Total synthesis of rapamycin

Article abstract of DOI:10.1002/anie.200604053

Rapamycin synthesis all wrapped up: A new convergent synthesis of rapamycin (1) is reported that involves a macroetherification/catechol tethering strategy for construction of the macrocyclic core of this intriguing natural product. Other studies on this commercialized potent immunosuppressant delineate new cell signaling pathways of relevance to cancer chemotherapy. (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200604053

Angewandte
Chemie
DOI: 10.1002/anie.200604053
Natural Products Synthesis
Total Synthesis of Rapamycin**
Matthew L. Maddess, Miles N. Tackett, Hidenori Watanabe, Paul E. Brennan,
Christopher D. Spilling, James S. Scott, David P. Osborn, and Steven V. Ley*
Rapamycin (1) is a macrocyclic natural product first isolated
in 1975 from Streptomyces hygroscopicus from a soil sample
collected on Easter Island (Rapa Nui).[1,2] While its initial
biological activity as an antifungal agent[3] attracted little
attention, it soon became recognized as a potent immuno-
suppressive agent, which was launched commercially by
Wyeth in 1999 for clinical usage following organ transplanta-
tion.[4] Not surprisingly, the interesting architecture and
important biological profile of rapamycin (1) attracted
interest from the organic synthesis community and cumulated
in four total syntheses in the 1990s.[5,6] Several molecules
related to rapamycin, such as FK506,[7] L-685-818,[8] merida-
mycin,[9] ascomycin,[10] and the antascomicins,[11] have also
been characterized and extensively studied. Over the years,
the detailed biology and the molecular targets for these
fascinating compounds have gradually been revealed. Despite
the importance and obvious value of the immunomodulating
effects,[12] more extensive studies are delineating whole new
fundamental signaling pathways that have significant biolog-
ical ramifications, especially for cancer chemotherapy.
Indeed, new analogues of rapamycin, such as CCI-779,
RAD001, and AP23573, have been developed and are rapidly
progressing through clinical trials for applications as anti-
tumor agents.[13,14]
Retrosynthetically, we sought to address the formation of
the rapamycin macrocycle by employing a transannular
catechol-templated Dieckmann-like reaction that was used
with success in our recent synthesis of the related molecule
antascomicin B.[11a] Further disconnection at the central olefin
0
ꢀ
(C20 C21) of the triene through a Pd -catalyzed Stille
coupling affords the simplified C10–C20 lactone 3 and C21–
C42 vinyl stannane 2. For the latter stannane (2), we
envisioned sequential carbanionic coupling of 4, 5, and 6,
whose syntheses were designed to highlight chemistry devel-
oped by our group (Scheme 1).
The synthesis of the C29–C32 vinyl bromide 4 commences
from the known monoprotected alcohol 7 (Scheme 2).[16]
Swern oxidation followed by dithiane formation with con-
comitant loss of the trityl group produced 8 in excellent yield.
Installation of the correct oxidation state in a protected form
at C32 prior to construction of the associated p system at
ꢀ
C29 C30 avoided any potential problems of epimerization at
the intervening C31 methyl stereocenter later in the synthesis.
The requisite olefin geometry was then installed through
The mammalian target for rapamycin, mTOR (also
known as FRAP, RAFT, RAPT, or SEP),[15] is a serine/
threonine protein kinase, which is involved in a variety of
intracellular events and plays a central role in regulating cell
proliferation, growth, differentiation, migration, and survival.
It is now recognized that deregulation of mTOR signaling
occurs in a diverse set of human tumors and confers higher
susceptibility to inhibitors of mTOR.[14] As a consequence,
there is renewed chemical interest in the area and, herein, we
report a new route for the total synthesis of rapamycin (1).
