Enantioselective synthesis of the ester side chain of homoharringtonine

Article abstract of DOI:10.1002/ejoc.200300111

Details of the synthesis of the methyl ester of the side chain of homoharringtonine, a natural product with antileukemic properties, are reported below. The key tactical element involved a Michael addition between the known chiral imine 4 and 2-acetoxyacr

Full text of DOI:10.1002/ejoc.200300111

FULL PAPER
Enantioselective Synthesis of the Ester Side Chain of Homoharringtonine
Laurent Keller,[a] Francoise Dumas,*[a] and Jean d’Angelo*[a]
¸
Keywords: Asymmetric synthesis / Michael additions / Ozonolysis / Protecting groups / Total synthesis
Details of the synthesis of the methyl ester of the side chain
of homoharringtonine, a natural product with antileukemic
properties, are reported below. The key tactical element in-
volved a Michael addition between the known chiral imine
This adduct was then converted into the target compound
(R)-2 by a linear sequence of ten chemical operations, in
6.0% overall yield.
4
and 2-acetoxyacrylonitrile (5), furnishing the adduct
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
(2R,1ЈR)-6 with a high degree of regio- and stereoselectivity.
Germany, 2003)
Introduction
translation by prevention of substrate binding to the ac-
ceptor site on ribosomes.[4] HHT has been clinically tested
in chronic myelogenous leukemia in late chronic phase, in
myelodysplastic syndrome (MDS), and in MDS evolving to
acute myeloid leukemia.[5] This drug is now used in China
as the front-line chemotherapy for acute myeloid leukemia,
particularly in acute promyelocytic leukemia. In the US, the
efficiency of HHT in the treatment of chronic myeloid leu-
kemia is being evaluated in a large-scale study.[6] In view of
their wide range of antitumor activities, the structure-ac-
tivity relationships among Cephalotaxus alkaloids are a
matter of prime importance. In this respect, it has been es-
tablished that cephalotaxine (1a), although much more
abundant in C. harringtonia than HHT and related esters,
is itself devoid of antileukemic activity. Therefore, the pres-
ence of a specific ester linkage branched at C-3 (relative to
the cephalotaxine core) is a critical structural requirement
for the antitumor potency of HHT and analogues. Further-
more, there is a marked influence of the structures of the
side chains of Cephalotaxus alkaloids on their antineoplas-
tic activity and toxicity; thus epi-HHT, which differs from
HHT only in the configuration of the stereogenic center at
C-2Ј, exhibited no significant antileukemic potency. As a
result of 30 years or so of intensive research, several stra-
tegies for the elaboration of the side chain of HHT, or its
cyclic equivalents, have been developed.[7] The problem with
those approaches, however, turned out to be the difficulty
of achieving stereoselectivity. Reported here is a highly ster-
eoselective synthesis of the methyl ester of the side chain of
HHT (2), in the natural (R) configuration, exploiting our
general methodology for the enantioselective construction
of quaternary carbon centers.[8]
Cephalotaxus, the only genus of the family Cephalotax-
aceae (Coniferae), with eight species known so far, is mostly
native of the southern provinces of China.[1] Conifers of the
genus Cephalotaxus are evergreen trees, with yew-like leaves,
or shrubs, growing in humid valleys or in forests. The pres-
ence of alkaloids in Cephalotaxus was first reported by
Paudler, who isolated cephalotaxine (1a) in 1963.[2] Since
the antitumor activity of several esters contained in Cephal-
otaxus was reported,[3] there has been a resurgence of inter-
est in developing synthetic routes to these alkaloids. Re-
search efforts have essentially focused on homoharrington-
ine (HHT, 1b), since it is the main natural ester of cephalot-
axine (1a) isolated from the leaves and stems of the
plumyew C. harringtonia, and the most potent in this family
of antitumor drugs (Figure 1).
