An approach to the site-selective deoxygenation of hydroxy groups based on catalytic phosphoramidite transfer

Article abstract of DOI:10.1002/anie.201109033

Selective: The deoxygenation of simple and complex natural products employing a readily synthesized phosphoramidite and tetrazole catalysts can be executed as a two-step process, without the need to isolate intermediate deoxygenation precursors. Furthermore, a peptide-based tetrazole catalyst controls the site selectivity of deoxyerythromycin synthesis (see scheme), thus overcoming the notorious challenges with unprotected erythromycin A. Copyright

Full text of DOI:10.1002/anie.201109033

Angewandte
Chemie
DOI: 10.1002/anie.201109033
Synthetic Methods
An Approach to the Site-Selective Deoxygenation of Hydroxy Groups
Based on Catalytic Phosphoramidite Transfer**
Peter A. Jordan and Scott J. Miller*
The site-selective, catalytic modification of
complex molecules is a long-standing goal
for chemists. Given the high efficiency of
many fermentation processes, the use of
natural products as scaffolds for diversifi-
cation is part of many epic drug-discovery
programs.[1] Yet, it is generally accepted
that these research efforts are challenging,
often requiring multistep syntheses of the
requisite analogues,[2] re-engineered bio-
synthetic pathways,[3] or enzymatic modifi-
cation of the natural product itself.[4] The
use of chemical catalysts to alter complex
scaffolds may represent a growing field
with potential to impact these interdiscipli-
nary research efforts.[5,6] The challenges at
the front end of this approach include the
identification of not only relevant reactions
to explore, but also the inherent architec-
tural and stereochemical molecular fea-
tures that the catalyst–substrate complexes
ultimately embody.
Among the more comprehensively
studied scaffold-modifying processes in
nature are oxidation reactions.[7] Chemists
can parallel natureꢀs course, which tends to
increase the overall oxidation state of
a substrate during the course of a biosyn-
thesis.[8,9] But, how might chemists turn the
biosynthetic clock back? Can chemists
take natureꢀs oxidized scaffolds and cata-
lytically and selectively achieve deoxygen-
Scheme 1. a) Peptide-catalyzed site-selective thiocarbonylation as a precursor to radical
deoxygenation. b) Thiocarbonylation of erythromycin A with N-methylimidazole catalyst.
ated analogues directly, without de novo
synthesis of a deoxygenated, complex mol-
ecule? While enzymes that deoxygenate
polyols are known,[10] they are perhaps less
c) Thiocarbamate formation on 2’-acetylerythromycin A. Boc=tert-butoxycarbonyl.
prevalent than their oxidase counterparts. Recognizing the
power of chemical deoxygenation, chemists have developed
a lexicon of deoxygenation protocols.[11] However, it might
reflect the state of the art that very few deoxygenation
protocols involve catalysis, and even fewer address selectivity
in polyfunctional molecules. One approach to these issues is
described below.
Our laboratory has been exploring methods for the site-
selective manipulation of polyols.[12] Among the reactions we
have explored, site-selective deoxygenation is one of the more
challenging.[13] We reported that peptides containing modified
histidine (1) could indeed effect catalytic, site-selective
thiocarbonylation of several simple polyols as a prelude to
deoxygenation (2!3!4; Scheme 1a).[14] However, a number
of limitations exist. For example, when the approach is
applied to erythromycin A (Ery A), side reactions can reduce
efficiency. Whereas direct thiocarbonylation of Ery A under
our previously developed conditions can deliver thiocarbon-
[*] P. A. Jordan, Prof. Dr. S. J. Miller
Department of Chemistry, Yale University
225 Prospect Street, New Haven, CT 06520-8107 (USA)
E-mail: scott.miller@yale.edu
[**] We are grateful to the National Institutes of General Medical
Sciences of the National Institute of Health Foundation (GM-
068649) for support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201109033.
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ate 5 in 76% yield (Scheme 1b), the same conditions applied
to 2’-acetyl-Ery A results in dealkylation of the amino group
(6, Scheme 1c).[15] Because natural products decorated with
amino sugars are common,[16] we suspected that such side
reactions would be a consistent liability with carbonyl-based
electrophiles when applied to this class of structures.
with peptide-embedded tetrazoles as catalysts (e.g., 8; ca.
5 mol% of the catalyst is typical for high conversion).
Moreover, we showed that the approach was amenable to
the transfer of stereochemical information, with desymmet-
rization of inositol derivative 9 as an example. The question
thus became whether or not these approaches could be
merged to enable catalytic, site-selective phosphoramidite
transfer. The key advance required the development of
previously unknown phosphoramidite 10b (Scheme 2c), and
the demonstration that it is amenable to selective transfer and
subsequent deoxygenation.
