An Effective Bifunctional Aldehyde Linchpin for Type II Anion Relay Chemistry: Development and Application to the Synthesis of a C16-C29 Fragment of Rhizopodin

Article abstract of DOI:10.1021/acs.orglett.5b03235

The design, synthesis, and validation of a new bifunctional aldehyde linchpin for Type II anion relay chemistry have been achieved. For this linchpin, the initial nucleophilic addition proceeds under Felkin-Anh control to generate the syn-alkoxide, which

Full text of DOI:10.1021/acs.orglett.5b03235

Letter
pubs.acs.org/OrgLett
An Effective Bifunctional Aldehyde Linchpin for Type II Anion Relay
Chemistry: Development and Application to the Synthesis of a C16−
C29 Fragment of Rhizopodin
Bruno Melillo,‡ Ming Z. Chen,†,‡ Roberto Forestieri, and Amos B. Smith, III*
Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104, United States
S
* Supporting Information
ABSTRACT: The design, synthesis, and validation of a new
bifunctional aldehyde linchpin for Type II anion relay chemistry
have been achieved. For this linchpin, the initial nucleophilic
addition proceeds under Felkin−Anh control to generate the syn-
alkoxide, which undergoes a 1,4-Brook rearrangement to relay the
negative charge, thus leading to the formation of a dithiane-stabilized carbanion. Subsequent trapping with an electrophile
furnishes a tricomponent adduct with an embedded propionate subunit, a ubiquitous structural motif found in polyketides. The
utility of this new linchpin is demonstrated with the construction of a potential C16−C29 fragment for the synthesis of
rhizopodin, an actin-binding macrolide.
anion-stabilizing group (ASG, e.g., dithiane), which adds to an
epoxide to form an alkoxide (2). Upon Brook rearrangement, the
negative charge is relayed back to the originating carbon, which is
then terminated with either the same electrophile (i.e.,
homocoupling) or a different electrophile (i.e., heterocoupling)
to deliver the three-component adduct 3. In Type II ARC, an
external nucleophile is first added to a bifunctional linchpin (4) to
generate alkoxide 5, which upon triggering the Brook rearrange-
ment, either by change in solvent polarity, temperature, and/or
counterion, the negative charge is then transferred to a new
carbon site.5b Subsequent trapping with an electrophile furnishes
the three-component adduct 6. Linchpins can also be added in
iterative fashion to form multicomponent adducts such as 8 via a
process not dissimilar to living polymerization.6
Given the considerable potential of the multicomponent ARC
tactic in assembling diverse molecular scaffolds with precise
stereocontrol, we initiated a program to focus on the design,
synthesis, and validation of a new aldehyde linchpin 9 that would
enable the construction of propionate-containing natural
products exploiting the Type II ARC tactic. The proposed
Type II ARC tactic with linchpin 9 is depicted in Figure 2A. Here,
addition of an external nucleophile to the aldehyde (9) would
proceed under Felkin−Anh control7 to generate syn-alkoxide 10,
which would then undergo 1,4-Brook rearrangement, triggered
by the addition of a polar additive (i.e., HMPA), to form anionic
dithiane 11. Termination with an electrophile would deliver the
three-component adduct 12, which upon reductive dithiane
removal would reveal a methylene group (13) or upon dithiane
hydrolysis a carbonyl group (14) for further functionalization.
To explore this scenario, we first constructed the prospective
racemic aldehyde linchpin 9 from 2-methyl-1,3-propanediol 15
(Figure 2B). Monoprotection of the diol with trityl chloride
ropionate and polypropionate subunits are ubiquitous
Pstructural motifs found in many polyketide natural products
possessing diverse biological properties.1 Stereocontrolled syn-
thesis of such structural motifs has attracted considerable interest
in the synthetic community due to the challenges that arise from
the inherent architectural complexity of many bioactive natural
products.2 Multicomponent anion relay chemistry (ARC), a
highly effective, stereocontrolled fragment union process
pioneered in our laboratory,3 holds significant promise for the
rapid construction of diverse polyketide natural products.
Over the past decade, we have reported extensive studies in the
area of fragment union.4 In the area of through-space anion relay
chemistry (ARC) (i.e., negative charge migration), we exploited
[1,n]-Brook rearrangements that have led to the discovery of
Type I and Type II ARC union tactics (Figure 1).5 In Type I
ARC, an anion is first generated on linchpin 1 facilitated by an
Figure 1. Through-space Type I and Type II ARC tactics. ASG: Anion-
Stabilizing Group.
