Formal synthesis of the anti-angiogenic polyketide (-)-borrelidin under asymmetric catalytic control

Article abstract of DOI:10.1002/chem.201001284

Borrelidin (1) is a polyketide that possesses extremely potent antiangiogenesis activity. This paper describes its formal total synthesis by the most efficient route to date. This modular approach takes optimal benefit of asymmetric catalysis and permits the synthesis of analogues; in addition, the high yields and selectivities obtained eliminate the need for separation of stereoisomers. The upper half of borrelidin has been accessed by iterative copper-catalysed asymmetric conjugate addition of methylmagnesium bromide, whereas synthesis of the lower half of the molecule was achieved by relying on asymmetric hydrogenation and cross-methathesis as key steps.

Full text of DOI:10.1002/chem.201001284

DOI: 10.1002/chem.201001284
Formal Synthesis of the Anti-Angiogenic Polyketide (À)-Borrelidin under
Asymmetric Catalytic Control
Ashoka V. R. Madduri and Adriaan J. Minnaard*[a]
Abstract: Borrelidin (1) is a polyketide
that possesses extremely potent anti-
angiogenesis activity. This paper de-
scribes its formal total synthesis by the
most efficient route to date. This mod-
ular approach takes optimal benefit of
asymmetric catalysis and permits the
synthesis of analogues; in addition, the
high yields and selectivities obtained
eliminate the need for separation of
stereoisomers. The upper half of borre-
lidin has been accessed by iterative
copper-catalysed asymmetric conjugate
addition of methylmagnesium bromide,
whereas synthesis of the lower half of
the molecule was achieved by relying
on asymmetric hydrogenation and
cross-methathesis as key steps.
Keywords: asymmetric catalysis
·
conjugate addition · hydrogenation ·
polyketides · total synthesis
Introduction
work was followed by Anderson et al. who assigned the ab-
solute configuration of the stereocentres by X-ray crystallog-
raphy.[10]
Natureꢀs bounty of molecules possessing inherent medicinal
value has changed the world.[1] Borrelidin (1), isolated by
Berger and co-workers in 1949 from Streptomyces rochei,[2]
is a molecule that exhibits a host of potent physiological ac-
tivities. The properties of borrelidin include anti-bacterial[3]
activity involving selective inhibition of threonyl-tRNA syn-
thetase,[4] anti-viral activity,[5] anti-malarial activity against
chloroquine-resistant strains[6] and the inhibition of cyclin-
dependent kinase Cdc28/Cln2 in Saccharomyces cerevisiae.[7]
Most importantly, however, borrelidin exhibits a sub-nano-
molar IC50 value for the inhibition of angiogenesis.[8] It is
this latter activity that is very important for anti-cancer re-
search. Although borrelidin is currently obtained in small
amounts by fermentation, its high cost limits the full explo-
ration of its possibilities in biological and medical research.
Keller-Schierlein and co-workers elucidated the planar ar-
chitecture of 1 by means of chemical degradation;[9] this
Results and Discussion
The dense arrangement of chiral centres in this 18-mem-
bered macrocycle, together with the peculiar and sensitive
Z,E-cyanodiene moiety, has attracted considerable attention
from organic chemists.[11] After an early study by Haddad
et al.,[12] the groups of Morken[13] and Hanessian[14] first re-
ported total syntheses of the compound, closely followed by
the groups of Theodorakis[15] and Omura.[16] The strategies
reported essentially rely on starting materials from the
chiral pool, chiral auxiliaries or kinetic resolution of ad-
vanced intermediates.[17] In the retrosynthesis applied by
Omura and co-workers,[16] 1 is disconnected into two parts
(Scheme 1). The upper part (A) contains the poly-1,3-
methyl array and a deoxypropionate unit flanked by two hy-
droxy groups. The lower part (B) contains a disubstituted
cyclopentyl motif together with a Z,E-cyanodiene unit. Ne-
gishi and co-workers[18] and Herber and Breit[19] achieved
the synthesis of part A by an iterative catalytic approach
and a chiral-reagent-based strategy, respectively. In view of
the need for a more efficient and cost-effective synthesis of
borrelidin and its derivatives, we were challenged to develop
a route in which all formed chiral centres would be under
catalyst control. This “catalytic total synthesis” should lead
to a significantly improved overall yield and avoid the tedi-
ous separation of diastereomers.
