Electrophile-induced ether transfer: Stereoselective synthesis of 2,4,6-trisubstituted tetrahydropyrans

Article abstract of DOI:10.1002/anie.200702018

(Chemical Equation Presented) A negative attack: Synthesis of 4-alkoxy-2,6-cis- and its stereocomplementary 4-alkoxy-2,6-trans- tetrahydropyrans has been achieved in high yield and with excellent stereocontrol by a common strategy: electrophile-induced ether-transfer, cyclization, and functionalization reactions (see scheme; Bn = benzyl; BPS = tert-butyldiphenylsilyl;TBS = tert-butyldimethylsilyl; TEA = triethylamine).

Full text of DOI:10.1002/anie.200702018

Communications
DOI: 10.1002/anie.200702018
Ether Transfer
Electrophile-Induced Ether Transfer: Stereoselective Synthesis of
2,4,6-Trisubstituted Tetrahydropyrans**
Rendy Kartika and Richard E. Taylor*
Polyketides represent an important class of natural products
owing to their unique and diverse biological activities. The
phorboxazoles,[1] a representative example, have become a
popular target for synthetic chemists. Total syntheses of these
complex structures have been accomplished by several
groups.[2] Furthermore, the development of synthetic methods
for the construction of their bis-tetrahydropyran C5–C15
region has been well documented.[3] Typically, different
cyclization strategies were employed to install each of the
stereocomplementary rings within this fragment.[4] Herein, we
wish to report our approach to a stereoselective synthesis of
both 4-substituted, 2,6-cis- and 2,6-trans-tetrahydropyran
rings through a common strategy, which is highlighted by
our newly developed methodology, electrophile-induced
ether transfer. Moreover, application of this method to the
synthesis of the C3–C17 bis-tetrahydropyran fragment of
phorboxazole A is presented.
protected homoallylic alcohol 1 through activation with ICl
(Scheme 1).[5] Mechanistically, we surmised that activation of
1 with electrophilic iodine monochloride produces chairlike
oxonium ion 2, leading to chloromethyl ether 3, which could
be quenched with a variety of nucleophiles depending upon
workup conditions.
Scheme 1. Electrophile-induced ether transfer. Bn=benzyl.
We envisioned that this methodology could be utilized to
access 2,4,6-trisubstituted tetrahydropyran rings with the
following rationale (Scheme 2). Conversion of intermediate
We recently reported that syn-diol mono- or diethers 4,
could be prepared in high yield and excellent diastereoselec-
tivity in a single step from a simple alkoxymethyl ether
[*] R. Kartika, Prof. R. E. Taylor
Scheme 2. Synthetic approach to 2,6-cis- or trans-tetrahydropyrans.
Department of Chemistryand Biochemistryand
the Walther Cancer Research Center
Universityof Notre Dame
251 Nieuwland Science Hall, Notre Dame, IN 46556-5670 (USA)
Fax: (+1)574-631-5674
3 to sulfone 5 would enable deprotonation of the acidic
a proton and cyclization to 6. Sulfonyl tetrahydropyran 6
could be then further functionalized, in a stereoselective
manner, to either 2,6-cis- or 2,6-trans-tetrahydropyrans 7 by
using chemistry that is analogous to that previously developed
by Ley and co-workers.[6,9]
E-mail: taylor.61@nd.edu
[**] Support provided bythe National Institutes of Health through the
National Institute of General Medical Science (GM007683) is
gratefullyacknowledged.
We began our exploration in the above-mentioned
tetrahydropyran methodology by installing sulfone function-
ality directly in the ether-transfer reaction (Scheme 3). Treat-
Supporting information (including the experimental details) for this
article is available on the WWW under http://www.angewandte.org
or from the author.
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sequence provided access to 4-alkoxy-2,6-cis-tetrahydropyr-
ans in good yield with excellent diastereoselectivity (Table 1).
For the stereocomplementary 2,6-trans-tetrahydropyran,
a direct ionization of 11 could be exploited. In fact, Ley and
Table 1: 2,6-cis-Pyran 14 from the alkylation–reduction sequence.
Scheme 3. Sulfone incorporation strategyand cyclization.
HMPA=hexamethylphosphoramide.
