Iterative deoxypropionate synthesis based on a copper-mediated directed allylic substitution: Formal total synthesis of borrelidin (C3-C11 fragment)

Article abstract of DOI:10.1002/chem.200600343

A new iterative strategy for the flexible preparation of any oligodeoxypropionate stereoisomer is presented which relies on an o-DPPB-directed copper mediated allylic substitution employing enantiomerically pure Grignard reagents; the reaction is working with perfect control over all aspects of the reaction selectivity. This key C-C bond-forming step features reversed polarity compared with established enolate alkylation methodology. It thus avoids existing problems of enolate alkylation strategies such as enolate reactivity as well as costs and problems associated with the chiral auxiliary. Practicability of this new method is demonstrated through application in natural product syntheses. Thus, an efficient synthesis of the northern part of the angiogenesis inhibitor borrelidin (28), the deoxypropionate building block 27, could be devised, representing a formal total synthesis.

Full text of DOI:10.1002/chem.200600343

DOI: 10.1002/chem.200600343
Iterative Deoxypropionate Synthesis Based on a Copper-Mediated Directed
Allylic Substitution: Formal Total Synthesis of Borrelidin
(C3–C11 Fragment)**
Christian Herber and Bernhard Breit*[a]
Abstract: A new iterative strategy for
the flexible preparation of any oligo-
deoxypropionate stereoisomer is pre-
sented which relies on an o-DPPB-di-
rected copper mediated allylic substitu-
tion employing enantiomerically pure
Grignard reagents; the reaction is
working with perfect control over all
aspects of the reaction selectivity. This
reversed polarity compared with estab-
lished enolate alkylation methodology.
It thus avoids existing problems of eno-
late alkylation strategies such as eno-
late reactivity as well as costs and
problems associated with the chiral
auxiliary. Practicability of this new
method is demonstrated through appli-
cation in natural product syntheses.
Thus, an efficient synthesis of the
northern part of the angiogenesis in-
hibitor borrelidin (28), the deoxypropi-
onate building block 27, could be de-
vised, representing a formal total syn-
thesis.
Keywords: allylation · asymmetric
synthesis
·
diastereoselectivity
·
Grignard reagents · polyketides
ꢀ
key C C bond-forming step features
Introduction
catalytic conjugate addition variant employing a chiral di-
phosphine copper catalyst was reported.[6] Furthermore, cat-
alytic enantioselective carboalumination has been used as
an elegant key step for iterative deoxypropionate construc-
tion.[7]
We herein report in full detail on an alternative iterative
strategy relying on our recently developed stereospecific di-
rected copper-mediated allylic substitution reaction.[8] Our
approach allows a flexible preparation of any desired oligo-
deoxypropionate stereoisomer of interest in a stereospecific
manner and has been used in order to prepare the northern
hemisphere of the angiogenesis inhibitor borrelidin.
Many biologically interesting natural products of polyketide
origin contain a fully reduced, “skip” 1,3,5,n (odd number)-
polymethyl-substituted carbon chain.[1] These deoxypropio-
nate structures are usually constructed relying on iterative
asymmetric enolate alkylations as originally introduced by
Evans[2] in the early 1990s. Significant improvements have
been achieved employing pseudoephedrine amide enolates[3]
and azaenolates derived from RAMP-hydrazones,[4] respec-
tively. Despite these advances, efficiency of this methodolo-
gy frequently suffers from either low enolate reactivity or
removability and costs of the chiral auxiliary, drawbacks
which are prohibitive for large scale applications. As a con-
sequence, during the last years many efforts have been de-
voted to explore alternative strategies for iterative and ster-
eoselective deoxypropionate construction. Among those are
methodologies relying on diastereoselective conjugate addi-
tion of organometallics.[5] More recently an enantioselective
Results and Discussion
The general strategy of our approach to deoxypropionates is
outlined in Scheme 1. Key step is a SN2’ reaction of the
chiral organometallic reagent 3 with the chiral allyl electro-
phile 2 providing dideoxypropionate 1. Iteration would be
feasible via oxidative alkene cleavage and transformation to
the corresponding organometallic reagent 4. Subsequent
stereospecific allylic substitution with 2 furnishes the deoxy-
propionate building block 5 of each given stereostructure.
This approach is complementary to the known enolate alky-
lation, since the growing propionate chain is introduced as a
nucleophile and not as an electrophile (“Umpolung”). This
may avoid some of the problems associated with the fre-
[a] C. Herber, Prof. Dr. B. Breit
Institut für Organische Chemie und Biochemie
Albert-Ludwigs-Universität Freiburg
Albertstrasse 21, 79104 Freiburg (Germany)
Fax : (+49)761-203-8715
E-mail: bernhard.breit@organik.chemie.uni-freiburg.de
[**] o-DPPB-Directed Copper-Mediated Allylic Substitution: Part 2; for
Part 1 see: P. Demel, M. Keller, B. Breit, Chem. Eur. J. 2006, 12,
DOI: 10.1002/chem.200600225.
6684
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Chem. Eur. J. 2006, 12, 6684 – 6691

FULL PAPER
quently observed sluggish reactivity of enolates towards b-
branched alkyl electrophiles. However, key to success of this
strategy is the availability of an allylic substitution reaction
that occurs with complete chemo-, regio- and stereoselectivi-
ty, as well as complete 1,3-chirality transfer. Our recently
developed “directed” copper-mediated allylic substitution
employing the ortho-diphenylphosphanylbenzoate (o-
DPPB) function as a reagent-directing leaving group meets
these requirements. However, compatibility with enantio-
merically pure b-branched Grignard reagents 3 was at that
time unknown. Furthermore, practical and scalable access to
enantiomerically pure building blocks 2 and 3 was mandatory.
Scheme 2. Preparation of enantiomerically pure o-DPPB allylic esters 8.
1) Novozym 435, vinylacetate, n-pentane, 308C; 2) o-DPPBA, DCC,
DMAP, CH2Cl2; 3) Novozym 435, pH 7 buffer, 58C; DCC: dicyclohexyl-
carbodiimide.
starting from 2-methylpropane-1,3-diol (11)[13] or a deriva-
tive thereof.[14]
First, bromide 10 was converted to the corresponding
Grignard reagent 12. It proved mandatory to employ mag-
nesium activated according to the dry stir method[15,16] in
order to assure a smooth magnesiation. Thus, addition of
one equivalent of a freshly prepared ethereal solution of
Grignard reagent 12 to the allylic electrophile (S)-(ꢀ)-8 in
the presence of 0.5 equiv CuBr·SMe2 initiated a clean allylic
substitution to give in perfect regio- (>99:1) and excellent
stereoselectivity (dr 97:3) the dideoxypropionate (+)-13 in
good isolated yield. Even better stereoselectivity was noted
upon reaction of Grignard 12 with the (R)-allyl electrophile
(+)-8 (dr 99:1). Thus, reactions producing the syn-relative
configuration appear to represent a matched case while
those producing the anti-configuration represent a mis-
matched case. However, it should be emphasized that even
in the mismatched case high selectivity is observed.