Received: November 9, 2015
© XXXX American Chemical Society
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a
Table 1. Tricomponent Type II ARC with Linchpin 9
Figure 2. (A) Type II ARC employing aldehyde linchpin 9. (B) Linchpin
synthesis in racemic series.
followed by oxidation of the free alcohol led to the corresponding
aldehyde, which upon treatment with 1,3-propanedithiol and
BF3·Et2O furnished dithiane 16 with concomitant removal of the
trityl group. Subsequent C-silylation with TMSCl/n-BuLi
followed by Parikh−Doering oxidation of the free alcohol
delivered the desired linchpin 9. This linchpin was also prepared
in highly enantiomerically enriched fashion starting from either
commercially available Roche ester (vide infra).
With the prospective linchpin in hand, we turned to the
proposed Type II ARC reaction. We first investigated n-BuLi and
allyl bromide as the initiating nucleophile and terminating
electrophile, respectively. After preliminary screenings, we
discovered that addition of n-BuLi to the linchpin in Et2O at
−78 °C, followed by introduction of allyl bromide and HMPA in
Et2O and warming of the reaction mixture to ambient
temperature over 4 h, furnished the desired three-component
adduct 17 as a single syn-diastereomer (vide infra) in 74% yield
after acid-mediated removal of the TMS group (Table 1, entry 1).
The use of Et2O as the reaction solvent for the initial nucleophilic
addition proved critical, since performing the reaction in THF
leads to premature Brook rearrangement, even at low temper-
ature (not shown).
a
Having established the optimal reaction conditions, a brief
substrate scope study was performed. As illustrated in Table 1,
phenyl-, alkynyl-, and allyllithium, as well as lithiated 2-methyl-
1,3-dithiane all proved viable initiating nucleophiles, with the
reactions proceeding to deliver the three-component adducts as
single syn-diastereomers in moderate to good yields (entries 2−
5). A range of electrophiles including benzaldehyde, (R)-1,2-
epoxybutane, (S)-epichlorohydrin, and (R)-glycidol benzyl ether
(entries 6−9) readily participated as electrophiles in the ARC
reactions to furnished the corresponding three-component
adducts also in good yield with excellent syn-selectivity as
expected. The relative stereochemistry of the three-component
adduct 21 (entry 5) was confirmed by single-crystal X-ray
diffraction and that of the other congeners was assigned by
analogy. Further confirmation was obtained by Mosher ester
analysis8 of a derivatized pre-Brook alcohol (see the Supporting
Information).
Reaction conditions: (i) NuLi, Et2O, −78 °C, 30 min; (ii)
electrophile, HMPA/Et2O (1/10, v/v), −78 °C to rt, 1 h, then rt, 3
b
h; and/or (iii) 1.0 N aq HCl, overnight. Syn/anti ratio was
determined by 1H NMR analysis of the crude reaction mixture.
c
The adduct was obtained as a 1:1 mixture of diastereomers.
Figure 3. Synthesis of (+)- and (−)-9.
Further validation of the new protocol as a viable synthetic
tactic logically required the synthesis of both enantiomers of 9.
To this end, (+)-9 was prepared first from known compound
(−)-16, the latter constructed from commercially available (R)-
Roche ester (−)-26 in four steps (Figure 3).9 Silylation at the
dithiane 2-position followed by Parikh−Doering oxidation
furnished aldehyde linchpin (+)-9 in 66% yield over two steps.
Importantly, following the oxidation step, removal of excess
triethylamine from the crude reaction mixture employing satd aq
CuSO4 proved critical in preserving the optical purity of the
linchpin. The enantiomer (−)-9 was then prepared in a similar
fashion. Pleasingly, X-ray quality crystals were obtained in this
case. Both series were carried out on multigram scale; chiral phase
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chromatography indicated high levels of enantiomeric excess
(>98%, see the Supporting Information).
With an effective bifunctional linchpin for Type II ARC in
hand, we turned to demonstrate the synthetic utility in polyketide
synthesis by employing linchpin (+)-9 in a convergent synthesis
of a potential C16−C29 fragment for rhizopodin (27, Figure 4), a
was constructed from diol 31 as follows: monoprotection with
TBSCl followed by Parikh−Doering oxidation14 afforded
aldehyde 32; Takai olefination15 then delivered 29 in 77% yield
(Figure 5A). In turn, elaboration of 30 entailed the asymmetric
crotylation of aldehyde 3316 to furnish homoallylic alcohol
(−)-34 in 93% yield. O-Methylation followed by epoxidation led
to 30, obtained as a 1:1 mixture of diastereomers at C24, and then
employed as such in preliminary studies of the ARC key step; in
fact, the stereoconfiguration at C24 ultimately becomes irrelevant
as it comprises a carbonyl in the targeted natural product (see
Figure 4). Having demonstrated the viability of 30 as a
terminating electrophile for the key fragment union (not
shown), we decided to move forward in our rhizopodin synthetic
studies with a single diastereomer of 30 in order to facilitate both
reaction monitoring and chromatographic separation. We thus
turned to the iodo carbonate cyclization of (−)-34 to install the
requisite epoxide functionality, which generally favors formation
of 1,3-syn stereoarrays with good selectivities.17 To our surprise,
the well-established protocols employing N-iodosuccinimide17b,c
resulted in diastereomeric mixtures when applied to the Boc
carbonate of (−)-34, while iodine17a led to loss of the terminal
BPS protection. Pleasingly, use of iodine monobromide, a
protocol developed in our laboratory,17d cleanly furnished the
desired stereoisomer (dr 11:1; the minor diastereomer was
removed by column chromatography). The synthesis of (−)-30
was thus completed by removal of the Boc-carbonate under basic
conditions with concomitant closure of the oxirane ring, followed
by O-methylation (Figure 5B).
