9.0 Hz),

4.41–4.29 (m), 4.20–4.14 (m), 4.08 (d, J=12.0 Hz), 4.04–3.87 (m), 3.82–

3.76 (m), 3.45 (s), 3.43 (s), 3.36 (s), 3.32 (s), 3.19 (s), 3.13 (s), 3.12 (s),

3.02 (s), 2.85 (d, J=4.5 Hz), 2.82 (d, J=4.0 Hz), 2.57–2.46 (m), 2.39–2.32

(m), 2.25–1.67 (m), 1.50 (d, J=6.5 Hz), 1.46 (d, J=10.0 Hz), 1.37 (s), 1.18

(d, J=7.5 Hz), 1.14 (d, J=6.5 Hz), 1.08–0.95 (m), 0.69–0.52 ppm (m);

¹³C NMR (125 MHz, C₆D₆) d=172.0, 170.8, 170.2, 169.9, 168.7, 168.2,

166.7, 166.49, 166.47, 166.40, 158.2, 157.5, 152.0, 151.9, 136.6, 135.8,

132.32, 132.25, 131.8, 131.0, 125.8, 121.1, 120.3, 115.4, 114.6, 104.5, 103.9,

100.3, 99.0, 78.4, 74.8, 74.7, 74.42, 74.39, 74.25, 73.5, 73.4, 69.2, 68.4, 67.8,

66.5, 66.4, 66.2, 66.0, 64.5, 50.79, 50.74, 50.6, 50.4, 48.9, 47.8, 45.5, 45.3,

44.2, 44.0, 43.6, 43.2, 43.0, 42.95, 42.2, 40.4, 39.7, 36.5, 36.2, 35.8, 35.0,

34.3, 33.9, 33.3, 32.0, 31.6, 31.2, 30.9, 30.4, 30.3, 30.2, 28.1, 27.2, 26.1, 25.4,

25.0, 21.6, 21.3, 20.8, 19.4, 18.5, 17.7, 15.6, 7.25, 7.19, 7.10, 6.0, 5.8,

5.2 ppm; IR (thin film): n˜ =3510, 1721, 1650, 1431, 1370, 1232, 1156,

Synthesis of compound 62: tBuLi (1.7 in pentane, 3.44 mL, 5.84 mmol)

was added to cooled Et₂O (6 mL) at À788C and then 5-boromo-1-pen-

tene (0.3 mL, 2.95 mmol) was added dropwise. The resultant yellow–

green solution was stirred at À788C for 40 min and a solution of zinc

chloride (0.41 g, 3.0 mmol, freshly flamed under a slow stream of nitro-

gen) in THF (6 mL) was added through a cannula. The yellow–green

color disappeared upon addition of the zinc chloride. The cold bath was

removed and the contents were warmed to room temperature during

which time it became a cloudy white solution. The reaction was then

stirred at room temperature for 45 min and the solvent removed in

vacuo. The residue was dissolved in THF (10 mL) to give 4-pentenyl zinc

chloride 61 (0.3m in THF). Zinc reagent 61 (5 mL+2 mL THF rinse) was

then added to a mixture of vinyl iodide 60 (157 mg, 0.277 mmol) and [Pd-

ACHTUNGTRENNUNG(PPh₃)₄] (32 mg, 0.03 mmol) at room temperature. The contents were