[*] Dr. M. L. Maddess, M. N. Tackett, Prof. H. Watanabe,
Dr. P. E. Brennan, Dr. C. D. Spilling, Dr. J. S. Scott, D. P. Osborn,
Prof. S. V. Ley
Department of Chemistry, University of Cambridge
Lensfield Road, Cambridge CB21EW (UK)
Fax: (+44)1223-336-442
E-mail: svl1000@cam.ac.uk
[**] The authors are grateful to Merck Research Laboratories (Academic
Development Program) and Novartis (Novartis Research Fellow-
ship to S.V.L.), NSERC (to M.L.M), EPSRC (for studentships to
M.N.T. and D.P.O.), the University of Tokyo for a study leave (to
H.W.), EPSRC (to P.B.), the Ramsay Memorial Trust (to J.S.S.), and
the University of Missouri for a study leave (to C.D.S.). The authors
also acknowledge all the other researchers who have contributed to
the early development of the project described herein, and Wyeth for
the generous donation of authentic samples of rapamycin.
Scheme 1. Retrosynthetic analysis for rapamycin (1). TBS=tert-butyl-
dimethylsilyl; PMB=para-methoxybenzyl; TES=triethylsilyl.
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Scheme 3. Reagents and conditions: a) Lipase PS-30 (8 wt%), DME/
vinyl acetate (5:1), room temperature, 14 h, 75%, 96–99% ee;
b) TBSCl, Im, CH2Cl2; c) K2CO3, MeOH; d) NaH, PMBCl, TBAI, THF;
e) TBAF, THF, 90% over four steps; f) SO3·Py, DMSO, DIPEA, CH2Cl2,
08C, 99% for both 13 and 14. Im=imidazole, TBA=tetrabutyl-
ammonium.
Scheme 2. Reagents and conditions: a) (COCl)2, DMSO, DIPEA,
CH2Cl2; b) HS(CH2)3SH, BF3·OEt2, CH2Cl2, ꢀ788C!RT, 99% over two
steps; c) SO3·Py, DMSO, DIPEA, CH2Cl2, 08C; d) KHMDS, [18]crown-6,
(CF3CH2O)2P(O)CH2CO2Me, Br2, THF, 96% over two steps; e) DIBAL-
H, CH2Cl2, ꢀ458C, 99%; f) MsCl, Et3N, DMAP, CH2Cl2, then LiBr,
DMF, 70%; g) LiBHEt3, THF, 08C, 99%. DMSO=dimethyl sulfoxide,
DIPEA=diisopropylethylamine, Py=pyridine, HMDS=bis-
(trimethylsilyl)amide, DIBAL-H=diisobutylaluminum hydride,
MsCl=methanesulfonyl choride, DMAP=4-dimethylaminopyridine,
DMF=N,N-dimethylformamide.
gram quantities of material. Moreover, by masking the C28
carbonyl as an olefin, protection of the C26 alcohol as its PMB
ether was facile. In the event, subjecting 17 to standard
conditions readily afforded the bis-protected derivative 18.
Direct ozonolysis of 18 proved problematic, thus, we
employed a two-step dihydroxylation/cleavage protocol to
afford the desired electrophile 5a in good yield. This
Parikh–Doering oxidation, followed by a Horner–Wads- approach had the added benefit of avoiding purification of
worth–Emmons reaction between the resulting aldehyde
and the brominated Still–Gennari phosphonate,[17] prepared
in situ, and produced the kinetic bromoalkene 9 as only one
detectable olefin isomer. This high stereoselectivity was
the sensitive a-chiral aldehyde 5a, as cleavage of 19 with
Pb(OAc)4 was exceptionally clean and high yielding
(Scheme 4). The second higher-yielding approach for con-
ꢀ
critical for our planned formation of the C29 C30 unsym-
metrical trisubstituted alkene through a vinylic carbon–
carbon s bond construction.[6c] However, this approach also
necessitated the subsequent removal of the ester function-
ality. Reduction of 9 to the primary alcohol 10 gave highest
yields with DIBAL-H in CH2Cl2, and of the various methods
to effect deoxygenation,[18] treatment of the allylic bromide 11
with Super Hydride was the most effective for synthesis of the
desired C29–C32 vinyl bromide. Overall, this robust approach
to the central dianion equivalent 4 provided ready access to
gram quantities of material ready for coupling to the
respective electrophiles 5 and 6.