Figure 4. Retrosynthetic analysis of the C16−C29 side chain of
rhizopodin.
With the three molecular fragments in hand [29, (+)-9 and
(−)-30], we turned to the central Type II ARC tricomponent
fragment union employing the new aldehyde linchpin (Figure 6).
C2-symmetric, 38-membered macrodiolide isolated from the
myxobacterium Myxococcus stipitatus10 that displays impressive
biological properties, including selective potent cytotoxicity
against a range of human cancer cell lines,11 with the enamide side
chain, a highly conserved moiety, responsible for protein
recognition.12 As such, 27 has been the object of numerous
synthetic efforts.13 Our retrosynthetic analysis of the C16−C29
fragment is depicted in Figure 4. Here, we envisioned a highly
convergent assembly of the full C16−C29 carbon segment 28 via
a single-flask Type II ARC tactic, involving lithiation of vinyl
iodide 29, Felkin-controlled addition to aldehyde (+)-9, [1,4]-
Brook rearrangement, and termination with epoxide 30.
The synthesis of 28 thus began with the preparation of the
requisite ARC fragments, 29 and 30 (Figure 5). Vinyl iodide 29
Figure 6. Fragment assembly via Type II ARC.
To our delight, addition of the vinyl lithium species derived from
29 to linchpin (+)-9, followed by triggering of the [1,4]-Brook
rearrangement with HMPA and trapping of epoxide (−)-30
delivered the desired adduct (+)-28 in 69% yield, thus permitting
a highly convergent construction of the C16−C29 carbon
framework of rhizopodin.
Having validated the key step, we focused on the further
elaboration of the ARC adduct [(+)-28] with the goal of
accessing aldehyde 37, a potentially suitable partner for the union
with the C1−C15 fragment developed by Nicolaou et al. in their
synthesis of related natural product monorhizopodin12d (Figure
Figure 5. ARC: synthesis of pronucleophile and electrophile.
C
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6). The synthesis of such aldehyde would require, notably (i)
reductive removal of the C22-dithiane and (ii) stereoselective
installation of the C18-acetate, the latter planned via Sharpless
asymmetric epoxidation18 followed by reductive epoxide open-
ing.19 Prior protection of the C24-hydroxyl was achieved
employing KHMDS and excess BnBr in up to 91% yield. Of
note, these conditions proved critical to suppress the byproduct
arising from undesired migration of the neighboring TMS with
concomitant benzylation of the C20-hydroxyl (see the
Supporting Information). Subsequent dithiane removal medi-
ated by Raney nickel under a hydrogen atmosphere, followed by a
mild acidic workup (0.2 N aq HCl), provided the free allylic
alcohol without loss of the terminal BPS ether (69% yield). Next,
Sharpless asymmetric epoxidation was accomplished utilizing
(−)-diethyl-D-tartrate [(−)-DET] as ligand to furnish the single
diastereomer (−)-36 in 73% yield. Disappointingly, all attempts
to date to effect the desired epoxide opening directed by the C20
hydroxyl, utilizing hydrides at various temperatures (e.g., Red-Al,
LiAlH4)19a,b or protocols relying on single-electron transfer,19c,d
have proved unfruitful, presumably due to the significant steric
hindrance at the projected reactive site. Alternative pathways are
currently being investigated in our laboratory.
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ASSOCIATED CONTENT
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Experimental procedures and NMR spectra for obtained
compounds (PDF)
X-ray data for compound 9 (CIF)
X-ray data for compound 21 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: smithab@sas.upenn.edu.
Present Address
†Pfizer Inc., 445 Eastern Point Road, Groton, CT 06340.
Author Contributions
‡B.M. and M.Z.C. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH through Grant No.
R01-GM-29028 and a NIH postdoctoral fellowship
(1F32CA171736) to M.Z.C. We thank Dr. Patrick J. Carroll at
the University of Pennsylvania for obtaining X-ray crystal
structures. We are also grateful to Drs. George Furst and Jun
Gu and Dr. Rakesh K. Kohli for assistance obtaining NMR and
high-resolution mass spectra, respectively.
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