[a] A. V. R. Madduri, Prof. Dr. A. J. Minnaard
Department of Bio Organic Chemistry
Stratingh Institute for Chemistry, University of Groningen
Nijenborgh 4, 9747 AG, Groningen (The Netherlands)
Fax : (+31)50-363-4296
E-mail: a.j.minnaard@rug.nl
Supporting information for this article (chromatograms, experimental
procedures for remaining compounds and spectra for all compounds)
is available on the WWW under http://dx.doi.org/10.1002/
chem.201001284.
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FULL PAPER
Scheme 1. Retrosynthesis of borrelidin (1). TBS: tert-butyldimethylsilyl;
TBDPS: tert-butyldiphenylsilyl; THP: tetrahydropyranyl.
The disconnection into upper part A and lower part B
was adopted. For part A, we were keen to apply our itera-
tive catalytic asymmetric conjugate-addition approach. This
has proven its effectiveness in the total synthesis of a variety
of natural products containing all-syn deoxypropionate
units.[20] Particularly challenging would be the introduction
of a methyl group with 1,3-anti stereochemistry at the left
end of A, after three syn-methyl groups, owing to the intrin-
sic substrate preference for an all-syn array.[21] The b-hy-
droxy acid unit was planned to be derived from the corre-
sponding keto ester through asymmetric hydrogenation. In
the reported synthesis of part B, the disubstituted cyclopen-
tyl fragment has been invariably prepared by using a chiral
auxiliary, for example, menthol, or through kinetic resolu-
tion. This, however, requires a lengthy synthesis route with
moderate overall yields. It was envisioned that, by starting
with 23, asymmetric hydrogenation would install both chiral
centres at once in an anti relationship. Although the report-
ed enantioselectivities were not sufficient, this presented an
appealing opportunity and would translate to a significant
improvement in the synthesis. Finally, we planned a chal-
lenging alkene metathesis in the synthesis of the cyanodiene
fragment.
Scheme 2. Synthesis of the upper part (A) of borrelidin (1). Reagents
and conditions: a) MeMgBr (1.2 equiv), 4/CuBr (1 mol%), tBuOMe,
À788C, 18 h; 96%, 98% ee for 3; 90%, syn/anti 98:2 for 7a; 87%, syn/
anti
>98:2
for
10;
b) DIBALH,
CH2Cl2,
À658C,
4 h;
c) (EtO)2OPCH2COSEt, nBuLi, THF, RT, 10 h; 81% over
2
steps;
d) MeMgBr, ent-4/CuBr (1 mol%), tBuOMe, À788C, 18 h; 89%, anti/syn
95:5; e) (EtO)2OPCH2COMe, nBuLi, THF, RT, 10 h; 92% over 2 steps.
Cy: cyclohexyl; DIBALH: diisobutylaluminium hydride; THF: tetrahy-
drofuran.
Substrate 2 (Scheme 2) gives excellent yield and enantio-
selectivity (96%, 98% ee) and complete regioselectivity in
the 1,4 addition of MeMgBr with 1 mol% CuBr/4. The reac-
tion was conveniently carried out on a 15 g scale. Bifunc-
tional building block 3 was reduced to the corresponding al-
dehyde 5 (see the Supporting Information), and this was fol-
lowed by a HWE reaction to give thioester 6. The nearly ex-
clusive syn selectivity (syn/anti 98:2) of the second conjugate
addition, leading to dimethyl thioester 7a, was deduced
from the 1H NMR spectrum through comparison with the
spectrum of the anti-dimethyl thioester 7b, prepared by
using ent-4 (Scheme 2). By repeating this sequence of reduc-
tion, HWE olefination with (EtO)2OPCH2COSEt and 1,4
addition once more, the third methyl group was introduced
in a syn fashion to give 10 in 87% yield after isolation and
with a syn/anti ratio of >98:2. Reduction of 10 with
DIBALH afforded aldehyde 11, and a subsequent HWE re-
action with (EtO)2OPCH2COMe resulted in a,b-unsaturated
ketone 12.
Earlier work by our group has demonstrated that the Cu/
Josiphos-catalysed (Josiphos: structure in Scheme 2) itera-
tive asymmetric conjugate addition of MeMgBr leads to ex-
cellent stereochemical control in the synthesis of 1,3-methyl
arrays. This has been successfully exploited in the first total
synthesis of mycocerosic acid and phthioceranic acid.[22] On
the basis of this efficient and robust methodology,
2
(Scheme 2) was chosen as the starting material because it
possesses a protected hydroxy function at the terminus of
the unsaturated thioester, which remains inert under the
iterative reaction conditions (conjugate addition, DIBALH
reduction and Wittig or Horner–Wadsworth–Emmons
(HWE) reaction). 2 is conveniently prepared from ethylene
glycol in three steps.