Scheme 1. Iterative strategy for the enantioselective construction of deoxy-
propionate structures relying on a directed copper-mediated allylic substi-
tution (RDG=Reagent-Directing Group).
Enzyme catalysis was chosen as a convenient method to
produce larger quantities of both optical antipodes of allylic
alcohols 6 (Scheme 2). Thus, enzymatic kinetic resolution of
readily available rac-6 was achieved with Novozym 435.[9]
Best results were obtained by shaking the reaction mixture
at 308C in n-pentane as the solvent. At a conversion of
54% the remaining alcohol (S)-6 was obtained in enantio-
merically pure form (>99% ee) which gives a selectivity
factor of E=68.[10] Subjecting scalemic acetate (R)-7 to en-
zymatic ester hydrolysis, employing the same enzyme (No-
vozym 435) again, furnished (R)-6 (96% ee). Both optical
antipodes of 6 were transformed through esterification using
the Steglich protocol to the corresponding ortho-diphenyl-
phosphanylbenzoates 8 which were purified by recrystalliza-
tion. According to this procedure, gram quantities of both
optical antipodes of allyl electrophile 8 could be prepared in
enantiomerically pure form. Allylic o-DPPB esters 8 could
be stored in crystalline form for months without notable de-
composition or oxidation to the corresponding phosphane
oxide.
Relative and absolute configuration of the dideoxypropio-
nates (+)-13 and (ꢀ)-14 was determined through derivatiza-
tion to the known alcohols (+)-16[17] and (ꢀ)-23,[18] respec-
tively (Scheme 4).
In order to demonstrate practicability as well as stereo-
chemical flexibility of our strategy, we decided to prepare
all possible diastereomers of a series of trideoxypropionates
in enantiomerically pure form (Scheme 3). The iteration of
this sequence started with oxidative alkene cleavage of di-
deoxypropionate derivatives (+)-13 and (ꢀ)-14 through ozo-
nolysis and reductive work up with NaBH4 to give the corre-
sponding alcohols in excellent yields (Scheme 3, step 1). At
this stage we decided to explore an alternative method for
Grignard generation relying on halogen–metal exchange.
This procedure turned out to be operationally more conven-
For the chiral organometallic reagent we chose the
Grignard reagent 12 derived from the known bromide 10
(Scheme 3).[11] Both enantiomers of this bromide are readily
accessible either from the commercially available Roche
esters (9)[12] or through enzymatic esterification processes
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6685

B. Breit et al.
Scheme 3. Enantioselective construction of di- and trideoxypropionate building blocks based on iterative o-DPPB-directed copper-mediated allylic sub-
stitution. 1) O3, NaBH4; 2) PPh3I2, Im; 3) 2 equiv tBuLi, MgBr2·OEt2, then (S)-(ꢀ)-8, CuBr·SMe2, Et2O.
tase and protein biosynthesis.[19] In addition to its recently
described CDK inhibitory activity,[20] borrelidin was found
to inhibit angiogenesis in rat aorta models at subnanomolar
concentrations (IC50 =0.4 ngmLꢀ1) through a so far un-
known mechanism of action.[21] These results render this
macrolide an attractive synthetic target for the development
of novel antiangiogenetic drugs. Very recently, four elegant
total syntheses have been reported[22] among which the syn-
Scheme 4. Proof of relative and absolute configuration.
thesis of Theodorakis[22c] became of particular interest to us.
Thus, in his synthesis the key building block for the northern
hemisphere of borrelidin, aldehyde (+)-27, which is a tetra-
ient for small scale reactions. For this purpose the above-de-
rived primary alcohols 15, 16 were converted to the corre-
sponding iodides 17, 18 (Scheme 3, step 2). Halogen–metal
exchange proceeded cleanly upon treatment with tert-butyl-
lithium followed by transmetallation to magnesium. Direct-
ed allylic substitution with allyl electrophiles (S)-(ꢀ)-8 and
(R)-(+)-8, respectively, in the presence of 0.5 equiv cop-
per(i) salt proceeded cleanly to give all four possible diaster-
eomeric trideoxypropionate building blocks 19–22 in good
yield, perfect regio- and excellent stereoselectivity as essen-
tially single stereoisomers.
deoxypropionate derivative, was prepared employing the
iterative enolate alkylation strategy developed by Myers
et al.[3] in 13 steps starting from iodide 29 in 36% overall
yield.[22c]
Our synthesis of the aldehyde (+)-27 commenced from
the all-syn trideoxypropionate (ꢀ)-22 which was subjected
to ozonolysis followed by reductive workup with NaBH4 to
give after Mukaiyama redox condensation the iodide (ꢀ)-25
in excellent yields. Transformation of (ꢀ)-25 to the corre-
sponding Grignard reagent and subjection to the conditions
of the directed allylic substitution with (S)-(ꢀ)-8 gave the
tetradeoxypropionate (+)-26 in excellent yield and stereose-
lectivity (Scheme 5). Ozonolysis followed by reductive
workup with triphenylphosphine furnished the known alde-
hyde (+)-27,[22c] thus representing a formal total synthesis of
borrelidin. Our synthesis required eight steps from bromide
10 in a global yield of 41% and thus compares favorably
with the approach towards (+)-27 reported by Theodorakis.
Formal total synthesis of borrelidin (C3–C11 fragment):
Borrelidin (28) is a biologically intriguing and structurally
unique macrolide antibiotic first isolated from Streptomyces
rochei in 1949 by Berger and co-workers.[1b] The compound
shows broad antiviral and antibacterial activity which pre-
sumably arises from its inhibition of threonyl-tRNA synthe-
6686
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6684 – 6691

Total Synthesis of Borrelidin
FULL PAPER
ture was shaken at this temperature until a conversion of 54% (NMR
control) was reached (typically 21 h). After filtration and washing with n-
pentane, the solution was poured directly on a flash column. Purification
by flash chromatography (n-pentane/diethyl ether 20:1!1:2) and remov-
ing the solvents under atmospheric pressure provided (R)-trans-hex-4-en-
3-yl acetate [(+)-7] (40 mmol, 50%, 86% ee determined after saponifica-
tion to the corresponding alcohol 6. [a]2D0 =+47.6 (c=5.80 in CHCl3)
and (S)-trans-hex-4-en-3-ol [(ꢀ)-6] (34 mmol, 42%, >99% ee, [a]D20
=
ꢀ2.0, c=0.93 in CHCl3) as colorless liquids. GC (CP-Chirasil-Dex-CB,
25 m”0.25 mm, 858C isothermal, 5 psi H2, tR[(R)-6] = 7.6 min, tR[(S)-6]
= 7.9 min). The analytical and spectroscopic data correspond to those re-
ported previously.[24]
Resolution of (R)-trans-hex-4-en-3-yl acetate [(+)-7]: Novozym 435
(1184 mg) was added at 58C to a solution of (+)-7 (8.42 g, 59.2 mmol,
86% ee) in diethyl ether (118 mL) and phosphate buffer pH 7 (178 mL)
and stirred at this temperature until a conversion of 73% was reached
(4 d). After filtration and washing with diethyl ether, the mixture was sa-
turated with NaCl, the phases were separated and the aqueous phase was
extracted with diethyl ether. The combined organic phases were washed
with conc. K2CO3 solution and dried over Na2SO4. The solvents were re-
moved through distillation under atmospheric pressure. Flash chromatog-
raphy with n-pentane/diethyl ether 20:1 furnished the alcohol (R)-6
(26.3 mmol, 44%, 96% ee) as a colorless liquid. [a]2D0 =+2.1 (c=0.85 in
CHCl3). The analytical and spectroscopic data correspond to those re-
ported previously.[24]
Scheme 5. Formal total synthesis (C3–C11 fragment) of borrelidin 28 via
iterative directed allylic substitution. 1) O3, NaBH4, (!24); 2) PPh3I2,
Im; 3) 2 equiv tBuLi, MgBr2·OEt2, then (S)-(ꢀ)-8, CuBr·SMe2, Et2O; 4)
O3, PPh3.
