Synthesis of the northern sector (C8-C19) of rapamycin via Chan rearrangement and oxidation of an α-acyloxyacetate

Article abstract of DOI:10.1016/j.tet.2009.06.026

Two routes to the masked tricarbonyl segment of the immunosuppressant rapamycin comprising C8-C19 were explored beginning from d-xylose. The first approach employed a protected form of 2,4,5-trihydroxypentanol to obtain dithiane 43, which failed to react

Full text of DOI:10.1016/j.tet.2009.06.026

Tetrahedron 65 (2009) 6642–6647
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Synthesis of the northern sector (C8–C19) of rapamycin via Chan rearrangement
and oxidation of an a-acyloxyacetate
*
James D. White , Scott C. Jeffrey
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, OR 97331-4003, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Two routes to the masked tricarbonyl segment of the immunosuppressant rapamycin comprising C8–C19
Received 19 March 2009
Received in revised form 3 June 2009
Accepted 5 June 2009
were explored beginning from D-xylose. The first approach employed a protected form of 2,4,5-trihy-
droxypentanol to obtain dithiane 43, which failed to react with dimethyl oxalate to give a 1,2,3-tri-
carbonyl unit corresponding to the northern sector of rapamycin. A second approach employing
carboxylic acid 61 derived from 43 utilized base-mediated (Chan) rearrangement of a-acyloxyacetate 62
Available online 12 June 2009
with trapping of the resultant enediolate as bis silyl ether 63. Epoxidation of this diene afforded masked
tri-keto ester 65 which underwent acid-catalyzed methanolysis to produce cyclic ketal 67.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
In 1975, a substance named rapamycin (1) was isolated from the
soil fungus Streptomyces hygroscopicus during a search for naturally
occurring antifungal agents.1 Although the antifungal properties of
1 were not particularly impressive, it later became apparent that
rapamycin was a potent immunosuppressant2 with a mode of ac-
tion similar to a related Streptomyces metabolite FK-506 (2).3 Both 1
and 2 were studied as prospective therapeutic agents for treatment
of graph rejection that accompanies organ and tissue trans-
plantation, and rapamycin is known to be particularly effective in
suppressing the immune response with relatively few side effects.
The ability of 1 to prevent the formation of antibodies against cell
surface antigens of transplanted tissue has placed it at the forefront
of medical practice in the area of organ transplantation and rapa-
mycin is now a recognized drug in combination with cyclosporine A
for treatment of host vs graft disease.4
The pipecolic keto amide sector of the rapamycin and FK-506
structures plays an important role as a peptidomimetic when these
immunosuppressants are bound to certain cytosolic enzymes
(immunophilins). Specifically, the rapamycin–immunophilin com-
plex acts as a prolyl cis–trans isomerase5 in which the C1–C10
segment of 1 mimics the transition state of a bound proline-con-
taining peptide.6 This results in inhibition of at least three protein
kinases and interferes with a signaling pathway that originates in
the interleukin-2 receptor.7 Thus, the functionality present in the
* Corresponding author.
E-mail address: james.white@oregonstate.edu (J.D. White).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.026