Electrophile Alkylation
Yield[b] Reduction
[%]
Yield[d]
[%]
product 13[a]
product 14[c]
ment of methoxymethyl (MOM)-protected homoallylic alco-
hol 8 with ICl in toluene at À788C, followed by quenching of
the intermediate chloromethyl ether with a thiophenol/
triethylamine (TEA) mixture afforded ether-transfer adduct
9 in 88% yield as a single diastereomer. Subsequent sulfide
oxidation by using an ammonium molybdate/H2O2 mixture
provided sulfone 10, which was then readily cyclized under
lithium hexamethyldisilazide (LiHMDS) to sulfonyl pyran 11
as a 3:2 mixture of diastereomers; both steps proceeded in
high yield. It is important to note that direct trapping of the
chloromethyl ether intermediate with sodium benzenesulfi-
nate did not produce sulfonyl ether 10.
Sulfonyl pyran 11 was then transformed to 4-methoxy-2,6-
cis tetrahydropyrans 14 through a two-step sequence: alky-
lation and reduction. After screening a variety of conditions,
we found that deprotonation of 11 with excess sodium
hexamethyldisilazide (NaHMDS) in toluene followed by the
addition of electrophiles successfully yielded an alkylation
product mixture of dihyropyran 12a and tetrahydropyranol
benzyl
bromide
79
91
82
72
66
allyl
bromide
85
97
82
methyl
iodide
BOMCl
[a] Typical alkylation conditions: NaHMDS (3 equiv) and alkylating agent
(4 equiv). [b] Isolated as a mixture of diastereomers. [c] Typical reduction
conditions: TMSOTf (3 equiv) and Et3SiH (2 equiv). [d] Isolated as a
1
single diastereomer. H NMR analysis of the crude mixture in all cases
indicated a greater than 20:1 d.r. [e] PPTS was not added during
methanolysis. [f] Reaction was warmed up to À408C.
co-workers have previously demonstrated the ionization of
benzenesulfonyl cyclic ethers by using aluminium chloride.[9]
In these 4-alkoxy substrates, we found that treatment of
sulfonyl pyran 11 with a slight excess of AlCl3 and a variety of
nucleophiles in toluene at À788C followed by warming up to
À408C over one hour afforded tetrahydropyrans 15 in high
yield and excellent diastereoselectivity (Table 2). The nucle-
ophiles screened included allylsilanes, enolsilanes, and silyl
ketene acetals. Once again, 1H NMR coupling-constant
determination of the relevant protons was utilized to
deduce the relative stereochemistry of the ring.
With the methodology to access the stereocomplementary
4-alkoxy-2,6-cis- and 2,6-trans-tetrahydropyrans in hand,
phorboxazole A, particularly its C5–C15 bis-tetrahydropyran
region, caught our interest. This natural product is an ideal
target which would demonstrate the applicability of our
method in complex-molecule synthesis. Our retrosynthetic
analysis indicated that the C5–C15 bis-tetrahydropyran of
phorboxazole A could be assembled through two successive
ether-transfer, cyclization, and functionalization reactions to
12b. This result was consistent with the finding reported by
Ley et al.[6] in which the sulfone functionality was cleanly
eliminated during the alkylation reaction. However, in these
4-alkoxy-substituted cases, hydration of 12a readily occurred
upon aqueous workup, and 12b was found to be the major
product.
Both 12a and 12b were conveniently converted to methyl
pyranoside 13 as a mixture of diastereomers upon standing in
methanol with a catalytic amount of pyridinium p-toluene-
sulfonate (PPTS). Exposure to a trimethylsilyl trifluorome-
thanesulfonate (TMSOTf) and Et3SiH mixture reduced
methyl pyranoside 13 to exclusively 2,6-cis-tetrahydropyran
14.[7,8] The relative stereochemistry of the ring was unambig-
uously assigned by 1H NMR coupling-constant analysis.
Several electrophiles, including benzyl bromide, allyl bro-
mide, methyl iodide, and benzyloxymethyl chloride (BOMCl)
were screened, and the sequential alkylation–reduction
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Table 2: 2,6-trans-Pyran 15 from the substitution reaction.[a]
Nucleophile
Substitution product 15
Yield[b] [%]
80
86
82
80
70
[a] Typical reaction conditions: AlCl3 (1.5 equiv) and nucleophiles
(3 equiv). [b] Isolated as a single diastereomer. H NMR analysis of the
crude mixture in all cases indicated a greater than 20:1 d.r.
