Catalytic Enantioselective Allylation of Acetylenic Aldehydes by Chiral Phosphoric Acid/Transition Metal Cooperative Catalysis: Formal Synthesis of Fostriecin

Formal Synthesis of Fostriecin

Letter

Catalytic Enantioselective Allylation of Acetylenic Aldehydes by

Chiral Phosphoric Acid/Transition Metal Cooperative Catalysis:

Shigenobu Umemiya and Masahiro Terada*

Cite This: Org. Lett. 2021, 23, 3767 −3771

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ABSTRACT: An enantioselective allylation of silyl-substituted

acetylenic aldehydes by chiral phosphoric acid (CPA)/transition

metal cooperative catalysis was developed. Enantioenriched

homoallylic propargyl alcohols were obtained in good yields with

excellent enantioselectivities (>99% ee) under mild conditions.

Moreover, the shortest formal synthesis of fostriecin was achieved

by the present enantioselective allylation protocol as the key step.

The known intermediate of fostriecin reported by McDonald and

co-worker was synthesized in only nine steps in 39% total yield.

ptically active propargyl alcohols are useful building

blocks for the synthesis of natural products and

intermediate (Figure 1b, highlighted in red). The development

of reactions to produce homoallylic propargyl alcohol A in an

enantioenriched form is an important task in synthetic organic

chemistry because an eﬃcient supply of this intermediate

would facilitate the syntheses of complex molecules.

pharmaceuticals, as the alkyne moiety can be converted into

various functional groups. In particular, propargyl alcohol A

synthesized by the asymmetric allylation of silyl-substituted

acetylenic aldehydes is a valuable synthetic intermediate for the

Asymmetric allylation reactions using stoichiometric chiral

reagents generated from chiral ligands and allylic metal species

are widely utilized in the synthesis of natural products.

Although these reactions are reliable, as they aﬀord the desired

product with high enantioselectivity, these reactions always

require expensive chiral sources stoichiometrically and the use

of water-sensitive reagents, thereby limiting utility and

increasing diﬃculty in handling. The catalytic enantioselective

allylation reactions of acetylenic aldehydes have attracted much

construction of complex molecules (Figure 1a). Indeed,

numerous total syntheses of natural products have been

reported using enantioenriched alcohol A as the key

attention in terms of green chemistry. Hall and co-workers

reported an enantioselective allylation of TMS-substituted

acetylenic aldehyde in the presence of a chiral catalyst

generated by SnCl and chiral diol F-vivol-8 (Scheme 1, eq

). Carter and co-workers achieved a total synthesis of

mandelalide A by using the Keck allylation protocol that

provides enantioenriched TMS-substituted propargyl alcohols

(

Scheme 1, eq 2). Although these two reactions are attractive

synthetic tools, there is still room for improvement regarding

enantioselectivity.

Received: April 5, 2021

Published: April 23, 2021

Figure 1. Synthetic utility of enantioenriched silyl-substituted

propargyl alcohols.

2021 American Chemical Society

767

Org. Lett. 2021, 23, 3767−3771

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Letter

Scheme 1. Catalytic Enantioselective Allylation of Silyl-

Substituted Acetylenic Aldehydes

Table 1. Optimization of Reaction Conditions

entry

CPA

additives

none

CuBr

CuI

yield/%

ee/%

(R)-4

(R)-5

(R)-6

(R)-5

−26

−4

CuTC

[CuOTf] ·PhMe

AgOBz

Bi(OAc)₃

Rh (OAc)₄

PtCl (PPh )

3 2

none

>99

CuBr

none

CuBr

>99

Unless otherwise noted, all reactions were carried out using 0.20

mmol of 1, 0.24 mmol of 2, and 0.010 mmol of CPA catalyst (5 mol

) in toluene. Isolated yield. Enantiomeric excess was determined

d e

by chiral stationary phase HPLC analysis. (R)-3 was obtained. (S)-3

was obtained. The reaction was performed at −60 °C for 24 h.

Aldehyde 7 was employed.

Recently, Krische and co-workers reported an excellent

method that generated TIPS-substituted homoallylic propargyl

alcohols via an enantioselective Ir-catalyzed reductive coupling

(

Scheme 1, eq 3). They successfully obtained the desired

allylation product in good yield with excellent enantioselectiv-

ity from an acetylenic aldehyde and an allyl acetate in the

presence of an Ir catalyst they themselves developed. This is

one of the most useful allylation reactions in modern organic

synthesis. However, the TMS-substituted acetylenic aldehyde

decomposed under the reaction conditions. A TMS-substituted

triple bond is a convenient functional group for the synthesis of

complex molecules because the TMS group can be easily and

selectively deprotected under mild conditions, in contrast to

common silyl protective groups, such as TES and TBS, of

substituted acetylenic aldehyde, giving allylation product (S)-

3 in excellent yield albeit with moderate enantioselectivity.

series of transition metals that are allowed to coordinate to the

triple bond of aldehyde 1 were evaluated, as shown in Table 1,

entries 3 to 10. Fortunately, when CuBr was used as the

additive, enantioselectivity was improved from 73% ee to 86%

ee. A similar cooperative eﬀect was observed when CuI was

used, forming the desired product with good enantioselectivity

(entry 4). Interestingly, no positive eﬀect was observed when

alcohols, which remain intact. Herein we report an

CuTC or [CuOTf] ·PhMe was used, aﬀording (S)-3 with only

enantioselective allylation of TMS-substituted acetylenic

aldehyde by a chiral phosphoric acid (CPA)/transition metal

cooperative catalyst system (Scheme 1, eq 4) and a concise

formal synthesis of fostriecin.