stirred at room temperature for 7 h, poured into phosphate buffer

(pH 7), and extracted with EtOAc. The combined organic extracts were

concentrated in vacuo. The residue was purified by flash column chroma-

tography on silica gel with EtOAc/petroleum ether (8% and 10%) to

give triene 62 (62 mg, 47%) and a 5:1 mixture of 62 and 39 (27 mg, 68%

combined yield). R_f=0.47 (15% EtOAc/petroleum ether); [a]²_D²=À12.7

1

(c=0.65 in CH₂Cl₂); H NMR (500 MHz, C₆D₆): d=6.20 (s, 1H), 5.97 (d,

J=15.5 Hz, 1H), 5.81 (s, 1H), 5.76 (dddd, J=7.0, 7.0, 10.5, 17.0 Hz, 1H),

5.33 (ddd, J=6.5, 6.5, 13.0 Hz, 1H), 5.04 (dq, J=2.0, 17.5 Hz, 1H), 4.98

(d, J=10.5 Hz, 1H), 4.16 (dddd, J=2.5, 2.5, 5.5, 13.0 Hz, 1H), 3.93 (ddd,

J=2.0, 8.5, 10.5 Hz, 1H), 3.65 (d, J=15.5 Hz, 1H), 3.52–3.46 (m, 1H),

3.35 (s, 3H), 3.34 (s, 3H), 2.55–2.49 (m, 1H), 2.01–1.95 (m, 4H), 1.64 (s,

3H), 1.51–1.30 (m, 4H), 1.29 (s, 3H), 1.11 ppm (d, J=6 Hz, 3H);

¹³C NMR (125 MHz, C₆D₆): d=168.6, 166.4, 153.7, 138.9, 138.0, 125.8,

116.8, 114.8, 107.9, 103.0, 78.5, 77.2, 72.2, 68.6, 51.0, 50.7, 46.4, 38.6, 34.0,

33.8, 32.8, 29.0, 27.52, 27.46, 24.8, 24.2, 20.6, 17.1 ppm; IR (neat film): n˜ =

3077, 1745, 1719, 1663, 1638, 1496, 1377, 1364, 1228, 1155, 1091, 1049,

1023 cm^À1; HRMS calcd for C₂₇H₄₁O₇: 477.2852 [MÀCH₃O]⁺; found:

477.2818.

1113, 1080, 1023, 728, 724 cm^À1

1157.6240 [M+Na]⁺; found: 1157.6104.

; HRMS calcd for C₅₉H₉₈O₁₇Si₂Na:

Synthesis of compounds 68 and 69: A solution of 66 and 67 (7 mg,

0.006 mmol) and PPTS (8 mg, 0.032 mmol) in CH₃OH was stirred at

room temperature for 4 h. The contents were poured into saturated

NaHCO₃and extracted with EtOAc. The combined organic extracts

were dried over Na₂SO₄, filtered, and concentrated. The residue was pu-

rified by preparative TLC (60% EtOAc/PE) to give 68 (2.6 mg) and 69

(2 mg; 82% combined yield).

Synthesis of compound 64: CH₂Cl₂(3.4 mL) and Et₃N (0.042 mL,

0.3 mmol) were added to a mixture of DMAP (1.2 mg, 0.01 mmol) and 2-

methyl-6-nitrobenzoic anhydride (MNBA; 34.4 mg, 0.1 mmol) at room

temperature. The contents were stirred at room temperature for 5 min,

after which a homogeneous light yellow solution had formed. The above

prepared solution (1.5 mL) was added to acid 50 (23.7 mg, 0.039 mmol)

in a V-shaped vial (rinsed with 0.3 mL of CH₂Cl₂). The mixture was

stirred at room temperature for 15 min, and then a solution of alcohol 63

(26.7 mg, 0.047 mmol) was added to the vial through a cannula. The reac-

tion was stirred at room temperature for 16 h and the contents were puri-

Characterization for 68: R_f=0.44 (75% EtOAc/petroleum ether); [a]_D²⁴

=

+72.2 (c=0.53 in CH₂Cl₂); ¹H NMR (600 MHz, C₆D₆): d=6.34 (d, J=

1.8 Hz, 1H), 5.92 (d, J=16.2 Hz, 1H), 5.87 (s, 1H), 5.75 (dd, J=7.2,

10.8 Hz, 1H), 5.47 (s, 1H), 5.46–5.42 (m, 2H), 5.39–5.34 (m, 1H), 5.32

(ddd, J=3.0, 6.0, 10.8 Hz, 1H), 4.49 (t, J=9.0 Hz, 1H), 4.37–4.33 (m,

2H), 4.20 (tt, J=2.4, 11.4 Hz, 1H), 4.11 (dd, J=1.8, 13.8 Hz, 1H), 3.90

(brs, 1H), 3.66–3.62 (m, 1H), 3.60–3.56 (m, 1H), 3.51 (quin, J=6.0 Hz,

1H), 3.46 (s, 3H), 3.33 (s, 3H), 3.17 (brs, 1H), 2.82 (s, 3H), 2.30–2.14 (m,

9802

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Chem. Eur. J. 2011, 17, 9789 – 9805