(3S,E)-3-[2-(Diphenylphosphanyl)benzoyloxy]-4-hexene [(ꢀ)-8]: Alcohol
(S)-6 (2.00 g, 20.0 mmol) was added dropwise at room temperature to a
solution of o-DPPBA[25] (6.13 g, 20.0 mmol, 1.0 equiv), DCC (4.13 g,
20.0 mmol, 1.0 equiv) and DMAP (2.45 g, 20.0, 1.0 equiv) in CH2Cl2
(80 mL). After 24 h the reaction mixture was filtered through a plug of
CH2Cl2-wetted Celite and washed with additional CH2Cl2. An appropri-
ate amount of silica gel was added to the filtrate, which was then concen-
trated to dryness. Flash chromatography (petroleum ether/tert-butyl
methyl ether 40:1) furnished after recrystallization first at 58C and then
at ꢀ208C (ꢀ)-8 (6.84 g, 17.6 mmol, 88%, >99%ee, >99:1 E/Z) as color-
less crystals. [a]2D0 =ꢀ16.5 (c=1.75 in CHCl3); m.p. 418C; HPLC
(DAICEL Chiralpak AD, 0.46”25 cm, 0.8 mLminꢀ1, n-heptane/isopropa-
Conclusion
A new iterative strategy for the flexible preparation of any
possible oligodeoxypropionate stereoisomer at will has been
developed. Key to success was an o-DPPB-directed copper
mediated allylic substitution employing enantiomerically
pure Grignard reagents, which occurs with perfect control
over all aspects of reaction selectivity. This fragment cou-
pling step features reversed polarity compared to establish-
ed enolate alkylation methodology. It thus avoids existing
problems of enolate alkylation strategies such as enolate re-
activity as well as costs of chiral auxiliary and problems with
its removal. Practicality and applicability in natural product
syntheses could be shown by the efficient synthesis of the
northern part of the angiogenesis inhibitor borrelidin 28, the
deoxypropionate building block 27, representing a formal
total synthesis.
nol 99:1, 158C, 260 nm, tR
A
G
1
tR[(R,E)-8] = 12.3 min, tR[(S,E)-8] = 17.5 min); H NMR (500.003 MHz,
A
N
CDCl3): d=0.81 (t, 3J=7.5 Hz, 3H; 1-CH3), 1.50–1.65 (m, 2H; 2-CH2),
1.63 (dd, 3J=6.7, 4J=1.6 Hz, 3H; 6-CH3), 5.21–5.32 (m, 2H; 3- and 4-
3
3
CH), 5.64 (dq, Jtrans =14.6, J=6.6 Hz, 1H; 5-CH), 6.88–6.91 (m, 1H; Ar-
H), 7.24–7.40 (m, 12H; Ar-H), 8.05–8.08 (m, 1H; Ar-H); 13C NMR
(125.741 MHz, CDCl3): d=9.6 (C-1), 17.7 (C-6), 27.4 (C-2), 77.3 (C-3),
128.1
A
G
G
129.1 (2C), 129.2 (C-4), 130.6 (d, J
AHCTREUNG
J
J
C
ACHTREUNG
G
ACHTREUNG
140.1 (d, J
A
ACHTREUNG
(125.741 MHz, CDCl3): d=ꢀ3.63; elemental analysis calcd (%) for
C25H25O2P (388.44): C 77.30, H 6.49; found: C 77.25, H 6.67.
A
Experimental Section
procedure was analogous to that used for the preparation of (ꢀ)-8. From
alcohol (R)-6 (1.46 g, 14.6 mmol), o-DPPBA (4.47 g, 14.6 mmol,
1.0 equiv), DCC (3.01 g, 14.6 mmol, 1.0 equiv) and DMAP (1.78 g,
14.6 mmol, 1.0 equiv) was obtained o-DPPB ester (+)-8 (4.71 g,
12.1 mmol, 83%, >99%ee, >99:1 E/Z) as colorless crystals. The spectro-
scopic data correspond to those of (ꢀ)-8. [a]2D0 =+16.8 (c=1.88 in
CHCl3); m.p. 418C; elemental analysis calcd (%) for C25H25O2P (388.44):
C 77.30, H 6.49; found: C 77.21, H 6.60.
General remarks: Reactions were performed in flame-dried glassware
under argon (purity > 99.998%). The solvents were dried by standard
procedures, distilled, and stored under argon. All temperatures quoted
are not corrected. 1H, 13C NMR spectra: Bruker AM-400, Bruker DRX-
500 with tetramethylsilane (TMS), chloroform (CHCl3), or benzene
(C6H6) as internal standards. 31P NMR spectra: Varian Mercury 300 with
85% H3PO4 as external standard. Melting points: Melting point appara-
tus by Dr. Tottoli (Büchi). Elemental analyses: Elementar Vario EL.
Flash chromatography: Silica gel Si 60, E. Merck AG, Darmstadt, 40–
63 mm. Reversed phase silica gel Polygoprep 100–50 C18, Macherey-
Nagel. tert-Butyllithium was purchased from Aldrich.
A
[(+)-13]:
CuBr·SMe2 (21 mg, 0.10 mmol, 0.5 equiv) was added at RT to a solution
of (ꢀ)-8 (78 mg, 0.20 mmol) in diethyl ether (4 mL) and the mixture was
stirred for 5 min at RT. The Grignard reagent 12 (2.4 mL, 0.24 mmol,
0.1m solution in diethyl ether, 1.2 equiv) was added dropwise at RT to
the yellow solution. After stirring for 2 h the suspension was quenched
by adding saturated aqueous NH4Cl solution (2 mL). The phases were
separated and the aqueous phase was extracted with CH2Cl2 (3”5 mL).
