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. Author manuscript; available in PMC: 2013 Mar 2.
Published in final edited form as: Org Lett. 2012 Feb 22;14(5):1322–1325. doi: 10.1021/ol300200m

Transition-Metal Catalyzed Synthesis of Aspergillide B: An Alkyne Addition Strategy

Barry M Trost 1,✉, Mark J Bartlett 1
PMCID: PMC3407809  NIHMSID: NIHMS359447  PMID: 22356535

Abstract

graphic file with name nihms359447f8.jpg

A catalytic enantioselective formal total synthesis of aspergillide B is reported. This linchpin synthesis was enabled by the development of new conditions for Zn-ProPhenol catalyzed asymmetric alkyne addition. This reaction was used in conjunction with ruthenium-catalyzed trans-hydrosilylation to affect the rapid construction of a late-stage synthetic intermediate of aspergillide B to complete a formal synthesis of aspergillide B in a highly efficient manner.

The aspergillides are a family of bioactive natural products originally derived from the marine fungus aspergillus ostianus.1 Aspergillide A, B and C, shown in Figure 1, share common macrolactone and pyran motifs but differ with respect to the stereochemistry at C3 and the unsaturation present in the pyran ring.2

Figure 1.

Figure 1

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The Aspergillide Family of Natural Products.

These compounds exhibit cytotoxicity towards a number of different cancer cell lines including, HL-60 (human promyelocytic leukemia), MDA-MB-231 (human breast carcinoma) and HT1080 (human fibrosarcoma) cell lines.3 These properties, along with the challenging structural features present, have motivated a number of groups to pursue the synthesis of aspergillides A–C.4,5 Our interest in the aspergillides stems from the potential application of our zinc-catalyzed asymmetric alkynylation and ruthenium-catalyzed trans-hydrosilylation-desilylation methodologies (Scheme 1) to provide access to two chiral allylic alcohol moieties that would ultimately lead to an efficient synthesis of aspergillide B.

Scheme 1.

Scheme 1

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Sequential Application of Asymmetric Alkynylation and Ru-Catalyzed Hydrosilylation.

This alkyne-based strategy envisioned to synthesize aspergillide B is outlined in Scheme 2. Retrosynthetic disconnection of the macrolactone leads back to diester 6, a late-stage intermediate used in a previous synthesis.4d Diastereoselective formation of the pyran ring was expected to arise from intramolecular oxy-Michael addition of the C8 hydroxyl group and the pendant α,β-unsaturated ester in 7. It was anticipated that the two chiral allylic alcohol moieties could be prepared using ruthenium-catalyzed hydrosilylation of the corresponding propargylic alcohols. Lastly, asymmetric alkyne addition would be used to access the aforementioned propargylic alcohols via separate addition of (S)-hept-6-yn-2-yl benzoate ((−)-9) and methyl propiolate (10) to each end of a butane dialdehyde equivalent 11 which is serving as a linchpin.

Scheme 2.

Scheme 2

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Retrosynthetic Analysis of Aspergillide B.

The invention of the ProPhenol ligand 4 has led to the development of a number of catalytic enantioselective transformations, including a direct aldol reaction.6 The ProPhenol ligand also facilitates the addition of a variety of alkynes to aryl and α,β-unsaturated aldehydes in excellent yield and enantioselectivity.7 Typically, these reactions require the use of 2.8 equivalents of alkyne and 2.95 equivalents of Me2Zn to obtain high levels of enantioselectivity.8 At the outset, we recognized that the use of a super stoichiometric amount of alkyne (−)-9 was particularly inefficient, given that this chiral intermediate is prepared using a multistep synthesis. Consequently, the use of a stoichiometric quantity of alkyne in ProPhenol-catalyzed alkynylations was investigated.

Using 1.2 equivalents of alkyne (±)-9,9 alkynylation of aliphatic aldehyde 11a resulted in only 22% yield of the desired product in 54% ee (Entry 1, Table 1).10 The traditional super stoichiometric conditions provided only modest improvements in yield and enantioselectivity (Entry 2 & 3). Low yields of the desired product 12a were primarily a consequence of competing aldol reactions.11 The predominance of this side reaction led to the hypothesis that incomplete formation of the alkynylzinc nucleophile may be leaving significant amounts of basic dimethylzinc in the reaction mixture. Consequently, we examined a number of additives and methods that have been shown to facilitate the formation of alkynylzinc nucleophiles.12 The use of N-methylimidazole (NMI), DMSO and DMF all resulted in lower yields of the desired product, 12a (Entries 4–6). Increasing the alkyne/Me2Zn/(S,S)-4 premix time and the catalyst loading provided improved yields of propargylic alcohol 12b (Entry 7 & 8). While the excess alkyne could be recovered quantitatively, this inefficiency along with the moderate yield and enantioselectivity prompted the investigation of the analogous unsaturated aldehyde, 11c. The ProPhenol-catalyzed addition of (±)-9 to 11c provided a much improved 84% yield and 95% ee (Entry 9). Reducing the stoichiometry of the alkyne to either 1.2 or 1.0 equivalents provided lower yield, although excellent ee was maintained in both cases (Entry 10 & 11). The moderate yield was presumably a consequence of poor reactivity and a solution to this problem was found in the use of fumaraldehyde dimethyl acetal (11d). The inductive effects of the dimethyl acetal create a more electrophilic aldehyde, and as a result, the desired propargylic alcohol 12d was obtained in 82% yield (Entry 12).

Table 1.

