Ring-closing metathesis protocol for a diastereocontrolled preparation of the C28-C34 segment of FK-506

Article abstract of DOI:10.1016/S0957-4166(00)00093-8

A new synthesis of the C₂₈-C₃₄ segment of FK-506 has been developed using a chiral building block having a 6,8-dioxabicyclo[3.2.1]octane framework by employing a ring-closing metathesis reaction as the key step. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00093-8

Tetrahedron: Asymmetry 11 (2000) 1601±1606
Ring-closing metathesis protocol for a diastereocontrolled
preparation of the C28±C34 segment of FK-506
Miwako Takeuchi, Takahiko Taniguchi and Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Received 10 February 2000; accepted 3 March 2000
Abstract
A new synthesis of the C28±C34 segment of FK-506 has been developed using a chiral building block
having a 6,8-dioxabicyclo[3.2.1]octane framework by employing a ring-closing metathesis reaction as the
key step. # 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
We recently developed the synthesis of the chiral building block 2 having a 6,8-dioxa-
bicyclo[3.2.1]octane framework by employing either a catalytic1 or an enzymatic2 procedure. Owing
to its high functionality con®ned in a biased framework, it allowed convex-face selective func-
tionalization leading to diastereocontrolled construction of all of the eight possible aldohexoses1,3
and (+)-l-noviose,4 a sugar moiety of the antibiotic novobiocin. Herein we describe an alternative
utilization of the building block on the basis of its convex-face selectivity for a diastereocontrolled
preparation of the C28±C34 segment (^)-1 of FK-506,5 a powerful immunosuppressant isolated from
the soil bacterium Streptomyces tsukubaensis, by employing a ring-closing metathesis6 as the key
step. Because of the remarkable biological properties of FK-506, more than a dozen methods for the
preparation of (^)-1 have been reported during the course of its total synthesis7 as well as of its
partial synthesis.8 However, the diastereocontrolled synthesis of (^)-1 was found to be unexpectedly
tedious and dicult.
2. Results and discussion
The present synthesis of (^)-1 starting from our chiral building block (+)-2 employing a ring-
closing metathesis is easily carried out and is unprecedented (Scheme 1).
* Corresponding author. Fax: +81-22-217-6845; e-mail: konol@mail.cc.tohoku.ac.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00093-8

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M. Takeuchi et al. / Tetrahedron: Asymmetry 11 (2000) 1601±1606
Scheme 1.
Thus, (+)-2 was treated with vinylmagnesium bromide in THF containing 3 equivalents of
hexamethylphosphoric triamide (HMPA) in the presence of 0.2 equivalent of a copper(I)
bromide±dimethyl sul®de complex at ^78ꢀC to give the vinyl ketone 3 as the single product in
77% yield by diastereoselective reaction from the convex-face of the molecule. Reduction of 3
with sodium borohydride in the presence of cerium(III) chloride9 gave a mixture of two epimeric
alcohols containing the desired endo-alcohol 4 as the major component which could not be
separated in pure form at this stage. Apparently, the introduced vinyl functionality hindered
diastereoselective reduction of the ketone functionality from the convex-face owing to the 1,3-steric
ꢀ
.
Scheme 2. Reagents and conditions: (i) vinylmagnesium bromide, CuBr SMe2, HMPA, THF, ^78 C (77%); (ii)
ꢀ
ꢀ
.
NaBH4±CeCl3 7H2O, MeOH, ^30 C; (iii) MeI, NaH, THF, 0 C±rt (77% from 3); (iv) TBAF, THF (95%); (v) MesCl,
Et3N, CH2Cl2, 0ꢀC±rt; (vi) LiI, THF, re¯ux, 17 h (90% from 6); (vii) Zn, AcOH:MeOH (1:10 v/v), rt; (viii) LiAlH4,
THF, 0ꢀC (81% from 8); (ix) Grubbs' reagent (10 mol%), CH2Cl2, re¯ux, 4 h; (x) H2, PtO2, AcOEt, rt (87% from 10)

M. Takeuchi et al. / Tetrahedron: Asymmetry 11 (2000) 1601±1606
1603
interaction. The mixture, therefore, was methylated without separation using iodomethane in the
presence of sodium hydride, and the product was separated at this stage by silica gel column
chromatography to give the endo-methoxy product 5 in 77% overall yield from 3. Stereo-
chemistry of 5 was con®rmed by NOE experiments in which signi®cant interaction between the
2-H and the 4-vinyl-(1-H) and no interaction between the 2-H and the 7-H were observed, thus
supporting the assigned structure.