Synthesis of Bryostatins

FULL PAPER

7H), 2.12–2.07 (m, 1H), 2.03 (d, J=12.6 Hz, 1H), 1.99 (dd, J=3.0,

13.2 Hz, 1H), 1.86 (t, J=13.2 Hz, 1H), 1.76 (s, 3H), 1.72–1.56 (m, 5H),

1.62 (s, 3H), 1.53–1.51 (m, 1H), 1.44–1.40 (m, 1H), 1.41 (s, 3H), 1.37 (s,

3H), 1.15–1.11 (m, 1H), 1.11 (s, 3H), 1.07–1.03 (m, 1H), 1.00 (s, 3H),

0.92 ppm (d, J=6.6 Hz, 3H); ¹³C NMR (125 MHz, C₆D₆): d=170.8,

169.9, 168.5, 166.7, 156.9, 152.2, 136.7, 132.0, 131.3, 129.4, 120.3, 115.4,

104.7, 99.4, 75.3, 74.97, 74.93, 69.9, 66.6, 66.4, 65.8, 50.64, 50.62, 47.9, 45.3,

44.6, 44.2, 42.5, 40.6, 39.0, 36.8, 36.3, 31.7, 31.2, 30.9, 28.5, 26.7, 25.2, 21.5,

20.9, 20.8, 20.6, 19.5, 16.3 ppm; IR (film): n˜ =3482, 1718, 1652, 1434,

1365, 1234, 1155, 1025, 983, 872 cm^À1; HRMS calcd for C₄₇H₇₀O₁₇Na:

929.4513 [M+Na]⁺; found: 929.4535.

1H), 3.76 (m, 1H), 3.33 (s, 2H), 2.91 (dd, J=6.0, 17 Hz, 1H), 2.53 (dd,

J=7.0, 17 Hz, 1H), 2.41 (dt, J=2.0, 13.5 Hz, 1H), 2.24 (d, J=13 Hz,

1H), 2.03 (s, 3H), 2.02–1.93 (2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.02 (s, 3H),

1.01 (s, 3H), 0.10 ppm (s, 9H); ¹³C NMR (CDCl₃, 125 MHz): d=210.9,

171.1, 152.4, 138.2, 129.9, 124.3, 79.0, 75.0, 71.7, 70.0, 47.8, 45.2, 44.1, 40.7,

38.5, 24.1, 23.8, 21.7, 21.67, 21.1, 0.5 ppm; IR (film): n˜ =3473, 2956, 1747,

1702, 1624, 1472, 1375, 1247, 1140, 1046, 974, 840 cm^À1; HRMS calcd for

C₂₃H₄₀O₅Si: 447.2543 [M+Na]⁺; found: 447.2545.