Optimization of Alkyne Addition.

graphic file with name nihms359447t1.jpg
entry aldehyde X/Y conditionsa yieldb eec
1 11a 1.2/1.5 20 mol% TPPO 22% 54%
2 11a 2.8/2.95 20 mol% TPPO 39% 62% (57%)d
3 11a 2.8/2.95 - 35% 45%
4 11a 1.2/1.3 30 mol% NMI 11% 72%
5 11a 1.2/1.4 4 eq. DMSO 4% 14%
6 11a 1.2/1.4 4 eq. DMF 10% 17%
7 11b 2.8/2.95 20 mol% TPPO, 24 h alkyne premix 58% 50%d
8 11b 2.8/2.95 40 mol% TPPO, 20 mol% ProPhenol, 24 h alkyne premix 69% 67%d
9 11c 2.8/2.95 c = 0.35 M 84% 95%
10 11c 1.2/1.5 20 mol% TPPO 56% 95%
11 11c 1.0/1.3 20 mol% TPPO 54% 95%
12 11d 1.0/1.3 20 mol% TPPOe 82% 90%
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All reactions were run on 0.1625 mmol scale using the standard ProPhenol alkynylation procedure.

a

All reactions were run at a concentration of 0.5 M with respect to alkyne unless otherwise noted.

b

Isolated yield.

c

Enantiomeric excess determined by chiral HPLC analysis.

d

Enantiomeric excess determined by 1H-NMR analysis of the corresponding (S)-methyl mandelate.

e

Reaction performed with (−)-9 on a 0.45 mmol scale.

TPPO = triphenylphosphine oxide, NMI = N-methylimidazole

The results in Table 1 provide a number of new insights into the proposed reaction mechanism for ProPhenol-catalyzed alkyne addition (Scheme 3). Incomplete formation of the alkynylzinc nucleophile was confirmed by 1H-NMR analysis of a standard premix with 1-octyne, Me2Zn and (S,S)-4 in toluene-d8.13 Despite the entropically favored release of methane gas, deprotonation of the terminal alkyne was not observed in the absence of ProPhenol ligand. The presence of significant amounts of dimethylzinc in the reaction mixture appears to have little effect on the outcome of alkyne additions to α,β-unsaturated aldehydes.14 However, enolizable aldehydes suffer from undesired aldol side reactions and typically only produce moderate yields of the desired propargylic alcohol. Methyl propiolate, a more acidic alkyne, has been shown to give significantly higher yields in additions to enolizable aldehydes under the standard conditions.15

Scheme 3.

Scheme 3

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Proposed Mechanism for ProPhenol-Catalyzed Alkyne Addition.

The synthesis of aspergillide B commenced with the preparation of chiral alkyne (−)-9 (Scheme 4),16 taking advantage of the Noyori asymmetric hydrogenation17 of ynone 14 and the alkyne zipper reaction of 16 to 17.

Scheme 4.

Scheme 4

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Preparation of Alkyne (−)-9.

Alkynylation of fumaraldehyde dimethyl acetal (11d)18 using just 1 equivalent of alkyne (−)-9 and 10 mol% of the (S,S)-ProPhenol Ligand provided 12d in 82% yield and 90% de (Scheme 5).19 Alkyne trans-hydrosilylation using benzyldimethylsilane (BDMS-H) and 2 mol% of Cp*Ru(CH3CN)3PF6, provided vinyl silane 18, regioselectively.20 Hydrosilylation of propargylic alcohols under these conditions typically results in silylation at the β-position. The dramatic reversal in regioselectivity is thought to be a consequence of a coordinative interaction between ruthenium and the electron poor alkene. The presence of the silicon on one of the double bonds provides a key for their differentiation towards hydrogenation. The disubstituted olefin of allylic alcohol 18 was then chemoselectively hydrogenated using Wilkinson's catalyst and silyl protected to give 19.21 Hydrolysis of the dimethyl acetal was performed under mild acid-catalyzed conditions, providing the desired aldehyde 20 for the second alkyne addition.

Scheme 5.

Scheme 5

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First Alkyne Addition in the Synthesis of Aspergillide B.

ProPhenol-catalyzed addition of methyl propiolate (10) to aldehyde 20 provided the desired propargylic alcohol 21 in 71% yield as a 5.2:1 mixture of diastereomers (Scheme 6).22 Protection of the propargylic alcohol was followed by a chemoselective alkyne reduction using our hydrosilylation/protodesilylation protocol for formation of E-double bonds.23 The basic reaction conditions used for this transformation resulted in spontaneous intramolecular oxy-Michael addition. Consequently, the desired 2,6-anti tetrahydropyran 6 was isolated in 38% yield (77% brsm) over 2 steps.24 Compound 6 can be transformed into aspergillide B in 3 additional steps.4d

Scheme 6.

Scheme 6

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Formal Synthesis of Aspergillide B.

In summary, an enantioselective formal total synthesis of aspergillide B has been accomplished using sequential Zn-catalyzed alkyne addition and Ru-catalyzed trans-hydrosilylation-desilylation to access E-alkenes. The hydrosilylation – desilylation protocol not only provides the E geometry but also allows chemoselective differentiation of the two double bonds in a susequent hydrogenation step. The development of new conditions for the Zn-ProPhenol catalyzed alkynylation has resulted in excellent yield and enantioselectivity using just a single equivalent of alkyne. Further research into the use of enolizable aldehydes in this methodology is currently underway.

Supplementary Material

1_si_001

Acknowledgment

We thank the National Science Foundation (CHE-0846427) and the National Institutes of Health (GM-33049) for their generous support of our programs. M.J.B thanks Victoria University of Wellington for the provision of a Ph.D. scholarship. We also thank Unicore for a generous gift of ruthenium salts.

Footnotes

Supporting Information Available: Experimental procedures and analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

References

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Associated Data

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Supplementary Materials

1_si_001
NIHMS359447-supplement-1_si_001.pdf (2.8MB, pdf)

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