Figure 1. Structures of cephalotaxine (1a) and homoharringtonine
(HHT, 1b)
Several teams have investigated the mechanism by which
HHT and related alkaloids exert their antineoplastic effects;
all have concluded that these drugs block protein biosynthe-
sis in the cell, through inhibition of the elongation phase of
[a]
´
´
Unite Associee au CNRS, Centre d’Etudes Pharmaceutiques,
´
Universite de Paris Sud,
´
ˆ
5, rue J.-B. Clement, 92296 Chatenay-Malabry, France
Fax: (internat) ϩ33Ϫ146835752
Results and Discussion
E-mail: francoise.dumas@cep.u-psud.fr,
jean.dangelo@cep.u-psud.fr
A key aspect of this work was to find a concise solution
to the problem of synthesizing the cornerstone keto ester
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300111
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Enantioselective Synthesis of the Ester Side Chain of Homoharringtonine
FULL PAPER
(R)-3. We envisaged stereoselective elaboration of 3 through with addition of Eu(fod)3 and Eu(hfc)3 as shift reagents.
asymmetric Michael addition of the known chiral imine 4[9] The relative configuration of the two stereogenic centers in
to a two-carbon electrophilic alkene (or its equivalent), pre- ketone 6 was assigned by NMR spectroscopy including
cursor of the acetate appendage of this keto ester. It was NOESY experiments at the level of the bicyclic derivatives
our original hope that nitroethylene or phenyl vinyl sulfone 10 and 16, and the absolute configuration was definitively
might play the role of a two-carbon Michael acceptor in secured by correlation of 6 with our goal (R)-2. The re-
the condensation with imine 4. However, the addition of markable complete stereocontrol over the two newly created
nitroethylene to chiral imines having proved to be non-re- stereogenic centers in adduct 7 can be interpreted by evok-
gioselective,[10] this electrophilic alkene was not suited to ing for the addition the compact approach 9, involving a
the task. Since addition of chiral imines to phenyl vinyl sul- synclinal arrangement of the two partners: electrophile 5
fone gave the desired adducts with high degrees of regio- and, as nucleophilic species, the more substituted secondary
and stereoselectivity,[11] condensation of imine 4 with this enamine 8, which is in tautomeric equilibrium with imine
electrophile might offer an alternative access to subgoal 3. 4.[8a,16] According to this model, the alkylation process
However, the sensitive imine 4 was found to be unstable takes place preferentially on the less hindered π-face of the
under the conditions required for these Michael conden- enamine 8 (anti to the bulky phenyl group), portrayed in its
sations (24 hours at 80 °C).[12] Consequently, the strategy energetically preferred conformation minimizing the A1,3
-
ultimately adopted for the introduction of the acetate side type strain (C1ЈЈϪH bond more or less eclipsing the cyclo-
chain of 3 was the elaboration of adduct 6, through Michael hexene ring). This accounts for the absolute configuration
condensation between imine 4 and the three-carbon ac- at C-1Ј in the resulting adduct 7. Control over the stereog-
ceptor 2-acetoxyacrylonitrile (5),[13] followed by the trans- enic center at C-2 in 7 originates from a concerted transfer
formation of the α-acetoxypropionitrile appendage of ad- of the NH proton of enamine 8 to the α-vinylic center of
duct 6 into an acetate moiety. The capto-dative electrophilic electrophile 5,[17] the nitrile end of this acceptor facing the
alkene 5 has previously been utilized by Barton[14] and nitrogen atom of the enamine (‘‘endo arrange-
Scheffold[15] as a two-carbon equivalent building block in ment’’)[8a,17,18] (Scheme 1).
the Michael-type trapping of radical species. The conver-
sion of Michael adduct 6 into the methyl ester of the HHT
side chain (2) would require three essential chemical oper-
ations: the transformation of the α-acetoxypropionitrile ap-
pendage into an acetate moiety (A), the regioselective oxi-
dative cleavage of the cyclohexane ring at the less substi-
tuted α-side of the carbonyl function (B), and the introduc-
tion of two geminate methyl groups to complete the
carbinol terminus (C) (Figure 2).
Scheme 1. Synthesis of Michael adduct 6; reagents and conditions:
(a) neat, room temperature; (b) 20% AcOH/THF, 1:1 (72%); tau-
tomeric equilibrium between imine 4 and enamine 8 and synclinal
approach of enamine 8 to Michael acceptor 5 (9)
Regeneration of the masked aldehyde function at C-2 in
6 was examined first. This requires a deacetylation step, fol-
lowed by dehydrocyanation of the resulting cyanohydrin.