On desilylation with tetrabutylammonium ¯uoride (TBAF), 5 a€orded the primary alcohol 6,
which was transformed into the iodide 8 via the mesylate 7 on sequential mesylation and sub-
stitution. Reductive cleavage of 8 with zinc in methanolic acetic acid proceeded without diculty
to give the hemiacetal 9, which was treated with lithium aluminum hydride to a€ord the acylic
diol 10 having two vinyl functionalities.
The key ring-closing metathesis of 10 using 10 mol% of Grubbs' catalyst in dichloromethane
terminated after 4 h at re¯ux to bring about the expected cyclization to furnish the cyclohex-
enediol 11 which was accompanied by a minor amount of an inseparable coloring material ori-
ginating from the catalyst. Thus, the product, without separation, was hydrogenated on Adams'
catalyst to a€ord the target cyclohexanediol (^)-1 in 87% overall yield from 10 after puri®cation
by column chromatography. Overall yield of the C28±C34 segment (^)-1 from the chiral building
block (+)-2 was 36% in 10 steps (Scheme 2).
In short, we have described an alternative utilization of our chiral building block having a 6,8-
dioxabicyclo[3.2.1]octane framework for construction of the C28±C34 segment of FK-506 on the
basis of the inherent convex-face selectivity by employing ring-closing metathesis as the key
step.
3. Experimental
Melting points were determined on a Yanagimoto hot-stage and are uncorrected. IR spectra
1
were recorded on a JASCO-IR 700 spectrometer. H NMR spectra were recorded on a Varian
Gemini-2000 (300 MHz) spectrometer. Optical resolutions were measured with a JASCO-DIP-
370 digital polarimeter. Enantiomeric purities were determined on a Gilson Model-307 instru-
ment equipped with a column with a chiral stationary phase.
3.1. (+)-(1R,4S,5R,7S)-7-tert-Butyldimethylsiloxymethyl-4-vinyl-6,8-dioxabicyclo[3.2.1]oct-2-one 3
To a stirred solution of THF (4 ml) containing HMPA (616 ml, 3.54 mmol) was added
ꢀ
.
CuBr SMe (49 mg, 1.18 mmol) at 0 C, then after 30 min, vinylmagnesium bromide (1 M in THF,
3.42 ml, 3.42 mmol) was added at ^20ꢀC. After 30 min at the same temperature, the solution was
cooled to ^78ꢀC and to this solution the enone (+)-2 (318 mg, 1.18 mmol) in THF (2 ml) was
added dropwise. After 30 min at the same temperature, the reaction was quenched by the addi-
tion of saturated aqueous NH4Cl and the mixture was extracted with Et2O. The extract was
washed with brine, dried (MgSO4), evaporated under reduced pressure, and chromatographed
(SiO2, 10 g, elution with AcOEt:hexane, 1:30 v/v) to give the ketone 3 (269 mg, 77%) as a faint
25
D
1
yellow oil: ‰ꢀŠ +13.5 (c 1.06, CHCl3). IR (®lm): ꢁ=1737 cm^1. H NMR (300 MHz, CDCl3):
ꢂ=5.83 (1H, ddd, J=17.0, 10.4, 8.0 Hz), 5.46 (H, s), 5.18 (1H, dt, J=10.4, 1.1 Hz), 5.16 (1H, dt,
J=17.0, 1.1 Hz), 4.38 (1H, s), 4.09 (1H, dd, J=8.2, 5.5 Hz), 3.63 (1H, dd, J=10.2, 5.5 Hz), 3.46
(1H, dd, J=10.2, 8.2 Hz), 2.84 (1H, td, J=8.0, 3.4 Hz), 2.68 (1H, dd, J=17.0, 3.4 Hz), 0.89 (9H,

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M. Takeuchi et al. / Tetrahedron: Asymmetry 11 (2000) 1601±1606
s), 0.06 (6H, s). 13C NMR (75 MHz, CDCl3): ꢂ=204.8, 136.9, 117.5, 10.4, 80.8, 78.2, 62.8, 46.3,
38.1, 25.8, 18.2, ^5.4, ^5.5. HRMS: m/z=calcd for C15H26O4Si: 298.1600; found: 298.1605.