Initially, we attempted to adapt the same catalytic strategy
described in Scheme 2b employing the diethylamino variant
of the phosphoramidite (10a) and 10 ꢁ molecular sieves.[20]
These conditions, however, proved to be incompatible with
low-molecular-weight substrate 11 (Table 1), and sluggish for
the phosphitylation of 2’-acetyl-Ery A. Furthermore, phos-
phoramidite 10a, in the absence of molecular sieves, was
highly prone to hydrolysis, and decomposed in the presence of
an alternative amine scavenger, phenyl isocyanate.[21]
Therefore, we pursued the synthesis of the much more
stable phosphoramidite 10b, based on diisopropylamino
substitution, for use in combination with phenyl isocyanate
as an amine scavenger (Scheme 2c). On a multigram scale,
phosphoramidite 10b can be synthesized from 2-(2-iodophe-
nyl)ethanol and methyl tetraisopropyl phosphordiamidite in
greater than 90% yield.[22] Not only did 10b prove to be
compatible with tetrazole catalysis (Table 1), it was also stable
to both hydrolysis and oxidation over the course of several
months without any special precautions.
To address limitations such as these, we undertook the
exploration of a new catalytic cycle for site-selective deoxy-
genation of polyols. With the goal of achieving the mildest of
conditions, such that diverse, complex natural-product func-
tionality could be tolerated, we were drawn to the efficient
deoxygenation of hydroxy groups pioneered by Koreeda and
Zhang.[17] With this synthetic method, hydroxy groups are
converted to the corresponding phosphites through phosphit-
ylation with PIII-based chlorophosphites that contain a pend-
ant iodoarene (7, Scheme 2a). Then, radical deoxygenation
occurs under standard conditions. While powerful, this PIII-
based approach is not readily adaptable to catalysis, given the
high reactivity of chlorophosphites. Thus, we wondered if it
might be adapted to a catalytic phosphoramidite transfer
process we had recently reported.[18] In this work (Sche-
me 2b), we showed that the venerable phosphoramidite
method described by Caruthers[19] could indeed be performed
We initially examined the catalytic phosphitylation of
simple alcohols 11 and 12 in the presence of only 10 mol%
phenyltetrazole as catalyst, and 1.5 equivalents each of 10b
and phenyl isocyanate (Table 1, entries 1 and 2). Both
substrates 11 and 12 were completely consumed within four
1
hours, and H NMR spectra of the resulting crude material
indicated a very clean transformation with no remaining
starting alcohol and evidence for the formation of the
corresponding phosphites (13 and 14, respectively), typically
to greater than 95% conversion (1H NMR spectroscopy
analysis).[22] Although it was clear that the catalytic phosphit-
ylation reaction proceeded with great efficiency, isolation of
the corresponding phosphites by silica-gel chromatography
proved to be much more problematic because of the
persistent co-elution with the side product urea derived
from reaction of the liberated diisopropylamine with the
isocyanate amine scavenger. Purification was further ham-
pered by the overall instability of the phosphite products.
Having demonstrated the feasibility of the catalytic
phosphitylation reaction with simple substrates, we next
sought to assess the overall deoxygenation strategy by
investigating whether the crude phosphite products of more
relevant, highly oxygenated substrates (Table 1, 15, 16, 17;
entries 3–5) could be carried through the deoxygenation step
without isolation and purification of the intermediate phos-
phites. Such a strategy would potentially streamline the
process and minimize the loss of material. Moreover, in the
context of chiral natural products, the structure of the
deoxygenated products would be easier to assign than the
Scheme 2. a) Dichlorophosphite strategy to form phosphite-based
deoxygenation precursors. b) Peptide-catalyzed, enantio- and regiose-
lective phosphitylation employing phosphoramidites. c) Peptide-cata-
lyzed site-selective formation of phosphite-based deoxygenation pre-
cursors employing phosphoramidites. AIBN=azobisisobutyronitrile,
PMB=p-methoxybenzyl, M.S.=molecular sieves, e.r.=enantiomeric
ratio, k.r.= kinetic resolution.
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Table 1: Catalytic phosphitylation and deoxygenation of alcohol substrates.