While basic treatment of 6 invariably furnished undefined
compounds, the bicyclic hemiacetal (2R,3aR,7aS)-10 was
Figure 2. Retrosynthetic analysis of diester (R)-2 (A, B, C: see text)
The first stage of the synthesis required the preparation formed in 77% yield when the reaction was conducted un-
of Michael adduct 6. For that purpose, racemic 2-benzyl- der acidic conditions. However, all efforts at generating al-
oxycyclohexanone was condensed with (R)-1-phenylethyla- dehyde 11 through dehydrocyanation of 10, a process which
mine (Ͼ 98% ee) in the presence of an activated catalyst at would in fact implicate the open form of this hemiacetal,
room temperature and the resulting crude chiral imine 4[9] were fruitless. In contrast, sequential treatment of 10 with
was subjected to a Michael reaction with 2-acetoxyacrylon- NaOMe and NaO2Cl[19] gave the sensitive bicyclic lactone
itrile (5), affording the adduct (2R,1ЈR,1ЈЈR)-7, which turned (1aS,3aR)-13, albeit in modest yield (ca. 35%). Formation
out to be stereochemically homogeneous by 1H and 13C spec- of compound 13 clearly involves the transient aldehyde 11,
troscopy.[8m] Hydrolysis of crude imine 7 next afforded in equilibrium Ϫ through the addition of a molecule of
cyclohexanone (2R,1ЈR)-6 (72% overall yield, calculated water Ϫ with the bis-hemiacetal 12, the in situ oxidation
from starting 2-benzyloxycyclohexanone). The de and ee in of the latter ultimately furnishing lactone 13. Incidentally,
1
6 were both Ͼ 95% as evidenced by H NMR spectroscopy another interesting observation was made when compound
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L. Keller, F. Dumas, J. d’Angelo
FULL PAPER
10 was subjected to the Swern reagent: the olefinic deriva- 10, being primarily hydrolyzed into the α-hydroxy amide 18,
tive (2R,3aR)-16 was isolated in 55% yield. This apparently precursor of the bicyclic derivatives 19 (Scheme 2).
unprecedented dehydration process can be interpreted by
In order to circumvent the above troublesome hemiaceta-
assuming the original formation at C-7a of a dimethylal- lization side-reactions, the masking of the carbonyl group
koxysulfonium ion[20] 14, which collapses to olefin 16, a of adduct 6 as a secondary alcohol function was investi-
fragmentation assisted by the neighboring oxygen atom and gated next. When, however, compound 6 was treated with
which probably implicates the intermediary oxonium ion NaBH4 in EtOH, an overreduction of the molecule took
15. An alternative route for the conversion of 10 into 16 place, furnishing diols 20 with a moderate yield (37%). Oxi-
was also investigated, with employment of Burgess’ inner dation of these derivatives with H5IO6 in the presence of a
[23]
salt (Et3NϩSO2NϪCOOMe)[21] as a dehydration agent (60% catalytic amount of CrO3
then produced a mixture of
yield). The transformation of cyanohydrins into the corre- hemiacetal 21 and lactone 22 in 64% yield. In contrast, the
sponding aldehydes has also been accomplished by treat- utilization of Zn(BH4)2 as a reducing agent was more
ment with silver nitrate in the presence of ammonium hy- satisfying, giving the desired alcohols 23 in 90% yield.
droxide at room temperature.[22] Under such conditions, Acidic cleavage of 23 was next attempted, but concomitant
however, the hemiacetal 10 was converted in 68% yield into hydrolysis of the nitrile end occurred during this reaction,
the bicyclic lactams 19. Such a result can be explained in furnishing lactones 24 (71% yield). At this juncture, it was
terms of the cyanohydrin 17, in equilibrium with hemiacetal deemed necessary to select a different carbonyl protecting
Scheme 2. Attempts at regeneration of the masked aldehyde function at C-2 in 6: hemiacetalization side-reactions; reagents and conditions:
(a) 1  HCl, THF, 50 °C (77%); (b) i. MeONa, MeOH, 0 °C; ii. NaO2Cl, tBuOH, H2O, NaH2PO4, 2-methyl-2-butene, room temperature
(35% Ϫ 2 steps); (c) i. (COCl)2, Me2SO, CH2Cl2; ii. Et3N (55%) or Burgess’ salt, toluene, 50 °C (60%); (d) AgNO3, NH4OH, Et2O, room
temperature (68%)
Scheme 3. Tentative approaches to protection of the carbonyl group of 6; reagents and conditions: (a) NaBH4, EtOH, room temperature
(37%); (b) H5IO6, cat. CrO3, CH3CN, H2O, 0 °C (64%, 1.5:1 mixture); (c) Zn(BH4)2, Et2O, 0 °C; (d) 1  HCl, THF, 50 °C (64%, 2 steps);
(e) 4 equiv. of 1,1-dimethylhydrazine, EtOH, mol. sieves, reflux (34%); (f) 1.1 equiv. of 1,1-dimethylhydrazine, EtOH, mol. sieves, reflux
(58%, 1:1 mixture)
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Enantioselective Synthesis of the Ester Side Chain of Homoharringtonine
FULL PAPER
group. Derivatization of 6 as a 1,1-dimethylhydrazone was
The oxidative cleavage of the cyclohexane ring of 3 was
first undertaken. Treatment of adduct 6 with an excess of then undertaken. For this purpose, this ketone was first
1,1-dimethylhydrazine resulted in the formation of bis-hy- converted into the silyl enol ether 31 (TMSCl, Et3N,
drazone 25. However, since we have demonstrated that the NaI),[27] which was ozonized (O3 then Me2S) into the sensi-
two hydrazones 26 and 27 were formed in approximately tive aldehyde 32 (not characterized). Slow addition of two
equal amounts when the two reagents were used in a stoi- equivalents of MeMgBr to crude aldehyde 32 at Ϫ40 °C[28]
chiometric ratio, this methodology was abandoned and subsequent esterification with CH2N2 then afforded an
(Scheme 3).