3.2. (+)-(1S,2R,4S,5R,7S)-7-tert-Butyldimethylsiloxymethyl-2-methoxy-4-vinyl-6,8-dioxabicyclo-
[3.2.1]octane 5
.
To a stirred solution of 3 (556 mg, 1.87 mmol) and CeCl3 7H2O (2.09 g, 5.60 mmol) in MeOH
(11 ml) was added NaBH4 (212 mg, 5.60 mmol) portionwise at ^30ꢀC and raised to room tempera-
ture. The mixture was evaporated under reduced pressure and the residue was extracted with
AcOEt. The extract was washed with brine, dried (MgSO4), evaporated under reduced pressure,
and chromatographed (SiO2, 10 g, elution with AcOEt:hexane, 1:2 v/v) to give a mixture con-
taining 4 as the major product. The mixture in THF (11 ml) was treated with NaH (60% oil
dispersion, 119 mg, 2.99 mmol) at 0ꢀC, then, after 10 min, with MeI (1.16 ml, 18.7 mmol) at the
same temperature and the stirring was continued for 20 min at room temperature. The mixture
was diluted with AcOEt and was washed with brine, dried (MgSO4), evaporated under reduced
pressure, and chromatographed (SiO2, 10 g, elution with AcOEt:hexane, 1:50 v/v) to give the
27
1
methyl ether 5 (454 mg, 77% from 3) as a colorless oil: ‰ꢀŠ +27.6 (c 1.10, CHCl3). H NMR
D
(300 MHz, CDCl3): ꢂ=5.86 (1H, ddd, J=17.3, 10.4, 7.8 Hz), 5.26 (1H, s), 5.13 (1H, d, J=17.3
Hz), 5.12 (1H, d, J=10.4 Hz), 4.43 (1H, d, J=3.3 Hz), 4.21 (1H, dd, J=8.7, 5.2 Hz), 3.65±3.58
(2H, m), 3.42 (1H, dd, J=9.8, 8.7 Hz), 3.37 (3H, s), 2.50 (1H, t, J=7.1 Hz), 1.90 (1H, dd,
J=13.5, 5.4 Hz), 1.77 (1H, ddd, J=13.5, 10.7, 6.3 Hz), 0.89 (9H, s), 0.07 (6H, s). 13C NMR (75
MHz, CDCl3): ꢂ=137.6, 116.4, 103.8, 74.8, 74.5, 72.1, 63.5, 56.4, 45.1, 28.2, 25.8, 18.1, ^5.5.
HRMS: m/z=calcd for C16H30O4Si: 314.1913; found: 314.1925.
3.3. (+)-(1S,2R,4S,5R,7S)-7-Hydroxymethyl-2-methoxy-4-vinyl-6,8-dioxabicyclo[3.2.1]octane 6
To a stirred solution of 5 (454 mg, 1.45 mmol) in THF (9 ml) was added TBAF (1.0 M in THF,
2.17 ml, 2.17 mmol) at 0ꢀC and the stirring was continued for 2 h at room temperature. The
mixture was diluted with AcOEt and was washed with brine, dried (MgSO4), evaporated under
reduced pressure, and chromatographed (SiO2, 9 g, elution with AcOEt:hexane, 1:2 v/v) to give
29
the alcohol 6 (276 mg, 95%) as a colorless oil: ‰ꢀŠ +0.6 (c 1.09, CHCl3). IR (®lm): ꢁ=3450 cm^1.