Resolution of rac-trans-hex-4-en-3-ol (6): Novozym 435[23] (800 mg) was
added at 308C to a solution of rac-6 (8.0 g, 80 mmol) in n-pentane
(40 mL) and vinyl acetate (7.6 g, 88 mmol, 1.1 equiv). The reaction mix-
Chem. Eur. J. 2006, 12, 6684 – 6691
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6687

B. Breit et al.
The combined organic phases were dried (Na2SO4) and the solvents were
removed in vacuo. Flash chromatography of the residue with petroleum
ether/tert-butyl methyl ether 50:1 yielded the title compound (+)-13 as a
colorless oil (46 mg, 83%, dr 97:3). HPLC (Macherey-Nagel EC 250/4
(pt, J=12.5 Hz, 2H; CH2-Ar), 6.87 (m, 2H; 3’-CH), 7.25 (m, 2H; 2’-
CH); 13C NMR (100.624 MHz, CDCl3): d=17.6 (CH3), 18.2 (CH3), 31.0
(CH), 33.3 (CH), 37.7 (C-3), 55.2 (O-CH3), 67.9 (C-1), 72.7 (CH2-Ar),
75.6 (C-5), 113.7 (2”C-3’), 129.1 (2”C-2’), 130.7 (C-1’), 159.1 (C-4’). The
analytical and spectroscopic data correspond to those reported previous-
ly.[17]
Nucleosil 100-5, 0.4”25 cm, 0.8 mLminꢀ1
,
n-heptane/ethyl acetate
200:0.3, 258C, 275 nm): tR[(ꢀ)-14]
=
52.4 min (2.8%), tR[(+)-13] =
55.0 min (97.2%). [a]D20 =+18.2 (c=0.68 in CHCl3); 1H NMR
(499.873 MHz, CDCl3): d=0.91 (d, 3J=6.8 Hz, 3H; CH3), 0.92 (d, 3J=
6.8 Hz, 3H; CH3), 0.95 (t, 3J=7.5 Hz, 3H; CH3), 1.08 (dt, 2J=13.5, 3J=
7.5 Hz, 1H; CH2), 1.29 (m, 1H; CH2), 1.81 (m, 1H; CH), 1.98 (m, 2H;
CH2), 2.14 (m, 1H; CH), 3.18 (dd, 2J=9.1, 3J=7.1 Hz, 1H; CH2), 3.32
(dd, 2J=9.1, 3J=5.4 Hz, 1H; CH2), 3.80 (s, 3H; O-CH3), 4.41 (d, 2J=
Triphenyliodophosphonium iodide:
A solution of triphenylphosphine
(13.1 g, 50.0 mmol) in CH2Cl2 (20 mL) was added dropwise at 08C to
iodine (12.8 g, 50.5 mol, 1.01 equiv) in CH2Cl2 (50 mL). The resulting sus-
pension was stirred for 30 min. A complete consumption of triphenyl-
phosphine was detected via TLC. The suspension was filtered, the filtrate
was concentrated in vacuo and the resulting solid was suspended in pe-
troleum ether (100 mL) and filtered. The combined solids were washed
with petroleum ether (100 mL) and dried in vacuo yielding the title com-
pound PPh3I2 (24.5 g, 47.5 mmol, 95%) as a yellow solid which was
stored at ꢀ208C under exclusion of light. Elemental analysis calcd (%)
for C18H15I2 (516.09): C 41.89, H 2.93; found C 41.92, H 2.96. The spectro-
scopic data correspond to those reported previously.[26]
2
3
11.7 Hz, 1H; CH2-Ar), 4.44 (d, J=11.7 Hz, 1H; CH2-Ar), 5.25 (ddt, J=
15.3, 7.6, 4J=1.4 Hz, 1H; CH), 5.38 (dtd, 3J=15.3, 6.2, 4J=0.9 Hz, 1H;
CH), 6.87 (m, 2H; Ar-H), 7.26 (m, 2H; Ar-H); 13C NMR (125.709 MHz,
CDCl3): d=14.0, 17.7, 20.7, 25.5, 31.0, 34.0, 41.2, 55.3, 72.6, 75.6, 113.7
(2C), 129.1 (2C), 129.9, 131.0, 135.6, 159.0; elemental analysis calcd (%)
for C18H28O2 (276.41): C 78.21, H 10.21; found C 77.90, H 10.32.
A
5-Iodo-1-(4’-methoxybenzyloxy)-(2S,4S)-dimethylpentane [(ꢀ)-17]:
A
procedure was analogous to that used for the preparation of (+)-13.
From o-DPPB ester (+)-8 (78 mg, 0.20 mmol), CuBr·SMe2 (21 mg,
0.10 mmol, 0.5 equiv) and Grignard reagent 12 (2.4 mL, 0.24 mmol, 0.1m
solution in diethyl ether, 1.2 equiv) was obtained alkene (ꢀ)-14 (44 mg,
0.16 mmol, 80%, dr 99:1) as a colorless oil. [a]2D0 =ꢀ3.9 (c=0.41 in
CHCl3); 1H NMR (499.873 MHz, CDCl3): d=0.89 (d, 3J=6.8 Hz, 3H;
CH3), 0.91 (d, 3J=6.8 Hz, 3H; CH3), 0.95 (t, 3J=7.5 Hz, 3H; 8-CH3),
1.01 (m, 1H; 3-CH2), 1.33 (m, 1H; 3-CH2), 1.79 (m, 1H; 2-CH), 1.98 (m,
2H; 7-CH2), 2.17 (m, 1H; 4-CH), 3.18 (dd, 2J=9.1, 3J=7.1 Hz, 1H; 1-
CH2), 3.27 (dd, 2J=9.1, 3J=5.8 Hz, 1H; 1-CH2), 3.80 (s, 3H; -O-CH3),
4.42 (pt, 2J=12.2 Hz, 2H; -O-CH2), 5.17 (ddt, 3J=15.2, 3J=8.3, 4J=
1.3 Hz, 1H; 5-CH), 5.40 (dtd, 3J=15.2, 3J=6.3, 4J=0.6 Hz 1H; 6-CH),
6.87 (m, 2H; 3’-CH), 7.26 (m, 2H; 2’-CH); 13C NMR (125.741 MHz,
CDCl3): d=14.0 (CH3), 16.9 (CH3), 22.0 (CH3), 25.5 (C-7), 31.0 (C-2),
34.2 (C-4), 41.3 (C-3), 55.2 (O-CH3), 72.5 (O-CH2), 76.2 (C-1), 113.7 (2”
C-3’), 129.0 (2”C-2’), 130.5 (C-6), 130.9 (C-1’), 134.9 (C-5), 159.0 (C-4’);
elemental analysis calcd (%) for C18H28O2 (276.41): C 78.21, H 10.21;
found C 78.36, H 10.44.