equimolar mixture of epimeric alcohols 33 in 35% overall
The protecting group that was finally adopted in order to yield, calculated from ketone 3. At this juncture, we stood
achieve our original objective was the 1,3-dioxolane group, ready to complete the synthesis of the methyl ester deriva-
which was easily introduced by condensation of the adduct tive of the HHT side chain. In the event, treatment of al-
6
with TMSOCH2ϪCH2OTMS in the presence of cohols 33 with pyridinium chlorochromate gave ketone (R)-
TMSOTf, furnishing acetal 28 (80% yield).[24] Transform- 34 (80% yield). Slow addition at Ϫ30 °C of one equivalent
ation of the protected cyanohydrin moiety of 28 into a of MeMgBr to 34 produced carbinol (R)-35 (in 42% yield),
methoxycarbonyl group now proceeded straightforwardly, which was transformed by hydrogenolysis of the benzyloxy
either by basic treatment (LiOH) followed by the in situ group (H2, Pd/C, quantitative yield) into our target com-
oxidation (NaO2Cl) of the intermediary aldehyde and es- pound, (R)-methyl 3,7-dihydroxy-3-methoxycarbonyl-7-
terification (CH2N2) of the resulting acid 29 (75% yield), or methyloctanoate (2), identical in all respects with the ester
more directly by treatment of 28 with MnO2 in MeOH in deriving from methanolysis of natural HHT[3] (Scheme 4).
the presence of NaCN (61% yield).[15,25] Unmasking of the
ketal group of ester 30 was then investigated. While treat-
ment of 30 under mildly acidic hydrolytic conditions to pro-
duce ketone 3 was to some avail, under more drastic con-
ditions side-reactions competed with removal of the ketal
Conclusion
To conclude, a highly stereoselective synthesis of the
group, ruining the structure. Finally, after extensive experi- methyl ester derivative of the HHT side chain 2 in the natu-
mentation, it was discovered that treatment of ketal 30 with ral R configuration, has been completed, in 4.3% overall
cerium() chloride heptahydrate in the presence of NaI in yield, from 2-benzyloxycyclohexanone by a linear sequence
MeCN at reflux[26] delivered the cornerstone ketone (R)-3 of twelve chemical operations (mean yield per step: 77%).
in 85% yield.