We were pleased to see that, with CuBr/ent-4 as the cata-
lyst, the introduction of the fourth methyl group onto 12
(Scheme 3) proceeded with excellent anti selectivity (>99:1)
to give 13a. Remarkably, the use of CuBr/4 resulted in
epimer 13b with identical excellent selectivity, which dem-
Chem. Eur. J. 2010, 16, 11726 – 11731
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11727

A. J. Minnaard and A. V. R. Madduri
reaction of 18 mediated by SmI2, followed by oxidation of
the resulting hydroxy ester, afforded the corresponding b-
ketoester 20. Gratifyingly, catalytic asymmetric hydrogena-
tion of 20 with 1 mol% (R)-[(RuCl(Tol-BINAP))
2ACHTUNGTRENNUNG(m-Cl)3-
AHCTUNGTRENNUNG
value of >99%. Protection of 21 with TBSOTf, followed by
basic hydrolysis resulted in A.
In connection with the synthesis of B, we started with a
careful study of the asymmetric hydrogenation of 23
(Scheme 5). This asymmetric hydrogenation, with [RuCl2ACHTUNGTRENNUNG(p-
Scheme 3. a) MeMgBr, ent-4/CuBr (1 mol%), tBuOMe, À858C, 18 h;
85%, anti/syn >99:1; b) MeMgBr, 4/CuBr (1 mol%), tBuOMe, À858C,
18 h; 88%, syn/anti >99:1.
onstrates the complete control of the catalyst in steering the
chirality of the newly formed stereocentre. Such overwhelm-
ing catalyst control, overriding the strong natural preference
of the substrate for syn addition, is unprecedented. As a
consequence of the excellent stereoselectivities obtained
throughout this part of the synthesis, the need for laborious
separation of diastereomers is completely avoided.
The conversion of 13a into alcohol 15 (Scheme 4) was ef-
ficiently accomplished through an optimised Baeyer–Villiger
oxidation and subsequent hydrolysis. Overall, 15 was pre-
pared in 33% yield from 2, which is a considerable improve-
ment over the literature yields.[16,18] Protection of the hy-
droxy group as the THP ether, followed by deprotection of
the TBDPS ether and TPAP oxidation of the formed alco-
hol, efficiently produced aldehyde 18. A Reformatsky-type
Scheme 5. Asymmetric hydrogenation of cyclic b-ketoester 23.
cymene)]2 and BINAP as the chiral ligand, had been report-
ed by Noyori et al.[24] to give 24 in 98% yield, 92% ee and
an anti/syn ratio of 99:1. Further catalyst optimisation by
variation of the ligand (Scheme 6) initially failed; the depict-
Scheme 6. Ligands used in the asymmetric hydrogenation. Tol: tolyl.
ed (Sa,Sc,Sc)-phosphoramidite, Josiphos and Taniaphos all
gave incomplete conversion (Table 1). Tol-BINAP and
xylyl-BINAP in combination with DPEN and DAIEPN,
however, gave significant improvements in the ee and d.r.
values. Finally, it turned out that, by applying 3,5-xylyl-
BINAP as the chiral ligand in combination with [RuI2ACHTUNGTRENNUNG(p-
cymene)]2 as the metal precursor, the outcome could be im-
proved to an excellent 98% yield, 97% ee and an anti/syn
ratio of >99:1. This strategy is very attractive for natural
product synthesis because it provides excellent selectivities
and is easily scalable to multigram quantities.