solution of alcohol (ꢀ)-15 (530 mg, 2.10 mmol) in CH2Cl2 (4 mL) was
added dropwise at RT under exclusion of light to PPh3I2 (1.30 g,
2.52 mmol, 1.2 equiv) and imidazole (345 mg, 5.07 mmol, 2.4 equiv) in
CH2Cl2 (9 mL). The suspension was stirred overnight. TLC showed a
quantitative conversion of the starting material. The suspension was con-
centrated in vacuo. Flash chromatography (petroleum ether/tert-butyl
methyl ether 20:1) furnished the title compound (ꢀ)-17 (699 mg,
1.93 mmol, 92%) as a colorless oil which was stored at ꢀ208C under ex-
clusion of light. [a]2D0 =ꢀ6.5 (c=1.79 in CHCl3); 1H NMR (400.136 MHz,
3
3
CDCl3): d=0.91 (d, J=6.9 Hz, 3H; CH3), 0.95 (d, J=6.4 Hz, 3H; CH3),
1.16–1.33 (m, 2H; 3-CH2), 1.61 (m, 1H; CH), 1.82 (m, 1H; CH), 3.14
(dd, 2J=9.5, 3J=6.0 Hz, 1H; 5-CH2), 3.18–3.25 (m, 2H; CH2), 3.27 (dd,
2J=9.0, 3J=6.0 Hz, 1H; 1-CH2), 3.80 (s, 3H; O-CH3), 4.42 (pt, J=
12.3 Hz, 2H; CH2-Ar), 6.87 (m, 2H; 3’-CH), 7.25 (m, 2H; 2’-CH);
13C NMR (100.624 MHz, CDCl3): d=17.1 (CH3), 18.3 (CH3), 20.3 (C-5),
31.1 (CH), 32.3 (CH), 40.8 (C-3), 55.3 (O-CH3), 72.7 (CH2-Ar), 75.9 (C-
1), 113.8 (2”C-3’), 129.1 (2”C-2’), 130.8 (C-1’), 159.1 (C-4’); elemental
analysis calcd (%) for C15H23IO2 (362.25): C 49.73, H 6.40; found C
49.76, H 6.30.
(2S,4S)-Dimethyl-5-(4’-methoxybenzyloxy)-pentan-1-ol [(ꢀ)-15]: Through
a solution of (+)-13 (276 mg, 1.00 mmol) in MeOH (10 mL) at ꢀ788C
was bubbled a stream of ozone (one bubble per s) until a quantitative
conversion was observed by TLC. Subsequently, the ozone was removed
by bubbling argon through this solution. NaBH4 (189 mg, 5.00 mmol,
5.0 equiv) was added at ꢀ788C and then the mixture was slowly warmed
to RT. NH4Cl solution (10 mL) was added, the solution was extracted
with ethyl acetate (3”10 mL) and dried (Na2SO4). An appropriate
amount of silica gel was added to the filtrate, which was then concentrat-
ed to dryness. Flash chromatography (petroleum ether/tert-butyl methyl
ether 20:1) furnished alcohol (ꢀ)-15 (240 mg, 0.950 mmol, 95%) as a col-
orless oil. [a]2D0 =ꢀ11.9 (c=1.78 in CHCl3); 1H NMR (499.873 MHz,
CDCl3): d=0.89 (pt, J=6.2 Hz, 6H; CH3), 1.21 (m, 2H; 3-CH2), 1.60
(brt, 1H; OH), 1.74 (m, 1H; 2- or 4-CH), 1.88 (m, 1H; 2- or 4-CH), 3.24
(dd, 2J=9.0, 3J=6.4 Hz, 1H; CH2), 3.27 (dd, 2J=8.9, 3J=6.4 Hz, 1H;
CH2), 3.42 (m, 2H; CH2), 3.80 (s, 3H; O-CH3), 4.43 (pt, J=11.9 Hz, 2H;
CH2-Ar), 6.88 (m, 2H; 3’-CH), 7.25 (m, 2H; 2’-CH); 13C NMR
(125.709 MHz, CDCl3): d=16.3 (CH3), 17.0 (CH3), 30.5 (CH), 33.0 (CH),
37.3 (C-3), 55.2 (O-CH3), 68.8 (C-1), 72.7 (CH2-Ar), 76.3 (C-5), 113.7 (2”
C-3’), 129.1 (2”C-2’), 130.7 (C-1’), 159.1 (C-4’); elemental analysis calcd
(%) for C15H24O3 (252.35): C 71.39, H 9.59; found C 71.45, H 9.75.
5-Iodo-1-(4’-methoxybenzyloxy)-(2S,4R)-dimethylpentane [(+)-18]: The
procedure was analogous to that used for the preparation of (ꢀ)-17.
From the alcohol (+)-16 (631 mg, 2.50 mmol), PPh3I2 (1.55 g, 3.00 mmol,
1.2 equiv) and imidazole (408 mg, 6.00 mmol, 2.4 equiv) was obtained
iodide (+)-18 (844 mg, 2.33 mmol, 93%) as a colorless oil. [a]2D0 =+1.1
(c=2.77 in CHCl3); 1H NMR (400.136 MHz, CDCl3): d=0.94 (d, 3J=
6.9 Hz, 3H; CH3), 0.98 (d, 3J=6.4 Hz, 3H; CH3), 0.98–1.07 (m, 1H; 3-
CH2), 1.43 (m, 1H; 3-CH2), 1.53 (m, 1H; CH), 1.80 (m, 1H; CH), 3.10
(dd, 2J=9.5, 3J=6.0 Hz, 1H; CH2), 3.21–3.25 (m, 2H; CH2), 3.30 (dd,
2J=9.0, J=5.6 Hz, 1H; CH2), 3.80 (s, 3H; O-CH3), 4.42 (pt, J=12.0 Hz,
2H; CH2-Ar), 6.87 (m, 2H; 3’-CH), 7.25 (m, 2H; 2’-CH); 13C NMR
(100.624 MHz, CDCl3): d=17.6 (CH3), 17.8 (CH3), 21.4 (C-5), 31.0 (CH),
32.0 (CH), 40.8 (C-3), 55.2 (O-CH3), 72.6 (CH2-Ar), 75.4 (C-1), 113.7 (2”
C-3’), 129.0 (2”C-2’), 130.8 (C-1’), 159.1 (C-4’); elemental analysis calcd
(%) for C15H23IO2 (362.25): C 49.73, H 6.40; found C 50.06, H 6.35.
3
2
A
[(+)-19]:
tBuLi (0.6 mL, 1.66m in pentane, 1.0 mmol, 2.0 equiv) was added drop-
wise at ꢀ1008C to a solution of the iodide (ꢀ)-17 (181 mg, 0.500 mmol)
in diethyl ether (1.0 mL). After 15 min TLC showed complete conversion
of the starting material. Then a freshly prepared ethereal solution of
MgBr2·OEt2 (from 1.00 mmol Mg,[27] 0.65 mmol dibromoethane, 0.7 mL
diethyl ether) was added and the solution was slowly warmed to RT
(30 min). The resulting colorless Grignard solution was added dropwise
at RT via a transfer needle within 30 min to a solution of the o-DPPB
ester (ꢀ)-8 (214 mg, 0.550 mmol, 1.1 equiv), CuBr·SMe2 (56 mg,
0.275 mmol, 0.55 equiv) in diethyl ether (11 mL). The resulting suspen-
sion was stirred overnight. Then saturated NH4Cl solution (3.5 mL),
aqueous NH3 solution (12.5%, 1.3 mL), and CH2Cl2 (11 mL) were added
and the mixture stirred until two clear phases were obtained. The phases
were separated and the aqueous phase was extracted with CH2Cl2 (3”
A
procedure was analogous to that used for the preparation of (ꢀ)-15.