D
1H NMR (300 MHz, CDCl3): ꢂ=5.85 (1H, ddd, J=17.4, 10.4, 8.0 Hz), 5.33 (3H, s), 5.14 (1H, d,
J=10.4 Hz), 4.34±4.30 (2H, m), 3.66±3.59 (3H, m), 3.37 (3H, s), 2.53 (1H, t, J=7.3 Hz), 2.24
(1H, br.s), 1.96 (1H, dd, J=13.2, 5.8 Hz), 1.78 (1H, ddd, J=13.2, 10.7, 6.6 Hz). 13C NMR (75 MHz,
CDCl3): ꢂ=137.2, 116.5, 103.9, 75.1, 74.9, 72.0, 64.0, 56.1, 44.8, 27.8. HRMS: m/z=calcd for
C10H16O4: 200.1049; found: 200.1034.
3.4. (+)-(1S,2R,4S,5R,7S)-7-Iodomethyl-2-methoxy-4-vinyl-6,8-dioxabicyclo[3.2.1]octane 8
To a stirred solution of 6 (276 mg, 1.38 mmol) in CH2Cl2 (6 ml) was added Et3N (577 ml, 4.14
mmol), followed by MesCl (160 ml, 2.07 mmol) at 0ꢀC, and the stirring was continued for 1 h at
room temperature. The mixture was diluted with AcOEt and washed with brine, dried (MgSO4),
and evaporated under reduced pressure to leave the mesylate 7. Without puri®cation, the crude 7
was dissolved in THF (6 ml) and was re¯uxed with LiI (1.85 g, 13.8 mmol) for 17 h. The mixture,
after cooling, was diluted with AcOEt and was washed with 10% aqueous Na2S2O3, saturated
aqueous NaHCO3, brine, and dried (MgSO4). After evaporation of the solvent under reduced

M. Takeuchi et al. / Tetrahedron: Asymmetry 11 (2000) 1601±1606
1605
pressure the residue was chromatographed (SiO2, 5 g, elution with AcOEt:hexane, 1:40 v/v) to
25
1
give the iodide 8 (384 mg, 90% from 6) as a colorless oil: ‰ꢀŠ +59.4 (c 1.17, CHCl3). H NMR
D
(300 MHz, CDCl3): ꢂ=5.84 (1H, ddd, J=17.6, 9.9, 8.0 Hz), 5.38 (1H, s), 5.14 (1H, d, J=17.6
Hz), 5.13 (1H, d, J=9.9 Hz), 4.50±4.43 (2H, m), 3.59 (1H, ddd, J=11.0, 6.0, 4.4 Hz), 3.42 (3H, s),
3.21 (1H, dd, J=9.6, 5.2 Hz), 3.11 (1H, t, J=9.6 Hz), 2.5 (1H, t, J=7.1 Hz), 1.93 (1H, dd,
J=13.5, 6.0 Hz), 1.77 (1H, ddd, J=13.5, 11.0, 6.6 Hz), 2.5 (1H, t, 7.1 Hz), 1.93 (1H, dd, J=13.5,
6.0 Hz), 1.77 (1H, ddd, J=13.5, 11.0, 6.6 Hz). 13C NMR (125 MHz, CDCl3): ꢂ=137.0, 116.8,
104.7, 77.1, 75.0, 72.0, 56.6, 44.7, 27.9, 7.1. HRMS: m/z=calcd for C10H15IO3: 310.0066; found:
310.0082.
3.5. (+)-(3R,4R,6S)-3-Hydroxy-6-hydroxymethyl-4-methoxy-1,7-octadiene 10
To a stirred solution of the iodide 8 (384 mg, 1.24 mmol) in methanolic acetic acid (10:1 v/v, 4.4
ml) activated Zn powder (1.62 g, 24.8 mmol) was added portionwise at room temperature. After
stirring for 1 h at the same temperature, the mixture was diluted with AcOEt and, after ®ltration
through a Celite pad, was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), evap-
orated under reduced pressure, and chromatographed (SiO2, 8 g, elution with AcOEt:hexane, 1:2
v/v) to give the hemiacetal 9.