Scheme 4. a) m-CPBA, CHCl3, 608C, 12 h, and repetition of the proce-
dure on the recovered starting material; overall yield 85%; b) K2CO3,
MeOH, RT, 3 h; 97%; c) dihydropyrane, PPTS, RT, 4 h; 98%; d) TBAF,
THF, 5 h; 96%; e) TPAP, NMO, 4 ꢂ MS, 1 h; 88%; f) 4-methoxybenzyl
2-bromoacetate, SmI2, 30 min; 90%; g) TPAP, NMO, 4 ꢂ MS, 1 h; 85%;
h) (R)-[(RuCl(Tol-BINAP))2ACHTUNGTRENN(UG m-Cl)3CAHTUNGTRENN[UGN NH2Me2] (1 mol%), 5 bar H2, EtOH,
Further reduction of 24 to primary alcohol 26 (Scheme 7)
was efficiently accomplished by THP protection of the sec-
ondary alcohol and reduction of the ester functionality. Pri-
mary alcohol 26 was PMB protected; this was followed by
deprotection of the secondary alcohol to give 28, which un-
derwent subsequent tosylation and substitution with cyanide
to result in 30. The vicinal stereochemistry of the substitu-
8 h; 90%, de >99%; i) TBSOTf, 2,6-lutidine, CH2Cl2, 1 h; j) LiOH, 4 h;
85% over 2 steps. (For compounds 4, 5, 8, 14, 16, 17, 19 and 22, see the
Supporting Information.) m-CPBA: meta-chloroperoxybenzoic acid; MS:
molecular sieves; NMO: 4-methylmorpholine N-oxide; PMB: para-me-
thoxybenzyl; PPTS: pyridinium para-toluenesulfonate; TBAF: tetrabut
ACHTUNGERTNyNUNG l-
ACHTUNGTRENNUNGammonium fluoride; Tf: trifluoromethanesulfonyl; Tol-BINAP: 2,2’-
bis(di-p-tolylphosphanyl)-1,1’-binaphthyl; TPAP: tetrapropylammonium
perruthenate.
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Chem. Eur. J. 2010, 16, 11726 – 11731

Synthesis of (À)-Borrelidin
FULL PAPER
Table 1. Catalyst optimisation for asymmetric hydrogenation of 23.[a]
tively by this approach turned out to be impossible. Invaria-
bly, Z,E mixtures were obtained. As the cross-metathesis of
unprotected homoallylic alcohols with methyl acrylate has
been documented, we decided to use this as a starting point.
We were very pleased to see that cross-metathesis of homo-
allylic alcohol 32 with acrolein diethylacetal[25] and a Hovey-
da–Grubbs second-generation catalyst, followed by careful
acidic workup, efficiently produced E-33 as the only isomer
Ligand
Ruthenium source
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuCl2A(p-cymene)]2
[RuI2A(p-cymene)]2
[RuI2A(p-cymene)]2
Yield [%]
d.r.
ee [%]
BINAP
phosphoramidite
Josiphos
Taniaphos
L1
L2
Tol-BINAP
3,5-xylyl-BINAP
Tol-BINAP
3,5-xylyl-BINAP
G
N
95
10
30
25
90
95
96
98
97
98
96:4
–
–
90
–
–
E
E
R
–
–
R
97:3
97:3
98:2
99:1
99:1
99:1
94
95
94
96
95
97
N
N
R
in 75% yield after isolation. Subsequent HWE oleACHTUNGTRENNUNGfinACHTUNGTRENNUNGation
of 33 with (EtO)2P(O)CH(Br)CN[26] completed the synthesis
of fragment B. This concise “catalytic synthesis” of B affords
a considerably higher overall yield than the reported routes
and is readily scaled up.
R
CHTUNGTRENNUNG
A
CHTUNGTRENNUNG
[a] Optimised reaction conditions: (R)-3,5-xylyl-BINAP (0.6 mol%),
[RuI2A(p-cymene)]2 (0.25 mol%), 100 bar H2, CH2Cl2, 48 h; 98% yield,
CHTUNGTRENNUNG
anti/syn 99:1, 97% ee. L1: (R)-3,5-xylyl-BINAP[(R)-DPEN]; L2: (R)-3,5-
xylyl-BINAP[(R)-DAIPEN]. DPEN: 1,2-diphenyl-1,2-diaminoethane;
DAIPEN: 1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine.
The characterisation data of A and B thus synthesised are
in excellent agreement with those reported in the literature.
The remainder of the synthesis (Scheme 8) can be carried
out as described by Omura et al.[16]
Scheme 8. Final steps in the synthesis of borrelidin (1).
