Total synthesis of 1α,25-dihydroxyvitamin D3 (calcitriol) through a Si-assisted allylic substitution

Article abstract of DOI:10.1039/c7cc04690a

Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D₃ (calcitriol). The synthetic strategy relies on an unprecedented Si-assisted S_N2′-syn displacement of carbamates by cuprates to set the challenging pivotal quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the catalytic asymmetric reduction of an α,β,γ,δ-unsaturated ester with CuH to generate the natural steroidal configuration at C20 and a Pauson-Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for structure-function studies and drug development.

Full text of DOI:10.1039/c7cc04690a

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Reactivity differences of Sc
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Total Synthesis of 1α,25-Dihydroxyvitamin D (Calcitriol) Through
3
,
§
a Si-Assisted Allylic Substitution
†
Received 00th January 20xx,
Accepted 00th January 20xx
a
b
a,
Borja López-Pérez, Miguel A. Maestro, and Antonio Mouriño *
DOI: 10.1039/x0xx00000x
3
Herein, we describe a versatile and efficient total synthesis of 1α,25-dihydroxyvitamin D (calcitriol). The synthetic strategy
N
relies on an unprecedented Si-assisted S 2’-syn displacement of carbamates by cuprates to set the challenging pivotal
www.rsc.org/
quaternary methyl group at the fused-ring junction of the CD-trans-hydrindane core. Other key transformations involve the
catalytic asymmetric reduction of an α,β,γ,δ−unsaturated ester with CuH to generate the natural steroidal configuration at
C20 and a Pauson-Khand cyclization to form the CD-ring skeleton. This strategy enables the syntheses of novel analogs for
structure-function studies and drug development.
1
1,12
catalyzed coupling reactions.
In most of these approaches, the
Introduction
CD-side chain fragment was prepared from the Inhoffen-Lythgoe
diol, which is easily available from the degradation of vitamin D2,
thus, limiting the access to unknown 1,25D analogs modified at the
bicyclic CD-ring system and/or at C20. Three elegant total syntheses
,2 of 1,25D and trans-hydrindane CD-ring building blocks have also been
1
α,25-Dihydroxyvitamin D (1,25D, calcitriol, 1, ), the active form of
3
3
vitamin D and the most potent steroid hormone known, regulates
mineral homeostasis and mediates pleiotropic actions, including cell
1
differentiation, cell proliferation, and immunomodulation.
13
13a,b
13d
reported. The Hoffmman-La Roche
and Wicha syntheses are
Recently, it was also found that 1,25D activates at least 229 genes
associated with several diseases, including arthritis, diabetes and
cancer, suggesting that 1,25D might have an even broader range of
biological functions than originally thought. 1,25D itself has clinical
applications, but the pharmacological doses required for treatment
based on the Hajos-Parrish ketone, which incorporates the
hydrindane all-carbon bridgehead stereocenter. The value of 1,25D
as a therapeutic agent and the need to explore the biological
activities of new 1α-hydroxyvitamin D3 analogs modified at the
CD-ring encouraged us to develop a versatile convergent synthetic
approach via the construction of a trans-hydrindane moiety, which
is also a common motif in other natural products, such as steroids
and cortistatins.
3
4,5
of cancer induce strong, undesired hypercalcemia. Structure-
function studies of numerous synthetic 1,25D analogs have proven
that the calcemic effects can be significantly suppressed during cell-
differentiating activities; however, the mechanism of this selectivity
1
,2,6
has not yet been unraveled.
The potential use of 1,25D and its
analogs in cancer treatment has led to a renewed interest in
vitamin D research with a main goal of developing of analogs with
high cell differentiation ability and low or negligible calcemic action.
Particularly compelling structural modifications that promote
dissociation properties include the removal of the 19-exo-double
6
7
8
bond, unnatural configurations at C14 and C20 and unsaturations
9
at the side chain or D-ring.
Over the last two decades, numerous active 1α-hydroxyvitamin D
analogs with modifications at the side chain and A-ring have been
synthesized by convergent approaches in which the CD-side chain
and the A-ring fragments have been efficiently coupled by different
1
0
strategies, including Wittig-Horner and Julia olefinations and Pd-
Scheme 1 Proposed Strategy for the Synthesis of 1,25D.
Scheme 1 illustrates the retrosynthetic analysis for the hormone 1,25D
a.