Synthesis of compound 71: Dry CH₂Cl₂(0.4 mL) was added to a mixture

of [AuACTHNUGTRENUNG(PPh₃)₃Cl] (10.2 mg, 0.020 mmol) and AgSbF₆(7.0 mg,

0.020 mmol) at room temperature under N₂. The resulting mixture was

stirred in the dark for 15 min and a purple precipitate was formed. The

supernatant solution (0.030 mL, ca. 0.0015 mmol, 20 mol%) was added to

a mixture of compound 82 (4.5 mg, 0.0071 mmol) and NaHCO₃(2.0 mg,

0.021 mmol) in CH₃CN (0.10 mL) at 08C under N₂. The resulting reaction

mixture was stirred vigorously in the dark at room temperature for

4 days. The suspension was poured into buffer (pH 7.0), and the mixture

was extracted with ethyl acetate four times and the combined organic ex-

tracts were dried over Na₂SO₄. The dihydropyran products were isolated

by silica gel flash column chromatography (20%, 30%, 40% then 50%

ethyl acetate/petroleum ether) as a light-yellow oil (2.4 mg, 53%, ratio of

Characterization for 69: R_f=0.63 (75% EtOAc/petroleum ether); [a]_D²³

=

+36.6 (c=0.24 in CH₂Cl₂); 1H NMR (600 MHz, C₆D₆): d=6.49 (d, J=

1.2 Hz, 1H), 5.97 (d, J=15.6 Hz, 1H), 5.84–5.80 (m, 2H), 5.73 (s, 1H),

5.55 (s, 1H), 5.56–5.48 (m, 2H), 5.23 (ddd, J=1.8, 6.6, 11.4 Hz, 1H),

4.30–4.24 (m, 3H), 4.13 (dd, J=2.4, 13.8 Hz, 1H), 3.94 (d, J=9.6 Hz,

1H), 3.83–3.71 (m, 3H), 3.52 (quin, J=6.6 Hz, 1H), 3.46 (brs, 1H), 3.39

(s, 3H), 3.26 (s, 3H), 3.09 (s, 3H), 2.35–2.30 (m, 1H), 2.20 (dd, J=7.8,

16.8 Hz, 1H), 2.14–2.10 (m, 2H), 2.09–1.98 (m, 4H), 1.92 (dd, J=3.0,

13.2 Hz, 1H), 1.86 (d, J=13.8 Hz, 1H), 1.74 (s, 3H), 1.71–1.67 (m, 1H),

1.62 (s, 3H), 1.61–1.53 (m, 5H), 1.48–1.43 (m, 1H), 1.42 (s, 3H), 1.27 (s,

3H), 1.23–1.19 (m, 1H), 1.14 (s, 3H), 1.08–1.04 (m, 1H), 1.05 (s, 3H),

0.97 ppm (d, J=6.6 Hz, 3H); IR (film): n˜ =3454, 1718, 1648, 1434, 1369,

1234, 1155, 1030, 974 cm^À1, HRMS calcd for C₄₇H₇₀O₁₇Na: 929.4513

[M+Na]⁺; found: 929.4597.

1

71/83/84, 5.1:1:1.3, based on the integration of H NMR peaks at d=5.34,

6.80, and 6.05 ppm, respectively). R_f=0.60 (40% ethyl acetate/petroleum

ether); [a]²_D³=16.1 (c=0.24 in CH₂Cl₂); see the Supporting Information

for the NMR data; IR (film): n˜ =34854 (br), 2953, 2931, 1708, 1610,

1379, 1226, 1153, 1094, 840 cm^À1; HRMS calcd for C₃₅H₅₆O₈Si: 655.3642

[M+Na]⁺; found: 655.3636.

Synthesis of compound (R)-70: Dess–Martin periodinane (6.95 g,

16.4 mmol) was added to a mixture of rac-70 (5.49 g, 15.6 mmol) and

NaHCO₃(4.2 g, 49.9 mmol) in CH₂Cl₂(66 mL) at 08C. The reaction was

stirred at RT for 30 min, before being quenched with saturated Na₂S₂O₃

and saturated NaHCO₃. The mixture was extracted with ethyl acetate

(3ꢃ150 mL), and the combined organic extracts were dried over Na₂SO₄.

The solvent was removed, and the crude ketone was dissolved with

CH₂Cl₂(112 mL). This solution was cooled to À788C, and (S)-2-methyl-

CBS-oxazaborolidine (0.78 mL, 1m in toluene) was added. The reaction

was stirred at À788C for 20 min before catechol borane (2.8 g,

23.4 mmol) was added. The resulting solution was stirred at À788C for

4 h, and then warmed to 08C. The reaction was stirred at 08C for 1 h,

before being quenched with NaH₂PO₄(1m). The mixture was extracted

with ethyl acetate and the combined organic extracts were dried over

Na₂SO₄. Compound (R)-70 was purified by silica gel flash column chro-

matography (5% then 10% Et₂O/petroleum ether) to give a colorless oil

(4.9 g, 90% over two steps, 90% ee, determined by chiral HPLC, OD

205 nm, 0.8 mLmin^À1, 99.5:0.5 heptane/iPrOH, t_major=7.9, t_minor=7.2 min).