Conclusion
Scheme 7. a) Dihydropyrane, PPTS, RT, 4 h; 96%; b) LiAlH4, THF, RT,
10 h; 93%; c) PMBCl, NaH, DMF, À208C, 1 h; 95%; d) PPTS, EtOH,
508C, 12 h; 96%; e) TsCl, pyridine, RT, 12 h; 98%; f) NaCN, DMSO,
508C, 12 h; 80%; g) DIBALH, CH2Cl2, À658C, 4 h; 85%; h) allyltrime-
thylsilane, MgBr2·Et2O; 86%; i) Hoveyda–Grubbs second-generation cat-
alyst (5.0 mol%), acrolein diethylacetal, CH2Cl2, 458C, 18 h; acidic work
up; 75%; j) (EtO)2P(O)CH(Br)CN, DBU, LiCl, 08C, 4 h; 93%. (For
compounds 25, 27 and 29, see the Supporting Information.) DBU: 1,8-
In conclusion, we have completed an efficient formal total
synthesis of borrelidin (1). This synthesis is significantly
shorter and produces 1 in much higher yield than previously
reported. The present approach makes maximum benefit of
asymmetric catalysis, in particular, the copper-catalysed
asymmetric conjugate addition of methylmagnesium bro-
mide and the ruthenium-catalysed asymmetric ketone hy-
drogenation. Due to the excellent stereoselectivities, separa-
tion of diastereomers is obsolete. This catalytic approach
paves the way for the preparation of borrelidin analogues,
particularly stereoisomers in addition to modifications of
the carbon skeleton, and further research will be focused in
this direction.
diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene; DMF: N,N-dimethylformamide; DMSO:
dimethylsulfoxide; Ts: toluene-4-sulfonyl.
1
ents in 30 was confirmed to be cis, as expected, by H-NOE
experiments (see the Supporting Information). Reduction of
syn-30 with DIBALH, followed by aqueous work up, led se-
lectively to the desired anti-aldehyde 31 (anti/syn>15:1) in
85% yield. This in situ epimerisation leading to the required
anti compound was hoped for and, indeed, takes place readi-
ly under the reaction conditions.
Experimental Section
Chelation-controlled allylation of 31 (Scheme 7) with al-
lyltrimethylsilane catalysed by the Lewis acid MgBr2·Et2O
afforded homoallylic alcohol 32 with high yield and excel-
lent stereoselectivity (anti/syn 20:1), as reported by Omura
et al.[16] From compound 32, we envisioned that the use of
olefin metathesis could drastically shorten the existing
routes to B and even avoid protection of the secondary alco-
hol. Direct installation of the cyanodiene unit stereoselec-
General: All reactions were carried out under a nitrogen atmosphere
with dried glassware. All solvents were dried and distilled before use ac-
cording to standard procedures. All reagents were commercially obtained
(Aldrich, Acros) at the highest commercial quality and used without fur-
ther purification, except where noted. Chromatography was performed
with Merck silica gel type 9385, 230–400 mesh; TLC was performed with
Merck silica gel 60, 0.25 mm. Components were visualised by staining
with Seebachꢀs reagent, a mixture of phosphomolybdic acid (25 g), ceri-
AHCTUNGTRENGNuNU m(IV) sulfate (7.5 g), H2O (500 mL) and H2SO4 (25 mL). High-resolu-
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A. J. Minnaard and A. V. R. Madduri
tion mass spectra (HRMS) were recorded on a AEI-MS-902 and FTMS
orbitrap (Thermo Fisher Scientific) mass spectrometer. 1H, 13C and APT
spectra were recorded on a Varian AMX400 spectrometers (400 and
100.59 MHz, respectively) with CDCl3 as the solvent. Chemical shift
values are reported in ppm with the solvent resonance as the internal
standard (CHCl3: d=7.26 ppm for 1H, d=77.23 ppm for 13C). Data are
reported as follows: chemical shifts, multiplicity (s: singlet; d: doublet; t:
triplet; q: quartet; br: broad; m: multiplet), coupling constants (Hz), and
integration. Optical rotations were measured on a Schmidt and Haensch
polarimeter (Polartronic MH8) with a 10 cm cell (c given in g per
100 mL). Enantiomeric excesses were determined by HPLC (Chiralcel
OB (250ꢃ4.6, 10 mm) or Chiralcel OD (250ꢃ4.6, 10 mm) column) and ca-
pillary GC analysis (Chiraldex A-TA (30 mꢃ0.25 mm) column) with a
flame-ionisation detector and by comparison with racemic products.