From alkene (ꢀ)-14 (470 mg, 1.70 mmol) and NaBH4 (322 mg,
8.51 mmol, 5.0 equiv) was obtained alcohol (+)-16 (394 mg, 1.56 mmol,
92%) as
a
colorless oil. [a]D20 =+2.5 (c=2.97 in CHCl3); 1H NMR
(400.136 MHz, CDCl3): d=0.87–0.98 (m, 1H), 0.93 (d, 3J=6.5 Hz, 3H;
CH3), 0.94 (d, 3J=6.9 Hz, 3H; CH3), 1.42–1.50 (m, 1H), 1.64–1.74 (m,
2H), 1.80–1.90 (m, 1H), 3.21 (dd, 2J=9.0, 3J=6.4 Hz, 1H; CH2), 3.28
(dd, 2J=9.0, 3J=5.6 Hz, 1H; CH2), 3.39 (dd, 2J=10.7, 3J=6.2 Hz, 1H;
2
3
CH2), 3.47 (dd, J=10.7, J=5.2 Hz, 1H; CH2), 3.80 (s, 3H; O-CH3), 4.42
6688
www.chemeurj.org
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6684 – 6691

Total Synthesis of Borrelidin
FULL PAPER
5mL). The combined organic phases were dried (Na2SO4). An appropri-
ate amount of silica gel was added to the filtrate, which was then concen-
trated to dryness. Flash chromatography (petrolether/tert-butyl methyl
ether 50:1) followed by reversed phase chromatography (acetonitrile/
water 75:25!80:20, the product fractions were first concentrated in
vacuo, then extracted with CH2Cl2 and dried over CaCl2) furnished the
alkene (+)-19 (127 mg, 0.40 mmol, 80%, dr 98:2) as a colorless oil. GC
(CP-SIL 5 Lowbleed/MS; 30 m”0.32 mm”0.25 mm: 508C (5 min isother-
C
[(ꢀ)-22]:
mal), ! 1508C (258Cminꢀ1, 10 min isothermal), ! 1708C (258Cminꢀ1
,
30.2 min isothermal), 2.5 mLminꢀ1 He, tR[(ꢀ)-22] = 36.9 min, tR[(+)-21]
= 37.5 min, tR[(ꢀ)-20] = 38.5 min, tR[(+)-19] = 40.4 min); [a]2D0 =+1.7
(c=1.14 in CHCl3); 1H NMR (499.873 MHz, CDCl3): d=0.81 (d, 3J=
3
3
6.5 Hz, 3H; CH3), 0.88 (d, J=6.6 Hz, 3H; CH3), 0.92 (d, J=6.6 Hz, 3H;
CH3), 0.95 (t, J=7.5 Hz, 3H; 10-CH3), 0.99–1.06 (m, 2H; 3- and 5-CH2),
3
1.16 (m, 2H; 3- and 5-CH2), 1.53 (m, 1H; 4-CH), 1.84 (m, 1H; 2-CH),
1.98 (m, 2H; 9-CH2), 2.15 (m, 1H; 6-CH), 3.16 (dd, 2J=9.1, 3J=7.1 Hz,
1H; 1-CH2), 3.27 (dd, 2J=9.1, 3J=5.5 Hz, 1H; 1-CH2), 3.80 (s, 3H; O-
2
2
CH3), 4.41 (d, J=11.7 Hz, 1H; CH2-Ar), 4.44 (d, J=11.7 Hz, 1H; CH2-
Ar), 5.17 (ddt, 3J=15.3 Hz, 8.1, 4J=1.5 Hz, 1H; 7-CH), 5.38 (dtd, 3J=
15.3, 6.4, 4J=0.8 Hz, 1H; 8-CH), 6.87 (m, 2H; 3’-CH), 7.25 (m, 2H; 2’-
CH); 13C NMR (125.709 MHz, CDCl3): d=14.1 (C-10), 17.0 (CH3), 19.3
(CH3), 21.7 (CH3), 25.6 (C-9), 27.3 (C-4), 30.8 (C-2), 34.2 (C-6), 41.5 (C-
3), 45.6 (C-5), 55.2 (O-CH3), 72.6 (CH2-Ar), 76.3 (C-1), 113.7 (2”C-3’),
129.1 (2”C-2’), 130.1 (C-8), 131.0 (C-1’), 135.3 (C-7), 159.0 (C-4’); ele-
mental analysis calcd (%) for C21H34O2 (318.49): C 79.19, H 10.76; found
C 79.04, H 10.73.
A
[(ꢀ)-20]:
The procedure was analogous to that used for the preparation of (+)-19.
From o-DPPB ester (+)-8 (214 mg, 0.550 mmol, 1.1 equiv), CuBr·SMe2
(56 mg, 0.275 mmol, 0.55 equiv) and iodide (ꢀ)-17 (181 mg, 0.500 mmol)
was obtained alkene (ꢀ)-20 (131 mg, 0.410 mmol, 82%, dr 98:2) as a col-
orless oil. [a]2D0 =ꢀ26.0 (c=1.71 in CHCl3); 1H NMR (499.873 MHz,
=
CDCl3): d=0.82 (d, J=6.6 Hz, 3H; CH3), 0.87 (d, J=6.6 Hz, 3H; CH3),
0.91 (d, J=6.6 Hz, 3H; CH3), 0.95 (t, J=7.4 Hz, 3H; 10-CH3), 1.07–1.13
(m, 4H; 3- and 5-CH2), 1.54 (m, 1H; 4-CH), 1.84 (m, 1H; 2-CH), 1.98
(m, 2H; 9-CH2), 2.16 (m, 1H; 6-CH), 3.18 (dd, 2J=9.0, 3J=6.9 Hz, 1H;
1-CH2), 3.26 (dd, 2J=9.1, 3J=5.9 Hz, 1H; 1-CH2), 3.79 (s, 3H; O-CH3),
4.41 (d, 2J=11.7 Hz, 1H; CH2-Ar), 4.44 (d, 2J=11.7 Hz, 1H; CH2-Ar),
5.21 (ddt, 3J=15.3, 7.9, 4J=1.4 Hz, 1H; 7-CH), 5.38 (dtd, 3J=15.3, 6.3,
4J=0.8 Hz, 1H; 8-CH), 6.87 (m, 2H; 3’-CH), 7.26 (m, 2H; 2’-CH);
13C NMR (125.709 MHz, CDCl3): d=14.1 (C-10), 16.8 (CH3), 19.8 (CH3),
21.0 (CH3), 25.6 (C-9), 27.3 (C-4), 30.9 (C-2), 34.0 (C-6), 40.7 (C-3), 45.7
(C-5), 55.2 (O-CH3), 72.6 (CH2-Ar), 76.5 (C-1), 113.7 (2”C-3’), 129.1 (2”
C-2’), 129.9 (C-8), 131.0 (C-1’), 135.6 (C-7), 159.0 (C-4’); elemental analy-
sis calcd (%) for C21H34O2 (318.49): C 79.19, H 10.76; found C 79.15, H
10.81.