For the synthesis of the C22–C28 electrophile 5, we
required large amounts of the enantiomerically enriched syn-
1,3-dimethylated alcohols 13 and 14. For this purpose, we
selected enzymatic desymmetrization[19,20] of the meso diol
12[21] which gave 13 in consistently high ee (96 to 99%).[22] The
resulting monoacetylated product 13 could then be readily
converted into the PMB analogue 14 through simple and
high-yielding protecting-group manipulations. Both 13 and 14
were cleanly oxidized to the corresponding aldehydes 15 and
16 under Parikh–Doering conditions (Scheme 3).
As the stereochemical configuration of the C26 alcohol is
ultimately of no consequence, we elected to pursue two
concurrent approaches for the synthesis of the C22–C28
electrophile (Schemes 4 and 5). In the first approach,
asymmetric Brown alkoxyallylation,[23] followed by cleavage
of the acetate protecting group to facilitate purification,
afforded the diastereomerically pure diol 17. The facial
selectivity of the alkoxyallylation was confirmed by X-ray
analysis of the bis-p-nitrobenzoate ester (20). Although the
yield for these two steps was lower than desired, the reaction
employs the product from enzymatic desymmetrization
directly, can be performed on a large scale, and easily affords
Scheme 4. Reagents and conditions: a) sBuLi, allylmethyl ether, THF,
ꢀ788C, then (ꢀ)-(MeO)BIpc2, then BF3·OEt2, then 15, 14 h, then 3n
NaOH, 30% H2O2, ꢀ788C!RT; b) K2CO3, MeOH, room temperature,
40% over two steps; c) NaH, PMBCl, TBAI, DMF, room temperature,
99%; d) OsO4, NMO, acetone/water, room temperature, 78%;
e) Pb(OAc)4, PhH, 99%; f) p-NO2C6H4C(O)Cl, Et3N, DMAP, CH2Cl2,
99%. Ipc=isopinocampheyl, NMO=N-methylmorpholine N-oxide.
ꢀ
struction of the C26 C27 carbon bond involved application of
our recently developed butane-2,3-diacetal (BDA, 21) variant
of glycolic acid[24] to effect a highly selective aldol condensa-
tion with either 15 or 16 in 82 and 92% yield, respectively
(Scheme 5).
An X-ray diffraction experiment performed on a deriv-
ative of adduct 22 confirmed that the R,R-configured lactone
21 led to the desired stereochemistry of 22,[24] however,
difficulties with protecting groups precluded the further
elaboration of this intermediate. In contrast, the use of
PMB-protected derivative 23 proved advantageous for fur-
ther manipulation, although, as expected, protection of the
secondary alcohol at C26 was extremely difficult as a result of
the b disposition of the ester carbonyl and numerous acetal
moieties present within 23. Extensive experimentation was
ultimately successful in identifying conditions[25] that allowed
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Scheme 5. Reagents and conditions: a) LiHMDS, THF, ꢀ788C, then
AcOH, 82% for 15, 92% for 16; b) PMB-TCA, TrBF4 (5 mol%), THF,
room temperature, 47%; c) CSA, MeOH, room temperature, 80%;
d) Ag2O, MeI, CH2Cl2, 508C, 74%; e) LiHMDS, MeO(Me)NH·HCl,
THF, ꢀ208C!ꢀ108C, 97%. Tr=trityl; TCA=trichloroacetimidate;
CSA=(ꢁ)-camphorsulfonic acid.
for introduction of the PMB ether (24). Although this
reaction did not go to completion, the starting material 23
could be recovered and recycled. Transesterification with
concurrent liberation of the hydroxy group at C27 was
effected by treatment of 24 with catalytic CSA in MeOH.[24]
Finally, methylation under mild silver oxide conditions,
followed by formation of the Weinreb amide, concluded a
viable route to our second C22–C28 electrophilic coupling
partner 5b (Scheme 5).
Control studies with D2O quenching indicated that the
C29–C32 vinyl bromide 4 could be cleanly transmetalated
with tBuLi at low temperature (ꢀ968C), and no evidence of
abstraction of the C32 dithiane proton was observed.