placed in an autoclave and purged with N2 and H2. Hydrogen was intro-
duced (5 bar) and the reaction mixture was stirred at room temperature
for 8 h. After the hydrogen pressure was released, the solution was con-
centrated under reduced pressure and purified by flash chromatography
(eluent: pentane/EtOAc, 50:10) to afford 21 (137 mg, 90%, anti/syn
>99:1). The diastereomeric ratio of 21 was determined by NMR spec-
troscopy by comparison with the spectra of the diastereomers prepared
by reduction of b-ketoester 20 with NaBH4; [a]2D5 =À19.2 (c=0.75,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.31 (s, 2H), 6.90 (s, 2H), 5.09
(s, 2H), 4.58 (s, 1H), 3.94 (s, 1H), 3.81 (s, 5H), 3.53 (d, J=25.0 Hz, 2H),
3.17 (d, J=36.2 Hz, 1H), 2.70 (s, 1H), 2.48 (ddd, J=19.3, 16.3, 6.3 Hz,
3H), 1.82 (s, 3H), 1.60 (s, 8H), 1.25 (s, 3H), 0.88 ppm (s, 16H); 13C NMR
(101 MHz, CDCl3): d=173.60, 159.91, 130.39, 127.92, 114.19, 99.28, 98.88,
74.18, 73.95, 70.72, 66.58, 62.52, 62.27, 55.50, 45.76, 41.08, 40.54, 39.33,
35.25, 30.98, 29.91, 27.38, 25.75, 20.99, 20.60, 19.87, 17.00, 14.70 ppm;
HRMS: calcd for C28H46O6 [M+Na+]: 501.3192; found: 501.3186.
1,4-Addition on a,b-unsaturated thioesters (15g scale): Synthesis of com-
pound 3: (R,SFe)-Josiphos (4)·CuBr complex (290 mg, 0.39 mmol,
1 mol%) was dissolved in tBuOMe (214 mL) under nitrogen. The solu-
tion was cooled to À858C and methylmagnesium bromide (15.6 mL,
46.8 mmol, solution in diethyl ether) was added dropwise over 20 min.
After the reaction mixture had been stirred for 20 min, a solution of thio-
ester 2 (15 g, 39.0 mmol) in tBuOMe (64 mL) was added with a syringe
pump over 2 h. The reaction mixture was stirred at À858C for 22 h, then
quenched by addition of MeOH and allowed to warm to room tempera-
ture. Saturated aqueous NH4Cl was added, and after phase separation
and extraction of the aqueous phase with diethyl ether, the combined or-
ganic phases were dried over MgSO4, concentrated under reduced pres-
sure and purified by flash chromatography (eluent: pentane/diethyl
ether, 40:1) to afford 3 as a colourless oil (95% yield, 98% ee). The
enantiomeric excess was determined by HPLC (Chiralcel OB, 250ꢃ4.6,
10 mm; eluent: heptane/IPA 95:5; 23.38 min (major), 28.78 min (minor))
to be 98% ee or by GC analysis (Chiraldex AT-A, 30.0 mꢃ0.25 mm;
1.0 mLminÀ1; initial temperature: 508C, then 58CminÀ1 to a final temper-
Catalytic asymmetric hydrogenation of cyclic b-ketoesters: Synthesis of
compound 24: A solution of 23 (5.0 g, 35.19 mmol), (R)-3,5-xylyl-BINAP
(155 mg, 0.211 mmol) and [RuI2ACTHNUTRGNE(UNG p-cymene)]2 (86 mg, 0.087 mmol) in
CH2Cl2 was placed in an autoclave and purged with N2 and H2. Hydrogen
was introduced (100 bar) and the reaction mixture was stirred at 608C
for 48 h. After the hydrogen pressure was released, the solution was con-
centrated under reduced pressure and purified by flash chromatography
(eluent: pentane/EtOAc, 1:1) to afford (1R, 2R)-24 (4.99 g, 98%); anti/
syn ratio determined by NMR spectroscopy: 99:1; enantiomeric excess
and absolute configuration determined by HPLC (Chiralcel OD, 250ꢃ
4.6, 10 mm; eluent: heptane/IPA, 99:1; 23.883 min (major), 29.856 min
(minor)): 97% ee; [a]2D5 =À49.8 (c=2.51, CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.36 (q, J=6.5 Hz, 1H), 3.80–3.61 (m, 3H), 2.76–2.62 (m,
1H), 2.19 (s, 1H), 2.12–1.91 (m, 2H), 1.89–1.54 ppm (m, 4H); 13C NMR
(101 MHz, CDCl3): d=175.75, 75.92, 52.46, 51.53, 34.18, 27.52,
22.19 ppm; HRMS: calcd for C7H12O3 [MÀHÀ]: 143.0786; found:
143.0702.