(
1). The synthetic plan pursues access to: 1) the CD-ring, 2) natural or
Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas,
14a
Universidad de Santiago de Compostela, Avda. Ciencias s/n, 15782 Santiago de
Compostela (SPAIN). E-mail: antonio.mourino@usc.es
Departamento de Química-CICA, Universidad de A Coruña,
unnatural configuration at C20, and 3) isotopic labeling at the end of
the synthesis. To assemble the triene system, we chose the Pd(0)-
catalyzed process previously developed in our laboratory, which
involves ring closure and Suzuki-Miyaura coupling between enol-triflate
b.
Campus da Zapateira s/n. 15071 A Coruña (SPAIN)
† Electronic Supplementary Informaꢀon (ESI) available: [Experimental procedures,
1 13
spectroscopic data and copies of H and C NMR spectra and characterization data
2
and alkenyl-boronic ester 3, providing a mild, small-scale access to an
for all new compounds. See DOI: 10.1039/x0xx00000x
§
In memory of José Barluenga Mur
array of test analogs for rapid screening to generate clinical
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12
candidates.
N
Despite extensive studies on the reduction of envisaged to arise by an intramolecular Cu-induced S 2’-syn
α,β-unsaturated ketones and esters with copper hydrides, the displacement of a reagent-directing leaving group derived from
1
5
reduction of α,β,γ,δ-unsaturated esters remains unexplored to date.
allylic alcohol 7. This reaction has not been previously used to form
1
7
Inspired by Buchwald’s catalytic asymmetric reduction of α,β- trans-hydrindane angular all-carbon quaternary stereocenters.
15b,c
unsaturated esters with chiral phosphine-CuH species,
we envisaged The intramolecular attack of the organocopper reagent to the ring-
the generation of the desired stereochemistry of 3 at C20 by the junction at the sterically congested concave face makes this
1
6
catalytic asymmetric reduction of the α,β,γ,δ-unsaturated ester 4.
transformation especially challenging. Most of the known
approaches to the installation of a methyl group at the trans-
The unsaturated side chain of 4 could arise from a Miyaura Pd- hydrindane angular carbon center utilize starting materials bearing
1
0-13,18
catalyzed coupling between the enol triflate derived from 6 and such a methyl group,
with the exception of the indirect
boronate 5. This strategy would also provide access to 16-ene- hydroxyl-directed intramolecular methylation of an allylsulfone with
1
9
modified analogs. We identified the construction of the CD-trans- AlMe
3
developed by Fuchs
and Corey’s hydroxyl-directed
2
0
hydrindane unit bearing an all-carbon quaternary stereocenter as Simmons-Smith process. The allylic alcohol 7 could be synthesized
21
the most challenging part of the synthesis. The installation of the from 5-hexyn-1-ol (8) via the Pauson-Khand reaction (PKR) that
pivotal quaternary methyl group at the fused-ring junction of 6 is would form the bicyclic CD-ring skeleton.
Scheme 2 Synthesis of the upper fragment 3. TBSCl = tert-butyldimethylsilyl chloride, NMO = N-methylmorpholine N-oxide, TBAF = tetra-n-butylammonium
fluoride, LDA = lithium diisopropylamide, PMHS = polymethylhydrosiloxane, tolBINAP = 2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthalene, DMP = Dess–Martin
2 2 3
periodinane, B pin = bis(pinacolato)diboron, PCy = tricyclohexylphosphine, dppf = 1,1′-ferrocenediyl-bis(diphenylphosphine), Tf = trifluoromethanesulfonyl,
pTs = p-toluenesulfonyl, DMF = dimethylformamide, DIBAL-H = diisobutylaluminum hydride, HMPA = hexamethylphosphoramide, PTS = polyoxyethanyl-α-
tocophenyl sebacate.