Although an excess (2 equiv) of the lithio anion of 4 was
required for improved yields, addition of solutions of either
Scheme 6. Reagents and conditions: a) tBuLi, THF, ꢀ968C, then 5a,
ꢀ968C!ꢀ788C, 66% (25a/25b 3:1); b) SO3·Py, DMSO, DIPEA,
CH2Cl2, 08C, 99%; c) Zn(BH4)2, Et2O, ꢀ208C, 3 days, 80%; d) TESOTf,
2,6-lut, CH2Cl2, ꢀ788C, 40 min, 99%; e) tBuLi, THF, ꢀ968C, then 5b,
ꢀ968C!ꢀ788C, 80%; f) Zn(BH4)2, Et2O, ꢀ208C, 2 h, 83%; g) TESCl,
Im, DMF, 508C, 93%. 2,6-lut=2,6-lutidine, TESOTf=triethylsilyl tri-
fluoromethanesulfonate.
conformational change induced by the opposite stereochem-
istry at this center. Differences were once again apparent in
the following TES protection, which was extremely sluggish
with TESOTf even at room temperature. Switching to TESCl
in DMF with heating resolved this issue and afforded a second
completed C22–C32 fragment 28 ready for coupling to the
epoxide 6 (Scheme 6).
ꢀ
5a or 5b resulted in the desired C C bond formation between
the two coupling partners (Scheme 6).
For 5a, a partially separable mixture of diastereomers
(25a/25b 3:1) was obtained in favor of the undesired
configuration of the C28 carbinol. This finding was ultimately
immaterial as the mixture of diastereomers could be cleanly
oxidized to the corresponding ketone and subsequently
reduced in high selectivity with Zn(BH4)2 to afford the
correct stereochemistry.[5d,23] Interestingly, relative to other
reports (and other substrates in our synthesis; see below) this
reduction was very sluggish and it proved surprisingly difficult
to remove residual zinc from the product. Finally TES
protection at low temperature afforded the completed C22–
C32 fragment 26 ready for coupling to the C33–C42 epoxide
(Scheme 6).
The addition reaction between 4 and Weinreb amide 5b
under identical conditions afforded a significantly improved
yield of the desired coupling partner 27 without the problems
of a diastereomeric mixture. In contrast to previous results,
subsequent reduction with Zn(BH4)2 was rapid but still
occurred with high selectivity and yield. The variation in
reactivity must originate either through direct interaction of
the C26 alkoxy function or perhaps indirectly through a
We had previously disclosed our approach[27] to the latter
C33–C42 epoxide 6 which highlighted the intramolecular
trapping of oxonium ions by allyl silanes.[28] Addition of tBuLi
to a cold (ꢀ788C) mixture of 6 and 26, or 28, in THF/HMPA
followed by rapid warming to ꢀ408C resulted in smooth
epoxide ring opening and construction of the C22–C42 carbon
framework.[6c] For dithiane 28, it was important to slightly
decrease the amount of HMPA and the reaction time to
maximize the yield. Removal of the dithiane moiety in both
29 and 32 using the Stork–Zhao bis(trifluoroacetoxy)iodo-
benzene protocol[29] occurred smoothly and was necessary to
permit esterification of the C34 alcohol of 29 and 32 with (S)-
Boc-pipecolinic acid. PMB deprotection with buffered DDQ,
followed by double oxidation at C26 and C22 employing
Swern conditions, afforded in excellent yield the common
intermediate 31, which was identical in all respects (NMR,
MS, IR, [a]D) starting from either 29 or 32. The use of Swern
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oxidation conditions was critical to avoid formation of the
undesired lactone between C22 and C26-OH (Scheme 7).[30]
Scheme 8. Reagents and conditions: a) DIBAL-H, toluene, ꢀ788C;
b) TBSCl, Im, DMAP, DMF, room temperature, 92% over two steps;
c) Pd(OH)2, H2, EtOAc, room temperature, 99%; d) TPAP, NMO, 4-ꢀ
M.S., CH2Cl2/CH3CN, room temperature, 99%; e) MeMgBr, THF,
ꢀ788C, 74% (d.r. =2:1); f) TPAP, NMO, 4-ꢀ M.S., CH2Cl2/CH3CN,
room temperature, 92%; g) (EtO)2P(O)CH2CN, NaHMDS, THF, 08C,
then ketone 35, ꢀ788C, 85% (E/Z 7:1); h) DIBAL-H, toluene, ꢀ788C,
91%; i) TBAF, AcOH/H2O/THF, room temperature; j) TPAP, NMO,
4-ꢀ M.S., CH2Cl2, 85% over two steps; k) CrCl2, CHI3, THF/dioxane,
08C, 80% (E/Z 6:1). TPAP=tetra-n-propylammonium perruthenate,
M.S.=molecular sieves, Bn=benzyl.