A
[(+)-21]:
The procedure was analogous to that used for the preparation of (+)-19.
From o-DPPB ester (ꢀ)-8 (214 mg, 0.550 mmol, 1.1 equiv), CuBr·SMe2
(56 mg, 0.275 mmol, 0.55 equiv) and iodide (+)-18 (181 mg, 0.500 mmol)
was obtained alkene (+)-21 (135 mg, 0.425 mmol, 85%, dr 97:3) as a col-
orless oil. [a]2D0 =+12.1 (c=2.11 in CHCl3); 1H NMR (499.873 MHz,
CDCl3): d=0.84 (d, 3J=6.6 Hz, 3H; CH3), 0.86–0.92 (m, 1H; CH2), 0.89
(d, 3J=6.6 Hz, 3H; CH3), 0.91 (d, 3J=6.6 Hz, 3H; CH3), 0.94 (t, 3J=
7.4 Hz, 3H; 10-CH3), 0.99–1.06 (m, 1H; CH2), 1.15 (m, 1H; CH2), 1.30
(m, 1H; CH2), 1.51 (m, 1H; 4-CH), 1.83 (m, 1H; 2-CH), 1.96 (m, 2H; 9-
CH2), 2.13 (m, 1H; 6-CH), 3.11 (dd, 2J=9.1, 3J=7.4 Hz, 1H; 1-CH2),
3.31 (dd, 2J=9.1, 3J=5.1 Hz, 1H; 1-CH2), 3.79 (s, 3H; O-CH3), 4.38 (d,
2J=11.7 Hz, 1H; CH2-Ar), 4.42 (d, 2J=11.7 Hz, 1H; CH2-Ar), 5.23 (ddt,
3J=15.3, 7.5, 4J=1.4 Hz, 1H; 7-CH), 5.36 (dtd, 3J=15.4, 6.3, 4J=0.8 Hz,
1H; 8-CH), 6.86 (m, 2H; 3’-CH), 7.24 (m, 2H; 2’-CH); 13C NMR
(125.709 MHz, CDCl3): d=14.1 (C-10), 18.2 (CH3), 20.5 (CH3), 20.6
(CH3), 25.6 (C-9), 27.7 (C-4), 30.9 (C-2), 33.9 (C-6), 41.7 (C-3), 44.7 (C-
5), 55.2 (O-CH3), 72.6 (CH2-Ar), 75.8 (C-1), 113.7 (2”C-3’), 129.0 (2”C-
2’), 129.6 (C-8), 131.0 (C-1’), 135.9 (C-7), 159.0 (C-4’); elemental analysis
calcd (%) for C21H34O2 (318.49): C 79.19, H 10.76; found C 78.97, H
10.85.
[(ꢀ)-
Chem. Eur. J. 2006, 12, 6684 – 6691
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6689

B. Breit et al.
3H; O-CH3), 4.34 (d, 2J=11.6 Hz, 1H; CH2-Ar), 4.38 (d, 2J=12.0 Hz,
1H; CH2-Ar), 6.83 (m, 2H; 3’-CH), 7.25 (m, 2H; 2’-CH); 13C NMR
(100.624 MHz, C6D6): d=17.9 (CH3), 18.5 (CH3), 20.5 (CH3), 21.6 (C-7),
27.7 (CH), 31.3 (CH), 31.6 (CH), 42.2 (CH2), 44.1 (CH2), 54.8 (O-CH3),
73.0 (CH2-Ar), 75.6 (C-1), 114.1 (2”C-3’), 129.3 (2”C-2’), 131.5 (C-1’),
159.7 (C-4’); elemental analysis calcd (%) for C18H30O3 (404.33): C 53.47,
H 7.23; found C 53.70, H 7.27.
b) borrelidin: J. Berger, L. M. Jampolsky, M. W. Goldberg, Arch. Bi-
ochem. 1949, 22, 476–478; c) pectinatone: J. E. Biskupiak, C. M. Ire-
land, Tetrahedron Lett. 1983, 24, 3055–3058.
[2] D. A. Evans, R. L. Dow, T. L. Shih, J. M. Takacs, R. Zahler, J. Am.
Chem. Soc. 1990, 112, 5290–5313.
[3] A. G. Myers, B. H. Yang, H. Chen, D. J. Kopecky, Synlett 1997, 457–
459.
[4] A. A. Birkbeck, D. Enders, Tetrahedron Lett. 1998, 39, 7823–7826.
[5] D. R. Williams, W. S. Kissel, J. J. Li, R. J. Mullins, Tetrahedron Lett.
2002, 43, 3723–3727; D. R. Williams, A. L. Nold, R. J. Mullins, J.
Org. Chem. 2004, 69, 5374–5382; for a substrate controlled diaster-
eoselective conjugate addition furnishing syn-deoxypropionate struc-
tures see: S. Hanessian, V. Mascitti, S. Giroux, Proc. Natl. Acad. Sci.
USA 2004, 101, 11996–12001.
[6] J. Schuppan, A. J. Minnaard, B. L. Feringa, Chem. Commun. 2004,
792–793; R. Des Mazery, M. Pullez, F. López, S. R. Harutyunyan,
A. J. Minnard, B. L. Feringa, J. Am. Chem. Soc. 2005, 127, 9966–
9967.
(2S,4S,6R,8S)-Tetramethyl-1-(4’-methoxybenzyloxy)-dodec-(9E)-ene
[(+)-26]: The procedure was analogous to that used for the preparation
of (+)-19. From o-DPPB ester (ꢀ)-8 (274 mg, 0.706 mmol, 1.2 equiv),
CuBr·SMe2 (73.0 mg, 0.355 mmol, 0.6 equiv) and iodide (ꢀ)-25 (238 mg,
0.588 mmol) was obtained alkene (+)-26 (182 mg, 0.505 mmol, 86%, dr
>
95:5) as a colorless oil. [a]2D0 =+8.3 (c=1.11 in CHCl3); 1H NMR
(499.873 MHz, CDCl3): d=0.81 (d, 3J=6.5 Hz, 3H; CH3), 0.84 (d, 3J=
3
3
6.6 Hz, 3H; CH3), 0.90 (d, J=6.6 Hz, 3H; CH3), 0.92 (d, J=6.8 Hz, 3H;
CH3), 0.95 (t, 3J=7.5 Hz, 3H; 12-CH3), 0.81–1.03 (m, 3H; 3-, 5- and 7-
CH2), 1.12–1.23 (m, 2H; 5- and 7-CH2), 1.27–1.33 (m, 1H; 3-CH2), 1.48–
1.59 (m, 2H; 4- and 6-CH), 1.83 (m, 1H; 2-CH), 1.97 (m, 2H; 11-CH2),
2.15 (m, 1H; 8-CH), 3.14 (dd, 2J=9.1, 3J=7.2 Hz, 1H; 1-CH2), 3.31 (dd,
2J=9.1, 3J=5.1 Hz, 1H; 1-CH2), 3.79 (s, 3H; -O-CH3), 4.39 (d, 2J=
[7] M. Magnin-Lachaux, Z. Tan, B. Liang, E. Negishi, Org. Lett. 2004, 6,
1425–1427; T. Novak, Z. Tan, B. Liang, E. Negishi, J. Am. Chem.