J.D. White, S.C. Jeffrey / Tetrahedron 65 (2009) 6642–6647
6643
terminal portion of this ‘northern’ domain of 1 is a pivotal com-
ponent of the architecture of this macrolide.
oxalate (Scheme 1). Precedent for this strategy existed in Corey’s
synthesis of aplasmomycin,12 a macrolide that contains a borate-
In addition to efforts directed toward clarifying the mode of
action of rapamycin and FK-506,8 a large number of synthetic
studies on these immunosuppressive agents has been carried out.
These investigations have resulted in five total syntheses of rapa-
mycin9 and three of FK-506,10 as well as numerous publications
reporting approaches to the tricarbonyl subunits of 1 and 2.11
Integral to any strategy for assembling the ‘northern’ (C8–C19)
subunit of 1 is the correct installation of stereocenters at C11, 14
and 16. Additionally, connection of this sector to a second major
subunit at C19–C20 requires placement of a functionalized tri-
substituted (E) alkene at C17–C18. With these prerequisites in
mind, a plan was conceived for synthesis of the C8–C19 portion 3
of rapamycin that envisioned this segment of the molecule as the
complexed 2,7-dihydroxy-3-ketolactone masked as a cyclic
hemiketal. Dithiane 4 was foreseen as emanating from a 2,4,5-
trihydroxypentanal 5 whose (2R,4S) configuration would origi-
nate in
a second generation plan was devised that employed
a manner different from the approach projected in Scheme 1.
Specifically, dithiane 4 was advanced to an -acyloxy acetate
D
-xylose (6). As it happened, this approach to 3 failed and
4
in
a
designed to undergo base-mediated (Chan) rearrangement to
a conjugated enediolate which, upon subsequent epoxidation,
would yield an a,b-diketo ester.
2. Results and discussion
acylation–hydrolysis product from dithiane
4 and dimethyl
2.1. First generation approach via acylation of a dithiane
The known diol 7, prepared in two steps from D
-xylose (6),13 was
selectively esterified at the primary alcohol with pivaloyl chloride14
to give 8 from which the residual secondary hydroxyl group was
excised by reduction of xanthate 9 with tri-n-butylstannane
(Scheme 2).15 Although hydrolysis of acetonide 10 proceeded
cleanly to diol 11, attempts to homologate the open form of this
cyclic hemiacetal by means of Wittig olefination were unsuccessful.
The apparent sensitivity of 11 towards basic conditions caused us to
redirect our planned route towards dithioacetal 12, which was
conveniently obtained by exposure of 10 to ethanethiol in hydro-
chloric acid. For reasons that became evident subsequently, it was
necessary to protect diol 12 as a relatively robust ketal for which
Scheme 2.
Scheme 1.

6644
J.D. White, S.C. Jeffrey / Tetrahedron 65 (2009) 6642–6647
Scheme 4.
of the allylic C–O bond), the most effective reagent for saturating
the double bond of 24 was diimide prepared in a pyridine–acetic
acid mixture (Scheme 5).18 Oxidation of the resultant alcohol 25
furnished aldehyde 26 which upon exposure to methanol in the
presence of acid yielded
a and b acetals 27 and 28. The acetals, in
which axial anomer 28 predominated, were readily identified by
their proton–proton coupling constants at C1 and C2 (8.3 Hz for 27
Scheme 3.
1,1-dimethoxycyclohexane proved to be the reagent of choice.
Dithioacetal 13 was then carefully hydrolyzed to aldehyde 14,
a sensitive substance that was transformed irreversibly into its
isomer 15 in the presence of acid.
Continuation towards dithiane 4 was initially pursued via cou-
pling of aldehyde 14 with sulfone 16 (Scheme 3). The latter had been
used successfully in a previous Julia olefination in these laborato-
ries,16 and the expected hydroxysulfone 17 (as a mixture of stereo-
isomers) was obtained in good yield. Unfortunately, reductive
elimination of 17 proceeded with only modest efficiency to give
trans alkene 18 which was contaminated with a significant quantity
of alcohol 19. Consequently, we turned towards Wittig olefination as
an alternative tactic for advancing aldehyde 14 towards 4.
An initial attempt along this line was disappointing since the
ylide from phosphonium iodide 20 produced cis alkene 21 in only
fair yield (Scheme 4). A more effective option proved to be use of
the ylide from phosphonium salt 22 in the presence of trime-
thylsilyl chloride,17 a process that afforded silyl ether 23 and then
alcohol 24 without the potentially troublesome deprotection of
p-methoxybenzyl ether 21.
Although hydrogenation of alkene 24 could be accomplished
over a platinum catalyst (palladium catalysts led to hydrogenolysis
Scheme 5.