Debenzylation of 34 with Pearlmanꢀs catalyst, TPAP[34]
oxidation, and addition of MeMgBr into the resulting
aldehyde gave the desired secondary alcohol as a 2:1 mixture
of diastereomers. A second oxidation with TPAP then
afforded ketone 35 for introduction of the C17–C18 alkene.
Homologation was then accomplished with commercially
available diethyl(cyanomethyl)phosphonate,[35] which at low
temperature (ꢀ788C) gave good levels of E/Z olefin geom-
etry (7:1) for the conjugated product as established by NOE
studies. Importantly, the major isomer could be separated and
subsequently reduced cleanly with DIBAL-H to afford the
corresponding enal 36. Desilylation of 36 with TBAF in the
presence of AcOH,[36] followed by oxidation of the resulting
lactol with TPAP, gave lactone 37 which was then subjected to
a Takai olefination[37] using the modified conditions reported
by Evans and Black.[38] The resulting vinyl iodide 3 was
formed as an inseparable mixture of olefin isomers (6:1) in
favor of the desired E configuration (Scheme 8).
Scheme 7. Reagents and conditions: a) 6, tBuLi, THF/HMPA (5:1),
ꢀ788C!ꢀ408C, 77%; b) THF/MeOH/H2O (10:9:1), PhI(OCOCF3)2,
room temperature, 84%; c) 30, DCC, DMAP, CH2Cl2, ꢀ58C, 24 h,
84%; d) DDQ, pH 7 buffer, CH2Cl2, room temperature, 93%;
e) (COCl)2, DMSO, Et3N, CH2Cl2, 99%; f) 6, tBuLi, THF/HMPA (9:1),
ꢀ788C!ꢀ408C, 81%; g) PhI(OCOCF3)2, THF/MeOH/H2O (10:9:1),
room temperature, 83%; h) 30, DCC, DMAP, CH2Cl2, ꢀ58C, 24 h,
99%; i) DDQ, pH 7 buffer, CH2Cl2, room temperature, 90%; j) (COCl)2,
DMSO, Et3N, CH2Cl2, 99%. HMPA=hexamethylphosphoramide,
DCC=1,3-dicyclohexylcarbodiimide, DDQ=2,3-dichloro-5,6-dicyano-
1,4-benzoquinone, Boc=tert-butyloxycarbonyl.
Our synthesis of an advanced intermediate for the
preparation of the C10–C20 lactone 3 has also been described
and highlights the utility of iron carbonyl methodology for the
construction of complex molecules such as lactone 33.[31]
Previous results[32] concerning construction of the triene
portion of rapamycin had suggested that a Stille coupling[33]
would be the best approach for coupling to the C21–C42
fragment. Furthermore, model studies within our group
indicated disconnection at the C20–C21 bond was optimal,
and in accordance with the observations of Smith et al.[5b] we
elected to employ the lactone portion of the molecule as the
vinyl iodide. The C11 methyl stereocenter proved extremely
susceptible to epimerization and necessitated reduction to the
lactol followed by protection as the TBS ether 34 (Scheme 8).