The key tactical element of the strategy involved the
Scheme 4. Synthesis of the HHT dimethyl ester side chain (R)-2 from 6; reagents and conditions: (a) i. TMSOCH2CH2OTMS, TMSOTf
cat., CH2Cl2, Ϫ78 °C to room temperature; ii. pyridine (80%); (b) i. LiOH, THF, room temperature; ii. NaO2Cl, tBuOH, H2O, NaH2PO4,
2-methyl-2-butene, room temperature (75%, 2 steps); (c) CH2N2, 0 °C to room temperature (100%); (d) MnO2, NaCN, MeOH, room
temperature (61%); (e) CeCl3·7H2O, NaI cat., CH3CN, reflux (85%); (f) TMSCl, NaI, Et3N, CH3CN, room temperature; (g) i. O3/O2,
CH2Cl2, MeOH, Ϫ78 °C; ii. Me2S, Ϫ78 °C to room temperature; (h) i. MeMgBr, THF, Ϫ40 °C; ii. CH2N2, 0 °C to room temperature
(35%, 4 steps); (i) PCC, CH2Cl2, room temperature (80%); (j) MeMgBr, THF, Ϫ30 °C (42%); (k) H2, Pd/C, MeOH, room temperature
(100%)
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uum to give the crude imine 4.[9] 2-Acetoxyacrylonitrile (5,
7.79 mL, 73.4 mmol) was added dropwise to this imine under nitro-
gen and the reaction mixture was stirred at room temperature for
36 hours. The excess of 2-acetoxyacrylonitrile was removed by low
pressure distillation to give crude imine 7. An aliquot of this imine
7 (oil) was taken up to record its spectroscopic data. IR (neat): ν˜ ϭ
2233, 1752, and 1658 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ 1.39
(d, J ϭ 6.5 Hz, 3 H, CH3CH), 1.32Ϫ2.48 (m, 8 H, cyclohexyl CH2),
1.98 (s, 3 H, CH3CO), 2.45 (dd, J ϭ 15.4, 6.2 Hz, 1 H,
CCHAHBCH), 2.79 (dd, J ϭ 15.4, 5.4 Hz, 1 H, CCHAHBCH), 4.00
Michael addition between chiral imine 4 and 2-acetoxyacry-
lonitrile (5), furnishing adduct 6 with a high degree of re-
gio- and stereoselectivity (Scheme 1). Conversion of adduct
6 into the target compound 2 was achieved through three
essential chemical steps: the transformation of the α-ace-
toxypropionitrile appendage into an acetate moiety (6 Ǟ
3), the regioselective oxidative cleavage of the cyclohexane
ring at the less substituted α-side of the carbonyl function
(3 Ǟ 32), and the introduction of two geminate methyl
groups to complete the carbinol terminus (32 Ǟ 35). Stud- (d, J ϭ 11.7 Hz, 1 H, CHAHBO), 4.36 (d, J ϭ 11.7 Hz, 1 H,
CHAHBO), 4.74 (q, J ϭ 6.5 Hz, 1 H, CHCH3), 5.55 (dd, J ϭ 6.2
and 5.4 Hz, 1 H, CHCN), 7.07Ϫ7.45 (m, 10 H, arom. CH) ppm.
13C NMR (50 MHz, CDCl3): δ ϭ 20.1 (CH3CO), 20.6 (cyclohexyl
CH2), 25.3 (CH3CH), 25.8 (cyclohexyl CH2), 27.0 (cyclohexyl
CH2), 36.2 (cyclohexyl CH2), 37.1 (CCH2CH), 58.2 (CHCH3), 58.4
(CH2CHCN), 63.9 (CH2O), 79.6 (C), 118.1 (CN), 126.4 (2 arom.
CH), 126.6 (arom. CH), 126.7 (2 arom. CH), 127.2 (arom. CH),
128.1 (2 arom. CH), 128.3 (2 arom. CH), 138.0 (arom. C), 145.8
(arom. C), 168.8 (CϭO or CϭN), 169.7 (CϭN or CϭO) ppm.
ies directed towards the elaboration of sterically less hin-
dered, cyclic forms of 2, suitable for coupling with cephalot-
axine (1a) to produce enantiopure HHT (1b), are currently
under investigation.
Experimental Section
General Remarks: All reactions not involving aqueous reagents
were carried out under a nitrogen atmosphere in flame-dried glass-
ware. Commercial reagents were used as purchased without further
purification. Tetrahydrofuran (THF), toluene, and diethyl ether
(Et2O) were distilled from sodium/benzophenone ketyl, dichloro-
methane, dimethyl sulfoxide, and acetonitrile were distilled from
calcium hydride, triethylamine (Et3N) was distilled from potassium
hydroxide, and ethanol and methanol were distilled from mag-
nesium. Reactions were followed by TLC, carried out on Merck 60
F254 silica gel plates, which were viewed by UV irradiation at
254 nm and/or by staining with p-anisaldehyde. A Fischer 500
ozone generator was used for ozonolyses. Flash column chromatog-
raphy was performed on Merck 230Ϫ400 mesh silica gel. Melting
points were recorded on a Büchi apparatus and are uncorrected.
Accurate mass spectra measurements were obtained on a Voyager-
DE STR, Perspective Biosystem by MALDI-TOF or on a Microm-
ass LCT by electrospray (ϩESI) at the Institut de Chimie des Sub-
stances Naturelles (ICSN, CNRS, Gif sur Yvette, France). Optical
rotations were recorded with a Polartronic E SchmidtϩHaensch
2095 polarimeter in 1 dm cells (concentrations are indicated in g
per 100 mL). Infrared spectra were recorded with a Bruker Vector
22 Fourier transform spectrometer. 1H NMR spectra were recorded
at 300 K on AC 200 P or ARX 400 Bruker spectrometers, at 200
or 400 MHz, with CHCl3 as the internal standard (δH ϭ 7.26 ppm).