1
4b,22
The upper fragment 3 was prepared from (-)-enyne 9,
as shown compound with Me CuLi led to recovery of the starting material in
2
in Scheme 2. Initially, we chose C-SiBnMe as a suitable moiety for accordance with the results obtained by Corey and coworkers on
2
2
0
assembling the side chain via Hiyama coupling in later stages of the structurally similar compounds. Reduction of 12 with DIBAL-H
synthesis. Protection of 9 (TBSCl) followed by deprotonation (nBuLi) furnished the key allylic alcohol 7a (99% yield), which is required to
and silylation (SiBnMe Cl) afforded enyne 11 in 91% overall yield for study the generation of the trans-hydrindane quaternary angular
2
the two steps. Exposure of 11 to Pauson-Khand cyclization methyl group by the S 2’-syn process. Attempts to generate the
N
2
4
conditions [Co (CO) , NMO] led to enone 12 as
a
single pivotal trans-hydrindane methyl group through Breit’s method
2
8
2
3
diastereoisomer in 80% yield. The relative stereochemistries at C8 employing the ortho-diphenylphosphanylbenzoate group (o-DPPB)
1
14b
and C14 were determined by H NMR. The availability of enone as the reagent-directing leaving group and CH MgBr resulted in the
3
1
2 gave us the opportunity to explore its behavior towards simple formation of the unexpected S 2’-anti-product 13b as the major
N
cuprates. Not surprisingly, treatment of 12 or its C17-desilylated compound together with substantial amount of the S 2-product
N
2
| J. Name., 2012, 00, 1-3
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1
4b
1
3c (S9).
The identity of 13b was established by comparison with 60 °C provided the ester 16 in 75% yield together with a small
the S
N
1
2’-anti-product obtained from the corresponding benzoate 7c amount of 1,6-reduction products (6%) and recovered starting
4b
(
S10).
These results led us to examine the behavior of the material (11%). The micellar catalysis accelerates the reaction and
2
5
carbamate group as the reagent-directing group. Notably, in a improves the regioselectivity on the 1,4-reduction product.
one-pot operation, deprotonation of 7a (nBuLi) followed by Sequential reduction and catalytic hydrogenation of 16 afforded
successive additions of PhNCO, CuCN and MeLi resulted in the alcohol 18 in 93% yield. X-ray analysis of the deprotected diol 19
formation of the desired trans-hydrindane 13a in 80% yield confirmed the relative configuration of the five stereogenic centers
3
0b,14b
together with the unreacted carbamate, which could be recycled of the molecule.
Alcohol 18 was transformed into the
back into the reaction under the same reaction conditions to give corresponding iodide 20, which upon treatment with the enolate of
1
4b
the desired product in similar yield.
To gain insight into this tert-butyl-acetate gave the ester 21 in 94% yield. Finally, the
transformation, we examined the behaviors of similar substrates in straightforward conversion of ester 21 into the desired boronate 3
which the C17-silyl group was replaced by hydrocarbon chains or was accomplished by a 4-step sequence in 60% overall yield
1
2
hydrogen. Interestingly, in both cases we recovered the following procedures previously developed in our laboratory:
corresponding carbamates, suggesting that the success of the S 2’- deprotection (TBAF), Dess-Martin periodinane oxidation (DMP),
N
2
2
syn allylic substitution is dependent on the substituent at C17.
Wittig-olefination (Ph P=CHBr), and Pd(0)-catalyzed sp CBr-sp CB
3
interchange.
We hypothesize that the Si atom favors initial intramolecular
complexation of Cu with a double bond (complex 7e) and stabilizes
the anionic transition state 7f, leading to the trans-hydrindane 13a,
which likely occurs by a concerted transfer of the methyl group
with concomitant displacement of the directing group (Scheme
Ph
N
Ph
N
Me
Me
O
O
Cu Si
Cu Si
δ
O
δ
O
δ
7a
13a
H
H
2
6,27
H
H
3
).
With key silyl compound 13a in hand, we next faced the task
TBSO
TBSO
7e
7f
of assembling the side chains at C17. Unfortunately, attempts to
directly install a side chain on compound 13a by Hiyama coupling
were unsuccessful likely due to the steric hindrance around C17. As
N
Scheme 3 Proposed Transition State for the Si-assisted S 2’-syn Allylic
Substitution.
an alternative, we conceived the installation of the side chain via a With the CD-ring in hand, the stage was set for the final convergent
Pd-catalyzed reaction on vinyl triflate 15. Therefore, the formation formation of the triene system (Scheme 5). Pd-catalyzed ring-
2
8
12
of ketone 6 from alkenylsilane 13a by Tamao-Fleming oxidation
closure of the enoltriflate 2 (1.1 equiv) and subsequent Suzuki-
was envisioned as a crucial issue. After extensive experimentation Miyaura reaction with boronate 3 (1 equiv) provided ester 25,
with several silyl groups, we found that the benzyldimethylsilane which upon reaction with MeLi and deprotection gave the desired
2
9
group in the presence of TBAF and H O resulted in the formation natural hormone 1,25D (1) (3% overall yield from 5-hexyn-1-ol, 21
2
2
1
13
of the desired ketone 6 in 71% yield (40% overall yield, 6 steps). steps), whose H and C NMR spectra were identical to those
1
4b,32
This ketone is an useful building block for the synthesis of various reported for this compound.