ature of 1708C; 19.5 min (major), 19.7 (minor)) to be 98% ee; [a]D25
=
À8.5 (c=1.7, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.66 (dd, J=6.8,
1.4 Hz, 4H), 7.47–7.35 (m, 6H), 3.54 (dd, J=10.0, 5.3 Hz, 1H), 3.46 (dd,
J=9.9, 6.3 Hz, 1H), 2.88 (q, J=7.4 Hz, 2H), 2.83 (dd, J=14.5, 5.3 Hz,
1H), 2.38 (dd, J=14.5, 8.4 Hz, 1H), 2.28 (m, 1H), 1.25 (t, J=7.4 Hz,
3H), 1.15 (s, 9H), 0.97 ppm (d, J=6.6 Hz, 3H); 13C NMR (100.6 MHz,
CDCl3): d=199.2 (s), 135.62 (d), 133.63 (s), 129.58 (d), 127.50 (d), 67.90
(t), 47.75 (t), 33.76 (d), 26.84 (q), 23.27 (t), 19.28 (s), 16.40 (q), 14.86 ppm
(q); HRMS: calcd for C19H23O2SSi [MÀtert-butyl]: 343.1188; found:
343.1183.
Synthesis of compound 31: DIBALH (4.46 mL, 4.46 mmol, 1.0m solution
in CH2Cl2) was added to a stirred mixture of 30 (500 mg, 2.03 mmol) in
CH2Cl2 (30 mL) at À658C under nitrogen. Stirring was continued until
the reduction was completed (3–4 h). The reaction mixture was quenched
with saturated aqueous Rochelle salt (potassium sodium tartrate; 30 mL)
and stirred for 30 min. The phases were separated and the aqueous layer
was extracted with CH2Cl2. The combined organic phases were dried
over MgSO4 and concentrated under reduced pressure to yield crude al-
dehyde 31 as a colourless oil (428 mg, 85% yield). The spectral data of
31 were consistent with those reported in the literature:[16a,b] [a]D25 =À25.8
(c=0.29, CHCl3); 1H NMR (400 MHz, CDCl3): d=9.65 (d, J=2.6 Hz,
1H), 7.25–7.22 (m, 2H), 6.89–6.85 (m, 2H), 4.44 (d, J=1.6 Hz, 2H),
3.81–3.79 (m, 3H), 3.46 (dd, J=9.1, 5.8 Hz, 1H), 3.33 (dd, J=9.1, 7.4 Hz,
1H), 2.58–2.43 (m, 2H), 1.83 (ddt, J=12.7, 6.6, 5.6 Hz, 4H), 1.70–1.58
(m, 2H), 1.38 ppm (dd, J=12.5, 7.8 Hz, 1H); 13C NMR (101 MHz,
CDCl3): d=204.02, 159.33, 130.71, 129.31, 113.96, 73.18, 72.89, 56.00,
55.48, 41.43, 29.59, 26.79, 25.19 ppm; HRMS: calcd for C15H20O3
[M+Na+]: 271.1310; found: 271.1295.
1,4-Addition on a,b-unsaturated ketones: Synthesis of compound 13a:
(R,SFe)-Josiphos (4)·CuBr complex (18.5 mg, 0.0249 mmol, 1 mol%) was
dissolved in tBuOMe (5 mL) under nitrogen. The mixture was cooled to
À808C and methylmagnesium bromide (0.996 mL 2.44 mmol, solution in
diethyl ether) was added dropwise over 10 min. After the reaction mix-
ture had been stirred for 10 min, a solution of thioester 12 (1.2 g,
2.49 mmol) in tBuOMe (7.2 mL) was added with a syringe pump over
1.5 h. The reaction mixture was stirred at À808C for 18 h, then quenched
by the addition of MeOH and allowed to warm to room temperature. Sa-
turated aqueous NH4Cl was added, and after phase separation and ex-
traction of the aqueous phase with diethyl ether, the combined organic
phases were dried over MgSO4, concentrated under reduced pressure and
purified by flash chromatography (eluent: pentane/diethyl ether, 40:1) to
afford 13a as a colourless oil (1.01 g, 85% yield): anti/syn ratio deter-
mined by NMR spectroscopy: >99:1; [a]2D5 =À19.4 (c=1.39, CHCl3);
1H NMR (400 MHz, CDCl3): d=7.67 (d, J=7.1 Hz, 4H), 7.39 (dd, J=
15.8, 8.6 Hz, 6H), 3.54–3.38 (m, 2H), 2.28 (dt, J=23.4, 12.6 Hz, 2H), 2.11
(s, 3H), 1.72 (dd, J=12.6, 5.9 Hz, 1H), 1.54 (dd, J=14.5, 8.8 Hz, 3H),
1.34 (dt, J=13.1, 6.5 Hz, 1H), 1.05 (d, J=0.5 Hz, 9H), 0.86 ppm (ddd,
J=27.2, 13.6, 6.5 Hz, 18H); 13C NMR (101 MHz, CDCl3): d=208.93,
135.76, 134.22, 129.64, 127.72, 68.94, 52.44, 46.19, 44.10, 41.61, 33.27,
30.58, 27.57, 27.35, 27.07, 26.85, 20.78, 20.38, 19.43, 18.25 ppm; HRMS:
calcd for C31H48O2Si [M+Na+]: 503.3321; found: 503.3315.