The hemiacetal 9 was dissolved in THF (4 ml), which was treated with LiAlH4 (94 mg, 2.48
mmol) at 0ꢀC with stirring. After 90 min at the same temperature, the mixture was diluted with
Et2O and the excess LiAlH4 was decomposed by addition of H2O. After ®ltration through a
Celite pad, the organic layer was separated, dried (MgSO4), evaporated under reduced pressure,
and chromatographed (SiO2, 8 g, elution with AcOEt:hexane, 1:1 v/v) to give the diol 10 (210 mg,
27
D
1
91% from 8) as a colorless oil: ‰ꢀŠ +26.4 (c 1.05, CHCl3). IR (®lm): ꢁ=3396 cm^1. H NMR
(300 MHz, CDCl3): ꢂ=5.89 (1H, ddd, J=16.5, 10.4, 6.0 Hz), 5.62 (1H, ddd, J=17.0, 10.3, 8.9
Hz), 5.35 (2H, dt, J=17.0, 1.4 Hz), 5.25±5.17 (3H, m), 3.57 (1H, ddd, J=10.4, 7.7, 5.5 Hz), 3.50±
3.36 (4H, m), 3.25 (1H, ddd, J=9.3, 5.5, 3.0 Hz), 2.54±2.36 (1H, m), 1.62±1.43 (3H, m), 2.26 (1H,
d, J=4.9 Hz), 1.69±1.56 (2H, m), 1.46 (1H, ddd, J=14.3, 9.9, 3.0 Hz). 13C NMR (125 MHz,
CDCl3): ꢂ=139.7, 137.8, 117.9, 116.6, 81.8, 74.5, 66.0, 58.9, 43.6, 32.4. HRMS: m/z=calcd for
C10H19O3: 187.1334; found: 187.1333.
3.6. (^)-(1R,2R,4R)-4-Hydroxymethyl-2-methoxycyclohexan-1-ol 1
A solution of the diene 10 (55 mg, 0.30 mmol) and Grubbs' catalyst [bis(tricyclohexylphos-
phine)benzylidene-ruthenium(IV) dichloride, 24 mg, 0.03 mmol] in CH2Cl2 (degassed, 15 ml)
was re¯uxed for 4 h. After evaporation of the solvent under reduced pressure, the residue was
chromatographed (SiO2, 2 g, elution with AcOEt:hexane, 2:1 v/v) to give the cyclohexenol 11.
Without further puri®cation, the 11 obtained was hydrogenated over PtO2 (4 mg) in AcOEt (2
ml) at room temperature to give the cyclohexane 1, which was puri®ed by column chromato-
graphy (SiO2, 2 g, elution with AcOEt:MeOH, 95:5 v/v) to give pure product (^)-1 (40 mg, 87%
30
D
23
D
from 10) as a colorless oil: ‰ꢀŠ ^56.9 (c 0.40, CHCl3) [lit.7c ‰ꢀŠ ^57.0 (c 0.30, CHCl3)]. IR (®lm):
ꢁ=3390 cm^1. H NMR (300 MHz, CDCl3): ꢂ=3.53±3.38 (3H, m), 3.42 (3H, s), 3.02 (1H, ddd,
J=11.3, 8.8, 4.4 Hz), 2.93 (1H, br.s), 2.23±2.20 (1H, m), 2.04 (1H, dq, J=12.9, 3.6 Hz), 1.95 (3H,
br.s), 1.80±1.74 (1H, m), 1.61±1.55 (1H, m), 1.42±1.39 (1H, m), 1.08 (1H, qd, J=12.4, 3.6 Hz),
0.86 (1H, q, J=12.4 Hz). 13C NMR (125 MHz, CDCl3): ꢂ=84.32, 73.83, 67.31, 56.32, 38.64,
31.15, 30.79, 26.72. HRMS: m/z=calcd for C8H16O3: 160.1099; found: 160.1090.
1

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M. Takeuchi et al. / Tetrahedron: Asymmetry 11 (2000) 1601±1606
References
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