13C NMR spectra were recorded at 300 K on the same spec-
trometers, at 50 or 100 MHz, with the central peak of CHCl3 as
the internal standard (δC ϭ 77.0 ppm). DEPT 135 and two-dimen-
sional NMR experiments (COSY, HMQC and HMBC) were used
for the assignments of signals in the 1H and 13C NMR spectra.
Elemental analyses were performed on a PerkinϪElmer 2400-CHN
(2R,1ЈR)-2-Acetoxy-3-[1Ј-benzyloxy-2Ј-oxocyclohexyl]propionitrile
(6): The preceding crude imine 7 was hydrolyzed with an aqueous
solution of acetic acid (20%, 25 mL) in THF (25 mL) for 4 hours
at room temperature. Solvents were removed in vacuo. The residue
was taken up in Et2O (75 mL) and aqueous HCl (1 , 15 mL),
and the aqueous layer was separated and extracted with Et2O (3 ϫ
50 mL). The combined organic layers were washed with a saturated
aqueous solution of sodium hydrogen carbonate (3 ϫ 25 mL) and
with brine (2 ϫ 30 mL), dried (MgSO4), and concentrated in vacuo.
The residue was purified by column chromatography (cyclohexane/
EtOAc, 9:1) to give the Michael adduct 6 as a white solid (8.32 g,
72%); m.p. 62 °C. [α]2D0 ϭ ϩ75.1 (c ϭ 2.13, EtOH). IR (neat): ν˜ ϭ
2251, 1756, 1721 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
1.51Ϫ1.64 (m, 4 H, cyclohexyl CH2), 1.99 (s, 3 H, CH3CO), 2.12
(m, 1 H, cyclohexyl CHH), 2.21 (dd, J ϭ 15.7, 7.1 Hz, 1 H,
CCHAHBCH), 2.27Ϫ2.40 (m, 2 H, cyclohexyl CH2), 2.67 (dd, J ϭ
15.7, 5.4 Hz, 1 H, CCHAHBCH), 2.77 (ddd, J ϭ 12.8, 12.2, 4.9 Hz,
1 H, cyclohexyl CHH), 4.17 (d, J ϭ 11.1 Hz, 1 H, CHAHBO), 4.53
(d, J ϭ 11.1 Hz, 1 H, CHAHBO), 5.43 (dd, J ϭ 7.1, 5.4 Hz, 1 H,
CHCN), 7.28Ϫ7.44 (m,
5
H, arom. CH) ppm. NMR 13C
(100 MHz, CDCl3): δ ϭ 20.2 (CH3CO), 20.4 (cyclohexyl CH2),
27.7 (cyclohexyl CH2), 34.3 (CCH2CH), 37.5 (cyclohexyl CH2),
39.1 (cyclohexyl CH2), 57.3 (CH2CHCN), 65.4 (CH2O), 81.3 (C),
117.1 (CN), 127.1 (2 arom. CH), 127.7 (arom. CH), 128.5 (2 arom.
CH), 136.8 (arom. C), 169.0 (CH3CO), 211.0 (CH2COC) ppm.
C18H21NO4 (315.4): calcd. C 68.54, H 6.71, N 4.44; found C 68.66,
H 6.81, N 4.36.
(2R,3aR,7aS)-3a-Benzyloxy-7a-hydroxyoctahydrobenzofuran-2-
carbonitrile (10): Aqueous HCl (2 , 40 mL) was added to a solu-
tion of Michael adduct 6 (2 g, 6.3 mmol) in THF (32 mL). The
reaction mixture was stirred at 50 °C for 30 hours and concentrated
in vacuo. The residue was taken up in water (10 mL) and EtOAc
(50 mL), and the aqueous layer was separated and extracted with
EtOAc (4 ϫ 50 mL). The combined organic layers were washed
with brine (2 ϫ 30 mL), dried (MgSO4), and concentrated in vacuo.
´
ˆ
analyzer at the Faculte de Pharmacie de Chatenay-Malabry.