Scheme 4. Synthesis of the C3–C13 region of phorboxazole A. DEAD=
diethylazodicarboxylate, DIPEA=N,N-diisopropylethylamine, p-NBA =
para-nitrobenzoic acid.
1
provide the advanced intermediate 16 (BPS = tert-butyldi-
phenylsilyl, TBS = tert-butyldimethylsilyl). Our successfully
implemented strategy is described below.
phenyl groups within the BPS ether were converted to
cyclohexadienes. Exposure to 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) provided 20 in an essentially quanti-
tative yield for the two steps. After silylation, oxidative
cleavage of the terminal olefin gave aldehyde 21 in good yield.
An addition of allylmagnesium bromide to this aldehyde
afforded a diastereomeric mixture of homoallylic alcohols 22
and 23 in a near-quantitative yield, which were easily
separated by column chromatography. The stereochemistry
of alcohol 22 was then converted by Mitsunobu inversion to
the desired alcohol 23,[12] and its absolute stereochemistry was
determined by Mosherꢀs ester analysis.[13] Attempts to control
the aldehyde-addition facial selectivity with a reagent-con-
trolled allylation were unsuccessful.
Homologation of the second tetrahydropyran fragment
was then accomplished on homoallylic alcohol 23. BOM-
protection, ether-transfer, and oxidation reactions gave the
sulfonyl ether 24 in satisfactory yield as a single diastereomer
(Scheme 5). The strength of the methodology is now clearly
demonstrated by its applicability to complex substrates.
Furthermore, the ether-transfer reaction proceeded very
smoothly and remarkably, no decomposition was detected
despite the reactive nature of iodine monochloride. Cycliza-
tion of 24 afforded the corresponding sulfonyl pyran, which
was then subjected to the alkylation–reduction sequence. In
this complex substrate, alkylation of the intermediate sulfone
anion proved slow under our initial conditions. However,
We began our synthesis to bis-tetrahydropyran 16 with
enantiomerically
enriched
homoallylic
alcohol
17
(Scheme 4).[10] BOM protection of 17 followed by ether-
transfer and subsequent sulfide-oxidation reactions provided
18 in 46% yield over three steps and as a single diastereomer.
Tetra-n-propylammonium perruthenate and N-methylmor-
pholine-N-oxide (TPAP, NMO) was a more-suitable oxi-
dant[11] in this particular substrate as sulfide oxidation with
ammonium molybdate/H2O2 was low yielding, presumably
owing to the limited solubility of starting material in the
reaction medium. LiHMDS-mediated cyclization of 18 fol-
lowed by cationic allylation of the resulting sulfonyl pyran set
up the first tetrahydropyran ring 19 in excellent yield and
diastereoselection. This ring represents the 2,6-trans-stereo-
chemistry of the C5–C9 region. The benzyl group was then
removed with a Li/NH3 mixture. Under these conditions, the
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Scheme 5. Completion of bis-tetrahydropyran fragment 16.
[4]For a review on the construction of tetrahydropyran rings in total
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after optimization, the alkylation product was isolated in 74%
yield as a mixture of diastereomers. The completion of the
synthesis of bis-tetrahydropyran fragment 16 was accom-
plished by a stereoselective reduction by using TMSOTf and
Et3SiH.
In conclusion, we have developed a new methodology for
the production of 2,4,6-trisubstituted tetrahydropyrans that
are common to biologically active polyketides. Stereocom-
plementary tetrahydropyran fragments are accessed from a
common intermediate that is readily obtained through
electrophile-induced ether transfer that was previously
reported by our laboratory. The successful application of the
chemistry to the stereoselective synthesis of the C5–C15 bis-
tetrahydropyran region of phorboxazole A supports the
methodꢀs broad scope and scalability. Further applications
of this methodology are currently ongoing in our laboratory
and will be reported in due course.
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Received: May 7, 2007
Published online: August 2, 2007
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Keywords: ether transfer · oxocarbonium ions ·
oxygen heterocycles · phorboxazoles · polyketides
.
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