The C21–C42 vinyl stannane was constructed through a
second Takai olefination, and proceeded smoothly to give the
E-vinyl iodide with no observable formation of the Z isomer
(Scheme 9). Cross-coupling with freshly prepared [Pd-
(PFur3)2Cl2][39] and hexamethyltin afforded the desired vinyl
stannane 2a. A second coupling reaction with the same
catalyst system and the E/Z isomeric mixture of lactones 3
effectively generated the desired triene 38. Interestingly, no
1
minor geometric isomers could be detected in the H NMR
spectrum of the Stille coupled product. One explanation of
this fortuitous result is that the minor Z component of 3 might
have equilibrated to the E isomer under the reaction con-
ditions. Alternatively, the Z isomer may react more slowly
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Scheme 9. Reagents and conditions: a) CrCl2, CHI3, THF, 08C!RT, 82%; b) [Pd(PFur )2Cl2], (Me3Sn)2, NMP, dark, room temperature, 68%;
3
c) [Pd(PFur3)2Cl2], 3, NMP, dark, room temperature, 69%; d) LiAlH(OtBu)3, THF, ꢀ108C, 81%; e) Alloc-Cl, 4-pyrrolidinopyridine, CH2Cl2, 81%;
f) 0.1m LiOH in H2O, THF, 08C, 89%; g) TESOTf, 2,6-lut, CH2Cl2, ꢀ208C!RT, 88%; h) BrCH CO2Br, 2,6-lut, CH2Cl2, ꢀ208C, 66%; i) catechol,
2
DCC, DMAP, CH2Cl2, 08C!RT, 88%; j) K CO3, DMF, room temperature, 81%; k) LiHMDS, THF, ꢀ788C!ꢀ208C, 78%; l) [Pd(PPh3)4], dimedone,
2
THF, room temperature, 80%; m) PhI(OAc)2, CH3CN/H2O (10:1), 08C; n) DMP, Py, CH2Cl2, room temperature, 61% over two steps; o) HF·Py,
THF, 508C, 61%. Fur=2-furyl, NMP=N-methyl pyrrolidinone, Alloc-Cl=allyloxycarbonyl chloride.
than the E isomer. To avoid recurring problems with b
elimination across C33–C34 later in the synthesis, the C32
carbonyl was selectively reduced at this point with LiAlH-
pleased that the catechol tethering strategy employing an
uncommon macroetherification[41] was demonstrated after
treatment of 42 with LiHMDS effected the templated Die-
ckmann-like condensation[42] to construct the C9–C10 bond.
Following Alloc deprotection, 43 was isolated in good yield.
Finally, catechol cleavage, oxidation of the C9 and C32
alcohols (44), and silyl group deprotection resulted in
spontaneous C10 lactol formation to complete the total
synthesis of rapamycin (1), which was identical in all respects
by comparison with an authentic sample of the natural
product.
[40]
(OtBu)3 to afford 39, which was subsequently protected
with Alloc-Cl (40). Further manipulation to a-bromoamide
41 was achieved by hydrolysis of the lactone to the carboxylic
acid, protection of the resulting secondary alcohol with
concomitant liberation of the secondary amine, and finally
amide formation with a-bromoacetyl bromide. This sequence
of events was critical to avoid epimerization of the C11
methyl stereocenter.
DCC-mediated coupling of catechol with the free carbox-
ylic acid 41, followed by alkylative ring closure afforded the
macrocyclic ether 42 in 71% overall yield. We were especially
In summary, we have presented a new and efficient
convergent route to an intriguing natural product, whose
applications continue to evolve to this day. The challenge
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K. Wüthrich, FASEB J. 1995, 9, 63; c) P. J. Belshaw, S. D. Meyer,
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posed by the total synthesis of (ꢀ)-rapamycin has been met
through a combination of established research procedures
and our own methods. The use of BDA chemistry as both a
protecting and stereodirecting functionality, iron carbonyl
chemistry, intramolecular trapping of oxonium ions by allyl
silanes, and an efficient macroetherification/catechol tether-
ing strategy for the formation of the formidable macrocyclic
core of rapamycin represent some of the highlights from this
approach.
[13] For
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[15] For reviews of mTOR, see: a) D. C. Fingar, J. Blenis, Oncogene
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1926.
Received: October 2, 2006
Published online: December 8, 2006
Keywords: antitumor agents · immunosuppressants ·
.
macrocyclization · natural products · total synthesis
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