36% ee or 74% ee, respectively (entries 5 and 6). Experiments

performed with Ag(I), Bi(III), Rh(II), and Pt(II) additives

revealed that these metal species have no cooperative eﬀect in

the present enantioselective allylation reaction (entries 7 to

10). SPINOL-type catalyst (R)-6 (Ar = 2,4,6-Cy -C H ) gave a

To determine the optimum conditions for the enantiose-

lective allylation of acetylenic aldehyde, TIPS-substituted

acetylenic aldehyde 1 was selected as the model substrate.

Aldehyde 1 was reacted with allylboronic acid pinacol ester 2

immediately at 0 °C in the presence of 1,1′-bi-2-naphthol

product with lower enantioselectivity than (R)-5 (entry 11 vs

entry 2). Finally, the reaction was performed at −60 °C in the

CPA/CuBr cooperative catalyst system using (R)-5 to furnish

the product in 98% yield with excellent enantioselectivity

(>99% ee) (entry 12). In the case of no additives, a lower

enantioselectivity (96% ee) was observed than that of the

cooperative system (entry 13 vs 12). These results clearly

reveal that the combination of (R)-5 and CuBr is eﬀective to

enhance the enantioselectivity in the present allylation reaction

6,7

(

BINOL)-derived CPA (R)-4 (Ar = 2,4,6- Pr -C H ), which

3 6 2

was reported as the best catalyst in Antilla’s allylation

conditions. Substrate 1 was consumed within 1 min to aﬀord

desired product (R)-3 in excellent yield but with low

enantioselectivity (Table 1, entry 1). Next, 1,1′-spirobiin-

dane-7,7′-diol (SPINOL)-derived CPA (R)-5 (Ar = 2,4,6- Pr -

even under low temperature conditions. With the optimal

C H ) was employed for the reaction, as Hu and co-workers

conditions in hand, TMS-substituted acetylenic aldehyde 7 was

employed in the reaction with allylboronic acid 2 under these

conditions. As expected, the desired product was obtained in

92% yield with >99% ee without any detrimental eﬀect such as

decomposition of substrate (entry 14).

reported that catalyst 5 is very eﬀective for the enantioselective

allylation of aldehydes including Ph- and alkyl-substituted

acetylenic aldehyde. The catalyst was also found to be

eﬀective for the enantioselective allylation of the TIPS-

768

Org. Lett. 2021, 23, 3767−3771

Organic Letters

considered to be an important class of compounds that

Letter

Previously, an enantio- and diastereoselective aldol reaction

of acetylenic aldehydes catalyzed by the organocatalyst−

transition metal−Brønsted acid cooperative system was

possess potent biological activities against leukemia, lung,

breast, and ovarian cancer cells. Fostriecin shows potent and

selective inhibition of certain serine/threonine protein

reported by Palomo’s group. They concluded that the

improvement of diastereoselectivity in the asymmetric aldol

reaction would be explained by the steric inﬂation of the alkyne

moiety by virtue of metal−alkyne association. In our case,

CuBr would associate with the alkyne moiety of the aldehyde,

phosphatases, such as PP2A (IC₅₀1.5 nM) and PP4 (IC₅₀3

nM). Unfortunately, the use of fostriecin as a drug has been

hindered by its chemical instability and the inconsistent purity

of the compound derived from natural sources. Thomasi and

co-workers reported the isolation of two new phosphorylated

resulting in increased steric hindrance. Hence, the alkyne

substituent tends to occupy the equatorial position in the six-

natural products, phosdiecins A and B. Krische and co-

workers achieved the ﬁrst total synthesis of phosdiecin A via an

enantioselective carbonyl reductive coupling to validate the

initial structure proposed by Thomasi and to explore the

membered transition state to enhance the enantioselectivity,

because the transition state giving the minor enantiomer would

be destabilized due to steric congestion.

Next, the utility of the allylation product derived from TMS-

substituted acetylenic aldehyde 7 is illustrated by selective

deprotection of the silyl group under basic or acidic conditions

biological properties of this natural product. Hence, the

development of synthetic strategies for fostriecin and related

compounds is valuable, as it would provide the desired product

and new analogs in good purity and suﬃcient quantity.