(2R,1ЈR,1ЈЈR)-2-Acetoxy-3-[1Ј-benzyloxy-2Ј-(1ЈЈ-phenylethylimino)-
cyclohexyl]propionitrile (7): A mixture of powdered molecular sieves
˚
(5 A, 9 g), basic aluminum oxide (Brockmann I, 2 g), and silica gel
(Merck 230Ϫ400 mesh, 1 g) was flame-dried under vacuum for 10
minutes, cooled to room temperature, and suspended in anhydrous
cyclohexane
(15 mL).
2-Benzyloxycyclohexanone
(7.5 g, The residue was purified by column chromatography (cyclohexane/
36.7 mmol) and (R)-(ϩ)-phenylethylamine (5.2 mL, 40.4 mmol)
were successively added to the suspension, and the resulting mix-
EtOAc, 6:1) to give hemiacetal 10 as a white solid (1.33 g, 77%);
m.p. 105 °C. [α]2D0 ϭ ϩ17.3 (c ϭ 2.95, CH2Cl2). IR (neat): ν˜ ϭ
3543, 2235 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 1.31Ϫ1.74 (m,
ture was stirred at 20 °C under nitrogen for 4 hours. [The reaction
1
was monitored by IR and H NMR, in CDCl3 containing a pinch 5 H, cyclohexyl CH2 and cyclohexyl CHH), 1.80 (m, 2 H, cyclo-
of K2CO3.] The catalyst was filtered off and washed with anhy-
drous THF (3 ϫ 30 mL), and the solvent was removed under vac-
hexyl CH2), 2.01 (m, 1 H, cyclohexyl CHH), 2.39 (dd, J ϭ 12.6,
8.6 Hz, 1 H, CCHAHBCH), 2.64 (dd, J ϭ 12.6 and 5.2Hz, 1 H,
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Eur. J. Org. Chem. 2003, 2488Ϫ2497

Enantioselective Synthesis of the Ester Side Chain of Homoharringtonine
FULL PAPER
CCHAHBCH), 3.73 (br. s, 1 H, OH), 4.47 (d, J ϭ 10.6 Hz, 1 H, give enol ether 16 as a white solid (84 mg, 60%); m.p. 107 °C.
CHAHBO), 4.57 (d, J ϭ 10.6 Hz, 1 H, CHAHBO), 4.71 (dd, J ϭ [α]D ϭ Ϫ30.4 (c ϭ 0.35, CHCl3). MS: m/z (MALDI-TOF) found
8.6, 5.2 Hz, 1 H, CHCN), 7.28Ϫ7.39 (m, 5 H, arom. CH) ppm.
278.1166 [MNaϩ], C16H17NO2 (M, 255.4) requires 278.1157. IR
13C NMR (100 MHz, CDCl3): δ ϭ 21.0 (cyclohexyl CH2), 22.3
(neat): ν˜ ϭ 2233 and 1705 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ
(cyclohexyl CH2), 29.9 (cyclohexyl CH2), 33.5 (CCH2CH), 36.8 1.34 (td, J ϭ 13.8, 3.5 Hz, 1 H, cyclohexyl CHH), 1.72 (m, 1 H,
(cyclohexyl CH2), 62.0 (CH2CHCN), 66.1 (CH2O), 81.3 (C), 105.0 cyclohexyl CHH), 1.84 (m, 1 H, cyclohexyl CHH), 2.02Ϫ2.13 (m,
(OCOH), 119.4 (CN), 127.9 (2 arom. CH), 128.4 (3 arom. CH), 2 H, cyclohexyl CHH and CCHAHBCH), 2.23 (m, 1 H, cyclohexyl
137.3 (arom. C) ppm. C16H19NO3 (273.4): calcd. C 70.31, H 7.01, CHH), 2.51 (dt, J ϭ 13.8, 3.5 Hz, 1 H, cyclohexyl CHH), 2.85 (d,
N 5.12; found C 70.25, H 7.03, N 5.02.
J ϭ 13.6 Hz, 1 H, CCHAHBC), 4.49 (d, J ϭ 10.3 Hz, 1 H,
CHAHBO), 4.58 (d, J ϭ 10.3 Hz, 1 H, CHAHBO), 4.99 (d, J ϭ
8.2 Hz, 1 H, CHCN), 5.12 (t, J ϭ 3.8 Hz, 1 H, CHϭC), 7.27Ϫ7.46
(m, 5 H, arom. CH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 17.3
(cyclohexyl CH2), 22.9 (cyclohexyl CH2), 30.1 (cyclohexyl CH2),
39.4 (CCH2CH), 64.7 (CH2CHCN), 66.3 (CH2O), 77.5 (C), 99.8
(ϭCH), 118.3 (CN), 127.6 (2 arom. CH), 128.4 (3 arom. CH), 137.5
(arom. C), 154.1 (CϭCH) ppm.