Synthesis of B through olefin cross-metathesis and HWE reaction: A
flame-dried Schlenk flask under a nitrogen atmosphere was charged with
32 (520 mg, 1.79 mmol), acrolein diethylacetal (820 mL, 5.37 mmol) and
CH2Cl2 (8.5 mL). Hoveyda–Grubbs second-generation catalyst (56 mg,
0.089 mmol) was added and the resulting solution was stirred for 18 h
with heating to reflux. The reaction was then quenched with water
(5 mL) and formic acid (0.4 mL) and stirred for 1 h. After phase separa-
tion and extraction of the aqueous phase with CH2Cl2, the combined or-
ganic phases were dried over MgSO4, concentrated under reduced pres-
sure and purified by flash chromatography (eluent: pentane/EtOAc,
40:8) to afford 33 as a colourless oil (427 mg, 75% yield, only the E
isomer observed). DBU (143 mg, 0.94 mmol) and lithium chloride
(40 mg, 0.94 mol) were added to a stirred mixture of 33 (150.5 mg,
0.47 mmol) and (EtO)2P(O)CH(Br)CN (360 mg, 1.41 mmol)[5] in MeCN
(5 mL) at 08C. The solution was stirred for 4 h, then quenched with satu-
rated aqueous NaHCO3, and after phase separation and extraction of the
aqueous phase with EtOAc, the combined organic phases were dried
Catalytic asymmetric hydrogenation of b-ketoesters: Synthesis of com-
pound 21: A solution of 20 (152 mg, 0.32 mmol) and (R)-[(RuCl(Tol-
BINAP))2ACHTUNGTRENNUNG(m-Cl)3ACHTUNGTRENNUNG[NH2Me2] (5.7 mg, 0.0032 mmol) in EtOH (3 mL) was
11730
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11726 – 11731

Synthesis of (À)-Borrelidin
FULL PAPER
over MgSO4, concentrated under reduced pressure and purified by flash
chromatography (eluent: pentane/EtOAc, 40:8) to afford B as a colour-
less oil (183 mg, 93% yield, E/Z 95/5). The spectral data of B were con-
sistent with those reported in the literature:[16a,b] [a]D25 =+11.1 (c=0.24,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.26–7.22 (m, 2H), 7.17–7.14
(m, 1H), 6.90–6.86 (m, 2H), 6.41 (dd, J=7.7, 5.5 Hz, 2H), 4.78 (d, J=
6.2 Hz, 1H), 4.50 (t, J=7.3 Hz, 2H), 3.84–3.78 (m, 3H), 3.56 (dd, J=8.7,
3.9 Hz, 1H), 3.41 (dd, J=11.4, 4.0 Hz, 1H), 3.14 (dd, J=10.7, 8.8 Hz,
1H), 2.53–2.43 (m, 1H), 2.23 (dd, J=14.5, 7.2 Hz, 1H), 2.04 (dd, J=9.0,
7.0 Hz, 1H), 1.77 (ddd, J=12.4, 9.4, 7.5 Hz, 2H), 1.64–1.46 (m, 3H),
1.31–1.18 ppm (m, 3H); 13C NMR (101 MHz, CDCl3): d=159.48, 150.28,
144.52, 129.61, 129.32, 127.38, 114.89, 113.99, 84.08, 74.80, 74.22, 73.11,
55.37, 52.51, 44.31, 39.91, 31.22, 29.90, 24.54 ppm; HRMS: calcd for
C21H26BrNO3 [MÀH+]: 418.1096; found: 418.0998.
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Received: May 12, 2010
Published online: August 23, 2010
Chem. Eur. J. 2010, 16, 11726 – 11731
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11731