It is worth noting that this
natural products containing the trans-hydrindane core. The strategy allows isotopic labeling at C18, C26 and C27 for biological
structure of 6, via its tosylate 14 was determined by X-ray and medical applications.
3
0a,14b
crystallography, which confirms the trans-hydrindane fusion.
Ketone 6 was then converted to vinyl triflate 15 and subsequently
cross-coupled with boronate 5 in the presence of K PO and
3
4
2 3 2
catalytic PdCl (PPh ) to afford the conjugate diene 4 (91% yield).
We next focused on the regio- and stereoselective reduction of 4.
Initially we used the Cu(I)/tolBINAP catalyst previously described by
Buchwald and co-workers for the 1,4-reduction of acyclic
α,β-unsaturated
polymethylhydrosiloxane).
reaction conditions found [PMHS (16 equiv), CuCl (0.1 equiv),
R)-tolBINAP (0.1 equiv), iPrOH (4 equiv), hexanes, 23°C, 48 h]
proceeded with complete diastereoselectivity to give the desired
ester 16 (natural steroid configuration at C20) in 55% yield together
with 1,6-reduction products (18%) and recovered starting material
esters
in
the
presence
of
PMHS
3
Scheme 5 Synthesis of 1α,25-dihydroxyvitamin D (1).
1
5b,c
(
The reduction of 4 under the best
In summary, we have developed an efficient convergent route to
the natural hormone 1α,25-dihydroxyvitamin D (1, calcitriol),
(
3
which allows isotopic labeling (longest sequence through the CD-
fragment: 19 steps, 8% overall yield). The synthetic approach
N
features a unique and efficient one-pot Si-assisted S 2’-syn allylic
substitution by cuprates to generate the challenging CD-trans-
hydrindane quaternary all-carbon bridgehead stereocenter. Other
salient features include: 1) the use of an intramolecular Pauson-
Khand reaction to access the steroidal CD-trans-hydrindane core,
and 2) a catalytic asymmetric reduction of unexplored α,β,γ,δ-
unsaturated esters with CuH in an aqueous micellar medium as a
new versatile and efficient entry to the natural steroidal
(
21%). Longer reaction times did not improve the yield on the
desired 1,4-reduction product. We then explored the micellar
catalysis in water previously used by Lipshutz and coworkers for the
3
1
1
,4-reduction of α,β-Michael acceptors. We were pleased to find
that that the reduction of 4 with PMHS in the presence of catalytic
Cu(OAc) and (R)-tolBINAP in aqueous polyoxyethanyl-α-
tocophenyl sebacate (PTS) as surfactant at
2
a
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configuration at C20. The described synthetic strategy appears to
be useful to generate novel CD-ring and side chain modified analogs
for structure-activity studies and for the development of new
anticancer agents. Moreover, adaptation of the Si-assisted allylic
substitution to the generation of other bicyclic scaffolds with
M. Kimura, S. L. Buchwald, J. Am. Chem. Soc., 2003, 125,
1253.
For previous entries to the steroidal natural and unnatural
stereochemistries at C20, see: (a) B. B. Shingate, B. G. Hazra,
Chem. Rev., 2014, 114, 6349; (b) H. Li, C. Mazet, J. Am. Chem.
Soc., 2015, 137, 10720.
1
1
6
different substituents at the quaternary bridgehead carbon would 17 (a) Quaternary Stereocenters. Challenges and Solutions for
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We thank the Spanish Ministry of Science and Innovation (MSI)
and the European Regional Development Fund (project:
Fletcher, Angew. Chem. Int. Ed., 2013, 52, 7995.
SAF2010-15291), Xunta de Galicia (project GPC2014/001), and 18 (a) K. Michalak, J. Wicha, J. Org. Chem. 2011, 76, 6906. (b) M.
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2
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4
5
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supporting information.
(a) C. Deutsch, N. Krause, Chem. Rev., 2008, 108, 2916; (b) D.
H. Appella, Y. Moritani, R. Shintani, E. M. Ferreira, S. L.
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