R_f=0.35 (10% Et₂O/petroleum ether, 1:9 v/v); [a]²_D⁰=+4.86 (c=0.64 in

CH₂Cl₂); ¹H NMR (CDCl₃, 500 MHz): d=5.72 (dd, J=1.0, 20 Hz, 1H),

5.47 (dd, J=8.0, 20 Hz, 1H), 4.20 (m, 1H), 3.28 (s, 2H), 2.45 (dd, J=2.5,

7.5 Hz, 2H), 2.02 (brs, 1H), 0.97 (s, 3H), 0.88 (s, 12H), 0.15 (s, 9H),

0.00 ppm (s, 6H); ¹³C NMR (CDCl₃, 125 MHz): d=140.1, 128.0, 103.0,

87.5, 71.7, 71.1, 38.2, 29.4, 26.0, 24.0, 18.4, 0.2, À5.4 ppm; IR (film): n˜ =

3336 (br), 2958, 2858, 2178, 1464, 1250, 1099, 843 cm^À1; HRMS calcd for

C₁₅H₂₉O₂Si₂+tBu: 297.1706 [MÀtBu]⁺; found: 297.1684.

Acknowledgements

We thank the National Institutes of Health (GM13598) and NSF for

their generous support of our programs. H.Y. thanks Amgen and Bristol–

Myers Squibb for fellowships. G.D. thanks Stanford University for a

Graduate Fellowship. Mass spectra were provided by the Mass Spectrom-

etry Regional Center of the University of California, San Francisco, sup-

ported by the NIH Division of Research Resources. Palladium and ruthe-

nium salts were generously supplied by Johnson–Matthey.

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⁺A[PF₆]^À(1.4 mg,

Synthesis of compound 79: [CpRuACTHNUTRGENNUG(CH₃CN)₃] CHTUGNTRENNUGN

0.0032 mmol) was added to a solution of compound (R)-70 (11.2 mg,

0.032 mmol) and compound 73 (17.4 mg, 0.094 mmol) in CH₂Cl₂(0.5 mL)

at 08C. The resulting yellow solution was stirred at room temperature for

12 h. The tetrahydropyran was isolated by silica gel flash column chroma-

tography as a mixture contaminated with (R)-70. THF (0.4 mL) was

added to this mixture and the resulting solution was cooled to 08C

before HF·pyridine (5 drops) was added. The reaction mixture was

stirred vigorously for 5 h at RT, before being quenched with saturated

aqueous NaHCO₃. The mixture was extracted with ethyl acetate (3ꢃ

20 mL), and the combined organic extracts were dried over Na₂SO₄.

Compound 79 was purified by silica gel flash column chromatography

(4:1 then 3:2 petroleum ether/ethyl acetate) to give a colorless oil

(8.3 mg, 62%, d.r. 6.7:1, d_major=2.91, d_minor=2.80 ppm). R_f=0.35 (40%

ethyl acetate in petroleum ether); [a]²_D³=À1.5 (c=0.40 in CH₂Cl₂);

¹H NMR (CDCl₃, 500 MHz): d=5.60 (dd, J=1.0, 16 Hz, 1H), 5.48 (dd,

J=5.5, 16 Hz, 1H), 5.29 (s, 1H), 4.10 (dd, J=11, 24 Hz, 2H), 3.88 (m,

Chem. Eur. J. 2011, 17, 9789 – 9805

ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

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ketone resonance at d=212.7 ppm in the ¹³C NMR spectrum

(125 MHz, C₆D₆) for 31, and changes in the IR spectrum (two peaks

[39] Large quantities of 74 are readily available in two steps from com-

mercially available, inexpensive 2,2-dimethylpropane-1,3-diol, see

reference [4]. Small quantities of 74 are available from SALOR.

[40] This was adapted from a procedure reported earlier by Wender

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9804

www.chemeurj.org

ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Chem. Eur. J. 2011, 17, 9789 – 9805

Synthesis of Bryostatins

FULL PAPER

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Received: October 11, 2010

Revised: April 26, 2011

Published online: July 21, 2011

[46] Formation of some uncyclized product was observed.

Chem. Eur. J. 2011, 17, 9789 – 9805

ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemeurj.org

9805

Article Doi

Total syntheses of bryostatins: Synthesis of two ring-expanded bryostatin analogues and the development of a new-generation strategy to access the C7-C27 fragment

DOI: 10.1002/chem.201002932

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