J.D. White, S.C. Jeffrey / Tetrahedron 65 (2009) 6642–6647
6645
However, significant erosion of configuration at the methoxy-
bearing carbon of 35 occurred during this sequence which, it was
discovered, could be avoided by replacing the Grignard reagent
with a less basic methylating agent prepared from methyllithium
and cerium(III) chloride.19
At this juncture, it became possible to correlate 36 with
a known compound, lactone 37, which had been synthesized by
Ley and also isolated from degradation of rapamycin (Scheme 6).20
Acidic hydrolysis of methyl glycoside 36 followed by oxidation of
the resultant hemiacetal yielded 37 with 1H and 13C NMR spectra
identical to those of the same lactone provided by Professor Ley.
With the structures of 35 and 36 secure, our next task was ex-
tension of these methyl ketones towards subunit 4 by attaching an
(E) trisubstituted alkene needed for C17–C18 of rapamycin. In
planning this construction, it was crucial to leave a functional group
at C19 that would permit linkage with the ‘southern’ segment of the
macrolide, and to this end 35 and 36 were each subjected to
a Horner–Wadsworth–Emmons reaction with the anion of ethyl
Scheme 6.
diethylphosphonoacetate (Scheme 7). The resulting
a,b-un-
and 3.2 Hz for 28) and were separated by radial chromatography;
each was carried forward separately. First, the alcohols were con-
verted to their methyl ethers 29 and 30. Reduction of the pivalate
ester then gave alcohols 31 and 32 which were oxidized to the
corresponding aldehydes 33 and 34. Conversion of 33 to ketone 35
was carried out in a two-step process that involved Grignard ad-
dition of methylmagnesium bromide followed by oxidation.
saturated esters 38 and 39 were both obtained with an E/Z ratio of
approximately 14:1. The E/Z mixture of esters was reduced to the
corresponding allylic alcohols 40 and 41, each of which was treated
with 1,3-propanedithiol in the presence of boron trifluoride
etherate to yield a single dithiane 42. This diol was then exhaus-
tively silylated to give bis-silyl ether 43.
With dithiane 43 in hand, we were ready to test our plan for
constructing the 1,2,3-tricarbonyl substructure of 1 by acylating the
dithiane anion from 43 with dimethyl oxalate. To our surprise, the
outcome from this reaction after workup was not the expected
b-
dithianyl -keto ester but instead was -unsaturated aldehyde 50
a
a,b
(Scheme 8). The latter presumably arises from hydrolysis of silyloxy
diene 51, a result which informs us that lithiation of 43 has oc-
curred, not at the dithiane carbon, but at the allylic carbon (C10).
Subsequent 1,4-elimination of methoxide leads transiently to pre-
hydrolysis intermediate 51, which in the course of its conversion to
50 undergoes isomerizaton of the trisubstituted alkene into
conjugation.
Scheme 8.
2.2. Second generation approach via Chan rearrangement–
oxidation
Our failure to acylate 43 with dimethyl oxalate caused us to
revise our plan outlined in Scheme 1 for acquiring 3 and prompted
us to consider a strategy used previously in our laboratory for
Scheme 7.

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J.D. White, S.C. Jeffrey / Tetrahedron 65 (2009) 6642–6647
assembling a similar structural motif to 3 present in the macrolides
discovered by Chan,24 is nominally an O/C acyl migration which
takes place by internal attack of enolate 54 to give transient epoxide
55. The latter then collapses to 56. Standard work up from 56
produces 53, but 56 can react with a second equivalent of base to
form enediolate 57 which, as bis silyl ether 58, serves as a masked
version of 56. For the purpose of reaching 3, oxidation of the Chan
rearrangement product would be needed and this could be pro-
grammed from either 53 or 58.
aplasmomycin21 and boromycin.22 Our new approach was based
upon reorganization of an
a-acyloxyacetate 52 to an a-hydroxy
b
-keto ester 53 (Scheme 9).23 This rearrangement, initially
Synthesis of the precursor for this new approach to 3 began by
conventional transformation of dithiane 43 to aldehyde 6025 and
then oxidation to carboxylic acid 6126 (Scheme 10). Treatment of
the potassium carboxylate from 61 with methyl bromoacetate
afforded
the presence of trimethylsilyl chloride. An initial UV-active product
shown to be -unsaturated ester 63 was formed but this com-
a-acyloxy acetate 62 which was reacted with excess LDA in
a,b
pound was unstable and was therefore treated promptly with
m-chloroperoxybenzoic acid in order to elevate the protected
enediol to the tricarbonyl oxidation level. Epoxide 64 was not seen
in this Rubuttom27 oxidation since it rearranged spontaneously to
bis-silyl ketal 65 which was purified by chromatography and was
fully characterized. Exposure of 65 to acidic ion-exchange resin in
the presence of methanol led directly to methyl ketal 67 pre-
sumably via the acylic diketo ester 66.
3. Conclusion
We have shown that an a-acyloxy ester bearing the three ster-
eocenters corresponding to C11, 14 and 16 of rapamycin undergoes
rearrangement and subsequent oxidation to provide the masked
tricarbonyl unit embedded in the C8–C19 portion of 1. The con-
gested functional groupings in this sector of rapamycin limit
Scheme 9.
Scheme 10.

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6647
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Acknowledgements
We are indebted to Professor Steven Ley and Michael Willis,
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through Grant No. GM50574.
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Supplementary data
Experimental procedures and characterization data for new
compounds. Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2009.06.026.
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