A Concise Stereoselective Synthesis of Preussin, 3-epi-Preussin, and Analogs

Abstract

A new stereoselective synthesis of the antifungal and antitumor agents Preussin and 3-epi-Preussin via a Pd-catalyzed carboamination of a protected amino alcohol is described. The key transformation leads to simultaneous formation of the N—C2 bond and the C1’-aryl bond, and allows installation of the aryl group one step from the end of the sequence. This strategy permits the facile construction of a variety of preussin analogs bearing different aromatic groups.

The natural product preussin (1) was first isolated in 1988 by Schwartz and coworkers from the fermentation extracts of Preussia sp. and Aspergillus ochraceus.¹ Initial screens revealed that this compound had significant antifungal activity,^{1, 2} and more recent work has demonstrated that preussin induces apoptosis in a number of human cancer cell lines and is a potent (IC₅₀ = 500 nm) inhibitor of cyclin-E kinase.³ Preussin has also shown antiviral activity, and is believed to inhibit —1 ribosomal frameshifting of RNA-based viruses.⁴ Interestingly, all eight stereoisomers of preussin exhibit biological activity.⁵

Owing to its interesting biological properties, preussin has been a popular target for total synthesis, and has been prepared via 22 different routes ranging from five steps to over 23 steps.^6,7,8,9 However, the large majority of these syntheses employ phenylalanine as the source of the C1’-phenyl group, and most other routes also install this group early in the synthetic sequence.^6,10 Thus, the previously described syntheses of preussin are generally not well suited to the rapid generation of preussin analogs that differ in the nature of the aryl substituent. A concise approach to this molecule that involves the installation of the aryl group near the end of the synthetic route would be of value for the straightforward construction of preussin derivatives, particularly if the arene could be incorporated in a manner that would permit synthesis of functionalized and/or heteroaryl analogs from readily available precursors.

Due to the limitations of existing synthetic routes, very little work has been conducted on the synthesis and study of preussin analogs.¹¹ However, limited studies on the effect of arene substitution on the activity of the related alkaloid anisomycin (2) have been performed that demonstrate the nature of the C1’-aryl group has a profound effect on biological activity.^12,13 For example, an anisomycin analog bearing a phenyl group in place of the p-methoxyphenyl moiety showed 40-fold less cytotoxic potency than 2 against a human KB cell line.¹³ Thus, a synthetic route to preussin that allows facile modification of the arene moiety may be of significant biological interest.

In this Letter we describe a new strategy for the stereoselective synthesis of (±)-preussin via the Pdcatalyzed carboamination¹⁴ of a protected amino alcohol. The key disconnection in this six-step route is the retrosynthetic cleavage of both the N—C2 bond and C1’—aryl bond to yield starting amino alcohol 5 and aryl bromide 6 (Scheme 1). This strategy has two significant implications for the construction of the molecule. It allows the installation of a variety of different functionalized arenes one step from the end of the sequence, which permits the facile construction of a number of preussin analogs. It also allows control of the relative stereochemistry at C2 through use of A^(1,3)-strain¹⁵ in conjunction with a favorable eclipsed orientation of the Pd-N and alkene C-C bonds during the stereochemistry determining step of the carboamination,¹⁴ which promotes cyclization through transition state 3 in which the C-3 oxygen substituent is oriented in a pseudoaxial position.

Scheme 1.

Key Disconnection and Stereocontrol

In order to probe the feasibility of the key Pd-catalyzed carboamination reaction, our initial studies focused on the development of a synthesis of (±)-preussin. As outlined in Scheme 2, aldol reaction between commercially available 2-undecanone and acrolein provided keto-alcohol 7 in 78% yield. Conversion of 7 to the O-benzyl oxime 8 proceeded smoothly, and was followed by a one-pot sequence of LiAlHL₄ reduction and Boc-protection to provide an 86% yield of a 1:1.2 mixture of readily separable amino alcohol diastereomers 9 and 10. Although stereoselective reductions of β-hydroxy oxime ethers have been previously described,¹⁶we elected to employ non-selective conditions to allow access to both syn- and anti-amino alcohol substrates for the Pd-catalyzed cyclization reactions, which ultimately provide two different biologically active pyrrolidine derivatives (1 and 14).

Scheme 2.

Synthesis of (±)-Preussin

TBS-protection of anti-amino alcohol 9 provided 5, the substrate for the key Pd-catalyzed carboamination reaction. In the event, treatment of 5 with bromobenzene and NaOtBu in the presence of catalytic Pd(OAc)₂/dpe-phos¹⁷provided pyrrolidine 11 in 62% isolated yield with >20:1 diastereoselectivity. As noted above, the desired stereoisomer most likely arises from transition state 3 (Scheme 1) in which the C₉-chain is oriented in a pseudoaxial position in order to minimize A^(1,3)-strain between this substituent and the N-Boc group.¹⁵ Although the C3-OTBS group is also pseudoaxial, the energetic cost of this conformation is lower than that of the A^(1,3)-strain in transition state 4 in which both the C₉-chain and the OTBS group are equatorial. One-pot reduction and deprotection of 11 afforded (±) — preussin (1) in 90% yield as a single diastereomer. This six-step sequence proceeded with an overall yield of 15% from 2-undecanone.