hypothesis was that a peptide-based appendage to
the catalytically active tetrazole moiety would
provide a handle for tuning site-selectivity, in
analogy to our early observations with other group
transfer processes.[24] The goal was to examine
whether catalyst control might overcome the well-
known high reactivity of the 2’-hydroxy group of
Ery A.[25] It is well precedented that the 2’-hydroxy
group reacts rapidly with many carbonyl-based
electrophiles, presumably through a neighboring
base-assisted mechanism. As such, methods to
modify the other hydroxy groups of erythromycin A
generally require protection of this position. To test
this prospect for catalyst-dependent reversal of site-
selectivity, without recourse to the use of a protec-
tive acetyl group, we subjected Ery A to the
phosphitylation conditions described above. Upon
workup, we analyzed the product distribution by
31P NMR spectroscopy. As indicated in Scheme 3a,
the simple catalyst phenyltetrazole gave a distribu-
tion of phosphite products, with four intense chem-
ical shifts. By analogy to the previously isolated 2’-
acetyl-4’’-phosphite of Ery A (see Table 1, entry 6,
21), we believe that the two 31P chemical shifts at d =
143 and 144 ppm correspond to the two 31P-epimers
of the 4’’-regioisomer. The other most significant
product of the reaction, with 31P-chemical shifts at
d = 140.0 and 140.5 ppm, would appear to be the
alternative 2’-phosphite. Subjection of this mixture
to deoxygenation conditions gives a corresponding
mixture of deoxygenation products. Of the two
major products that are formed, one is indeed
identical to 23 that was obtained from the deoxy-
genation of thiocarbonyl 5 (Scheme 1b). The other
may be assigned as the 4’’-regioisomer (22), albeit at
low relative abundance. Notably, this catalytic
protocol delivers the mixture in an approximate
3:1 ratio (1H NMR spectroscopy analysis), reflect-
ing an inherent preference for the 2’-deoxy isomer
(23), with the simple phenyltetrazole catalyst.[22]
On the other hand, the peptide-embedded
tetrazole-based catalyst 24 provides the putative
4’’-regioisomer with near-complete selectivity
[a] Yields of the isolated deoxygenated species are given for the two-step process.
[b] Yield of isolated product determined from phosphite 21 after methanol cleavage
of 2’-acetyl protecting group. [c] Conversion determined by NMR spectroscopy.
epimeric P-chiral phosphites. We therefore subjected com-
pounds 15–17 to the same catalytic phosphitylation conditions
described for 11 and 12. Then, after basic workup, each
phosphite was immediately treated with the standard radical
deoxygenation conditions. We were delighted to find that the
two-step strategy gave the corresponding deoxygenated
products 18, 19, and 20, respectively, in good overall yields.
Moreover, as shown in Table 1 (entry 6), we applied the new
catalytic phosphitylation strategy to 2’-acetyl-Ery A, observ-
ing clean conversion to the 4’’-phosphite product 21, which
was isolated in 83% yield. This phosphite product was readily
deoxygenated under standard conditions, and after metha-
nolic deacylation gave 4’’-deoxy-Ery A (22) in 84% yield.[23]
We next wished to assess prospects for catalyst-depen-
dent, site-selective phosphitylation/deoxygenation of a com-
plex, native polyol with the newly developed protocol. Our
(Scheme 3c). Furthermore direct radical deoxygenation of
the corresponding crude reaction mixture gives 4’’-deoxy-
Ery A (22), in 50–60% yield of isolated product, from Ery A.
It is notable that the peptide-catalyzed phosphitylation/
deoxygenation protocol results in both clean reactions and
altered selectivity in comparison to the results achieved with
the simple phenyltetrazole catalyst. Moreover, it is also
relevant to our efforts that the most efficient paths to either
the 2’-deoxy-Ery A (23) or the 4’’-deoxy-Ery A (22) turn out
to employ different protocols—thiocarbonylation with
a simple catalyst in the former case, and phosphitylation
with a peptide-embedded tetrazole in the latter case. These
findings emphasize the need to evaluate multiple approaches
in parallel for the goal of site-selective deoxygenation of
complex polyols, in pursuit of multiple and various deoxy-
genated analogues.
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Scheme 3. a) Nonselective, phenyltetrazole-catalyzed phosphitylation gives multiple phosphite products as shown in the 31P NMR spectrum
(crude sample). Deoxygenation yields 23 as the major product. b) N-methylimidazole-catalyzed thiocarbonylation and subsequent radical
deoxygenation to give 23. c) Peptide 24 directly delivers the 4’’-phosphite product (31P NMR spectrum, crude sample) for efficient deoxygenation
to give 4’’-deoxyerythromycin A (22). A larger-scale representation of the NMR spectra is presented in the Supporting Information as Supplemental
Figure 3.
We conclude this report with several thoughts regarding
these findings. First, we are intrigued by our ongoing
observation of catalyst-dependent reversal of inherent selec-
tivity in derivatization reactions of this type.[5] From the
pragmatic perspective, it may be that this approach will
represent an addition to the tools available to chemists for the
direct manipulation of complex structures. Notably, our work
in this area has revealed that there is a premium on the use of
catalysts for complex molecule derivatizations since improve-
ments in selectivity can greatly facilitate isolation of pure
materials and, eventually, their large-scale synthesis. Maybe
most important, however, is the identification of orthogonal
catalysts and protocols that provide access to unique natural
product analogues. Perhaps we can aspire to comprehensive
and general approaches to problems like catalytic, site-
selective deoxygenation of complex structures. But, our
studies in this area reveal that, at present, diverse approaches
may be most enabling. In this vein, we also anticipate that
libraries of catalysts, for example those bearing the tetrazo-
lylalanine, will be needed to generalize these findings to other
classes of compounds. Our extension of these studies to other
families of complex-molecule deoxygenations are ongoing
and shall be reported in the future.
Keywords: deoxygenation · erythromycin · natural products ·
organocatalysis · synthetic methods
.
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