Soc. 2005, 127, 2838–2839.
2
3
11.7 Hz, 1H; CH2-Ar), 4.43 (d, J=11.7 Hz, 1H; CH2-Ar), 5.24 (ddt, J=
4
3
4
15.3, 7.6, J=1.4 Hz, 1H; 9-CH), 5.37 (dtd, J=15.3, 6.3, J=0.8 Hz, 1H;
10-CH), 6.86 (m, 2H; 3’-CH), 7.24 (m, 2H; 2’-CH); 13C NMR
(125.709 MHz, CDCl3): d=14.1 (C-12), 18.4 (CH3), 20.4 (CH3), 20.7
(CH3), 21.0 (CH3), 25.6 (C-11), 27.6 (C-4 and C-6), 30.9 (C-2), 34.0 (C-8),
41.7 (C-3), 44.7, 45.4 (C-5 and C-7), 55.2 (O-CH3), 72.6 (CH2-Ar), 75.7
(C-1), 113.7 (2”C-3’), 129.0 (2”C-2’), 129.6 (C-10), 131.0 (C-1’), 136.0
(C-9), 159.0 (C-4’); elemental analysis calcd (%) for C18H30O3 (360.57): C
79.94, H 11.18; found C 79.91, H 11.03.
[8] B. Breit, P. Demel, Adv. Synth. Catal. 2001, 343, 429–432; B. Breit,
P. Demel, C. Studte, Angew. Chem. 2004, 116, 3874–3877; Angew.
Chem. Int. Ed. 2004, 43, 3786–3789; B. Breit, C. Herber, Angew.
Chem. 2004, 116, 3878–3880; Angew. Chem. Int. Ed. 2004, 43, 3790–
3792; for an alternative approach employing allylic substitution see:
C. Spino, M. Allan, Can. J. Chem. 2004, 82, 177–184.
[9] a) Novozym 435 is a lipase from Candida antarctica lipase B, hydro-
lase. For more details see www.novozymes.com; b) for selected ex-
amples of 2-alkanols resolved by CAL-B, see U. T. Bornscheuer,
R. J. Kazlauskas, Hydrolases in Organic Synthesis, Wiley-VCH,
Weinheim, 1999, pp. 70–72.
[10] Program to calculate E values: K. Faber, H. Hoenig, “Selectivity”,
http://www.cis.TUGraz.at/orgc/.
[11] D. Sawada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2000, 122,
43, 10521–10532.
[12] (S)-10: S. D. Meyer, T. Miwa, M. Nakatsuka, S. L. Schreiber, J. Org.
Chem. 1992, 57, 5058–5060.
[13] a) E. Santaniello, P. Ferraboschi, P. Grisenti, Tetrahedron Lett. 1990,
31, 5657–5660; b) C. Bertucci, A. Petri, G. Felix, B. Perini, P. Salva-
dori, Tetrahedron: Asymmetry 1999, 10, 4455–4462; c) P. Grisenti, P.
Ferraboschi, A. Manzocchi, E. Santaniello, Tetrahedron 1992, 48,
3827–3834; d) Z.-F. Xie, H. Suemune, K. Sakai, Tetrahedron: Asym-
metry 1993, 4, 973–980.
[14] T. Akeboshi, Y. Ohtsuka, T. Ishihara, T. Sugai, Adv. Synth. Catal.
2001, 343, 624–637.
[15] K. V. Baker, J. M. Brown, N. Hughes, A. J. Skarnulis, A. Sexton, J.
Org. Chem. 1991, 56, 698–703.
9-(4’-Methoxybenzyloxy)-(2S,4R,6S,8S)-tetramethylnonanal
[(+)-27]:
Through a solution of (+)-26 (72 mg, 0.20 mmol) in MeOH (3 mL) at
ꢀ788C was bubbled a stream of ozone (one bubble per s) until quantita-
tive conversion was monitored by TLC. Subsequently, the ozone was re-
moved by bubbling argon through this solution. Triphenylphosphine
(63 mg, 0.24 mmol, 1.2 equiv) and CH2Cl2 (2 mL) were added at ꢀ788C
and then the mixture was slowly warmed to RT. Water (3 mL) was
added, the solution was extracted with tert-butyl methyl ether (3”5mL)
and dried (Na2SO4). An appropriate amount of silica gel was added to
the filtrate, which was then concentrated to dryness. Flash chromatogra-
phy (petroleum ether/tert-butyl methyl ether 100:1) yielded the aldehyde
(+)-27 (59.6 mg, 0.178 mmol, 89%) as a colorless oil. [a]2D0 =+5.0 (c=
1
1.09 in CH2Cl2, lit.[22c] =+5.4, c=0.5 in CH2Cl2); H NMR (499.873 MHz,
3
3
CDCl3): d=0.83 (d, J=6.5 Hz, 3H; CH3), 0.84 (d, J=6.6 Hz, 3H; CH3),
3
3
0.90 (d, J=6.8 Hz, 3H; CH3), 1.04 (d, J=6.9 Hz, 3H; 2-CH-CH3), 0.90–
1.00 (m, 1H), 1.19–1.33 (m, 4H), 1.36–1.43 (m, 1H), 1.50–1.65 (m, 2H),
1.78–1.85 (m, 1H), 2.35–2.44 (m, 1H; 2-CH), 3.16 (dd, 2J=8.9, 3J=
6.9 Hz, 1H; 9-CH2), 3.29 (dd, 2J=9.1, 3J=5.2 Hz, 1H; 9-CH2), 3.78 (s,
3H; O-CH3), 4.38 (d, 2J=11.7 Hz, 1H; CH2-Ar), 4.42 (d, 2J=11.7 Hz,
1H; CH2-Ar), 6.85 (m, 2H; 3’-CH), 7.23 (m, 2H; 2’-CH), 9.59 (d, 3J=
1.9 Hz, 1H; -C(O)H); 13C NMR (125.709 MHz, CDCl3): d=13.1 (CH3),
18.3 (CH3), 20.0 (CH3), 20.7 (CH3), 27.4, 27.5, 30.9, 37.0, 41.7, 44.2, 45.5,
55.3 (O-CH3), 72.7 (CH2-Ar), 75.6 (C-9), 113.7 (2”C-3’), 129.0 (2”C-2’),
130.9 (C-1’), 159.0 (C-4’), 205.3 (C-1). The analytical data correspond to
those reported previously.[22c]
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This work was supported by the Fonds der Chemischen Industrie, the
Deutsche Forschungsgemeinschaft, the Alfried Krupp Award for young
university teachers of the Krupp foundation (to B.B.). We thank C.
Steinger for technical assistance and Novartis AG for generous gifts of
chemicals.
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6690
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ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2006, 12, 6684 – 6691

Total Synthesis of Borrelidin
FULL PAPER
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Received: March 10, 2006
Published online: June 14, 2006
Chem. Eur. J. 2006, 12, 6684 – 6691
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
6691