The syn-amino alcohol 10 was converted to (±)-3-epi-preussin (14)^8a,c using a sequence of reactions analogous to that described above (Scheme 3). The stereoselectivity of the Pd-catalyzed cyclization of 12 was high, although the chemical yield obtained in the reaction of the syn-diastereomer 12 (54%) was slightly lower than that achieved for the reaction of the anti-isomer 5 (62%). This route provided the desired pyrrolidine 14 as a single isomer in an overall yield of 15%. Thus, the strategy described herein provides straightforward access to both racemic preussin diastereomers in comparable yields and stereoselectivities.¹⁸

Scheme 3.

Synthesis of (±)-3-epi-Preussin.

Having demonstrated the feasibility of Pd-catalyzed carboamination for the construction of Preussin, we turned our attention towards the development of an asymmetric synthesis of the naturally occurring (+)-enantiomer. As shown in Scheme 4, addition of allylmagnesium bromide to enantiopure sulfinylimine 15 under Ellman’s conditions¹⁹ afforded 16, which was isolated in 77% yield as a single diastereomer upon purification.²⁰ Cleavage of the chiral auxiliary and protection of the resulting primary amine afforded 17 in 85% yield. Ozonolysis of 17 (63%) followed by vinylcuprate addition²¹ to the resulting β-amino aldehyde 18 generated (+)-9 with 3:1 diastereoselectivity; the desired pure anti-diastereomer was obtained in 54% yield after chromatographic separation. The remaining three steps proceeded with similar yields and selectivities to those obtained from the racemic route, and provided (+)-preussin {[α]²³_D +21.2° (c 1.0, CHCl₃) [lit.² [α}²⁵_D +22.0° (c 1.0, CHCl₃)]} with an overall yield of 12% in nine steps from commercially available decanal.

Scheme 4.

Synthesis of (+)-Preussin

In order to demonstrate the amenability of this strategy toward the synthesis of differentially arylated preussin analogs, Pd-catalyzed reactions of 5 and 12 were conducted with a variety of different aryl bromide coupling partners. To illustrate the utility of this method for the rapid generation of useful quantities of analogs the Pd/dpe-phos catalyst was employed for all substrate combinations. However, previous studies indicate that other ligands may provide superior results for certain aryl bromide coupling partners.^14c Thus, the yields obtained in these transformations are not optimized on a case-by-case basis. As shown in Table 1, the cyclization reactions proceed in moderate to good yields for a variety of different aryl bromides including strates that are electron-rich (entries 3-4),²² electron-poor (entries 1-2, 5-6, 9, and 12), or sterically hindered (entry 8). Several functional groups are tolerated, and heterocyclic aryl bromides can also be employed (entries 10-11). In most cases examined, the cyclizations of anti-amino alcohol derivative 5 proceeded in higher yield than the analogous reactions of syn-amino alcohol derivative 12. In all cases the reactions proceeded with >20:1 diastereoselectivity as judged by ¹H and ¹³C NMR analysis.

Table 1.

Synthesis of N-Boc-O-TBS-Preussin Analogs

entry	substrate	ArBr	product	yield (%)
1	5			70
2	12			65
3	5			52
4	12			49
5	5			69
6	12			52
7	5			69
8	5			57
9	5			62
10	5			54
11	5			40
12	5			70

Conditions: 1.0 equiv substrate, 1.2 equiv ArBr, 2.3 equiv NaOtBu, 2 mol% Pd(OAc)₂, 4 mol % dpe-phos, toluene, 90 °C.

To illustrate that the N-Boc-O-TBS-preussin analogs could be converted to N-methyl-3-hydroxy-2-(arylmethyl)pyrrolidines that are closely related to the natural product, a subset of the products shown in Table 1 were deprotected in a 1-2 step sequence. As shown in Table 2, deprotection was effected using LiAlH₄ followed by treatment with aqueous base or TBAF for products bearing unreactive aromatic functionality. Alternatively, deprotection was also achieved through one-pot Boc-cleavage and reductive amination with formic acid/formaldehyde followed by treatment with TBAF. The latter conditions tolerate functional groups (e.g., ketones, trifluoromethyl substituents) that would be reduced by LiAlH₄. Both deprotection protocols provided the desired products in excellent yields.

Table 2.

Deprotection of N-Boc-O-TBS-Preussin Analogs

entry	substrate	method	product	yield (%)
1	19	B		83
2	20	B		84
3	21	A		85
4	22	A		89
5	23	B		80
6	24	B		81

Conditions: Method A: i) LiAlH₄, THF, 60 °C; ii) H_2O or TBAF. Method

B: i) HCO₂H, HCHO; ii) TBAF, THF.

In conclusion, we have developed concise, stereoselective routes to (+)-preussin, (±)-preussin and (±)-3-epi-preussin. These routes feature a new strategy for the synthesis of 2-benzylpyrrolidine alkaloids that allows the construction of both the C2-N and the C1’ -Ar bonds in a single step near the end of the synthetic sequence. This strategy allows the facile synthesis of differentially arylated preussin analogs, and provides straightforward access to derivatives that could not be easily and rapidly prepared using previously developed routes. This strategy is potentially applicable to other members of this class of natural products; further studies in this area are currently underway.