In 2009, McDonald and co-worker reported an elegant total

(Scheme 2). The TMS group on the triple bond could be

synthesis of fostriecin via a convergent synthetic strategy. We

imagined that McDonald’s intermediate 8 would be a key

structure to provide fostriecin in a short and eﬃcient manner

Scheme 2. Selective Deprotection of Silyl Groups

(

Figure 2). Indeed, 8 can be converted into the ﬁnal product in

only seven steps. Our synthetic plan is shown in Figure 2. The

homoallylic propargyl alcohol moiety embedded in 8 would be

synthesized via an enantioselective allylation of boronate 2

with aldehyde 7 in the CPA/CuBr cooperative catalyst system,

in which enantiomeric (S)-5 was employed to construct the

stereochemistry at C11.

The present enantioselective allylation reaction of TMS-

substituted acetylenic aldehyde 7 with allylboronic ester 2 was

conducted under the optimal conditions to give desired

homoallylic alcohol (R)-9 with excellent enantioselectivity

removed selectively in the presence of the secondary TBS ether

under mild basic conditions (Scheme 2, eq 5). On the other

hand, the secondary TBS ether was converted into the

corresponding alcohol under the 10-camphorsulfonic acid

(

Scheme 3). It is noteworthy that the allylation smoothly

(

CSA)/MeOH condition without loss of the TMS group

Scheme 3. Enantioselective Synthesis of Intermediate 14

attached to the triple bond terminus (Scheme 2, eq 6). During

the course of these desilylation reactions, the enantiomeric

purity remained unchanged. These selective removal

conditions highlight that the TMS-substituted propargyl

alcohol should be useful in the late-stage functionalization of

complex molecules.

Subsequent to the development of a highly enantioselective

allylation of TMS-substituted acetylenic aldehyde 7, we

embarked on an investigation of a concise and eﬃcient

synthesis of fostriecin (CI-920), a phosphorylated polyketide

(

Figure 2). Fostriecin is a metabolite produced by

Streptomyces pulveraceus isolated from a Brazilian soil

sample.

Fostriecin and related natural products are

proceeded in the presence of only 2 mol % of (S)-5 and 4 mol

of CuBr. The successive TBS protection of the secondary

alcohol gave TBS ether 10 in 86% yield in two steps. Oleﬁn

cross metathesis catalyzed by Grubbs-II catalyst between 10

and methacrolein aﬀorded corresponding α,β-unsaturated

aldehyde 11 in 65% yield with recovery of substrate 10 in

20% yield (78% brsm). The obtained aldehyde was subjected

to the Horner−Wadsworth−Emmons reaction to furnish

α,β−γ,δ-unsaturated ester 12 in 95% yield. Reduction of

ester 12 using DIBAL-H followed by oxidation of generated

Figure 2. Synthetic plan of fostriecin via enantioselective allylation.

769

Org. Lett. 2021, 23, 3767−3771

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Complete contact information is available at:

Letter

allylic alcohol 13 by MnO delivered α,β−γ,δ-unsaturated

AUTHOR INFORMATION

■

aldehyde 14 in 72% yield in two steps.

Corresponding Author

Next, aldehyde 14 was treated with allylboronic acid pinacol

ester 2 in the presence of (S)-5 to give allylation product 15 in

Masahiro Terada − Department of Chemistry, Graduate

School of Science, Tohoku University, Sendai 980-8578,

Japan; orcid.org/0000-0002-0554-8652;

Email: mterada@tohoku.ac.jp

,25

3% yield with excellent diastereoselectivity (Scheme 4).

Scheme 4. Formal Synthesis of Fostriecin

Author

Shigenobu Umemiya − Department of Chemistry, Graduate

School of Science, Tohoku University, Sendai 980-8578,

Japan; orcid.org/0000-0002-1793-856X

https://pubs.acs.org/10.1021/acs.orglett.1c01166

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was partially supported by a Grant-in-Aid for

Scientiﬁc Research on Innovative Areas “Hybrid Catalysis for

Enabling Molecular Synthesis on Demand” (JP17H06447)

from MEXT, Japan (M.T.) and a Grant-in-Aid for Young

Scientists (JP20K15270) from JSPS, Japan (S.U.).

The newly generated alcohol was protected with acryloyl

chloride followed by ring closing metathesis using Grubbs-II

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■

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ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.1c01166.

Experimental procedure and characterization data

(PDF )

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25) The diastereoselectivity of the allylation product was

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presence of (R)-5 with CuBr as well as without CuBr to give almost

the same enantioselectivity. This result indicates that CuBr does not

aﬀect the enantioselectivity of the allylation reaction using p-

tolualdehyde which does not possess an alkyne moiety. Consequently,

it is considered that CuBr does not coordinate to the oxygen atom of

chiral phosphoric acid, boron reagent, or aldehydes. See the

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about the role of CuBr.

(

determined by H NMR measurement after converting 15 into the

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15) The enantiomeric excess of the desilylation products was

determined by chiral column HPLC after converting the products

into known compound 3. See Supporting Information for details.

(

16) For isolation of Fostriecin, see: (a) Tunac, J. B.; Graham, B. D.;

Dobson, W. E. Novel Antitumor Agents CI-920, PD 113, 270 and PD

13, 271 I. Taxonomy, Fermentation and Biological Properties. J.

771