(1aS,3aR)-3a-Benzyloxy-7a-hydroxyhexahydrobenzofuran-2-one
(13): A solution of sodium methoxide (0.7 , 0.6 mL, 0.34 mmol)
in methanol was slowly added, under nitrogen and at 0 °C, to a
solution of hemiacetal 10 (100 mg, 0.36 mmol) in dry methanol
(3 mL) and dry chloroform (4 mL). The reaction mixture was
stirred at 0 °C for 30 minutes, hydrolyzed with aqueous HCl (1 ,
0.3 mL), and extracted with CH2Cl2 (4 ϫ 5 mL). The combined
organic layers were dried (MgSO4) and concentrated in vacuo to
give the intermediary aldehyde 11 as a pale yellow oil. This oil was
not characterized, due to its instability, and was used without
further purification. 2-Methyl-2-butene (0.17 mL, 2.09 mmol) and
aqueous sodium hydrogen phosphate (1 , 0.45 mL, 0.45 mmol)
were added successively to a solution of crude aldehyde 11 (90 mg)
in tert-butyl alcohol (4 mL). Sodium chlorite (100 mg, 1.04 mmol)
was added portionwise at 0 °C, and the reaction mixture was al-
lowed to warm up and was stirred vigorously overnight at room
temperature. The solvent was removed in vacuo and the residue was
purified by column chromatography (cyclohexane/EtOAc, 1:1.5) to
give lactone 13 as a white, sensitive solid (33 mg, 35%). IR (neat):
(3S,4aR,8aR)- and (3S,4aR,8aS)-4a-Benzyloxy-3,8a-dihydroxyocta-
hydroquinolin-2-ones (19): An aqueous solution of silver nitrate (1
, 0.18 mL, 0.18 mmol) and an aqueous ammonia solution (20%,
15 µL, 0.18 mmol) were successively added to a solution of hemia-
cetal 10 (50 mg, 0.18 mmol) in Et2O (1 mL). The reaction mixture
was vigorously stirred at room temperature for 24 hours and hy-
drolyzed with water (1 mL). The aqueous layer was separated and
extracted with Et2O (3 ϫ 5 mL). The combined organic layers were
dried (MgSO4) and concentrated in vacuo. The residue was purified
by column chromatography (cyclohexane/EtOAc, 1:3) to give α-
hydroxy lactams 19 as a colorless oil (36 mg, 68%, mixture of dia-
stereomers at C-8a). IR (neat): ν˜ ϭ 3477 and 1657 cmϪ1. 1H NMR
(400 MHz, CDCl3): δ ϭ 1.48 (m, 4 H, cyclohexyl CH2), 1.61 (m, 2
H, cyclohexyl CH2), 1.80 (m, 1 H, cyclohexyl CHH), 1.96 (m, 1 H,
cyclohexyl CHH), 2.36 (dd, J ϭ 19.6, 8.6 Hz, 1 H, CHAHBCHOH),
2.41 (dd, J ϭ 19.6, 6.8 Hz, 1 H, CHAHBCHOH), 3.79 (br. s, 1 H,
OH), 4.29 (d, J ϭ 10.5 Hz, 1 H, CHAHBO), 4.36 (dd, J ϭ 8.6,
6.8 Hz, CHOH), 4.47 (d, J ϭ 10.5 Hz, 1 H, CHAHBO), 5.30 (br. s,
1 H, NH or OH), 6.85 (br. s, 1 H, NH or OH), 7.28Ϫ7.35 (m, 5
H, arom. CH) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 21.1 (cyclo-
hexyl CH2), 22.5 (cyclohexyl CH2), 29.5 (cyclohexyl CH2), 33.7
(cyclohexyl CH2), 36.2 (CCH2CH), 66.1 (CH2O), 77.5 (CHOH),
81.9 (COBn), 104.5 (OCNH), 127.8 (3 arom. CH), 128.5 (2 arom.
CH), 137.6 (arom. C), 176.6 (CO) ppm.
ν˜ ϭ 3383 and 1769 cmϪ1 1H NMR (200 MHz, CDCl3): δ ϭ
.
1.09Ϫ1.95 (m, 5 H, cyclohexyl CH2 and cyclohexyl CHH),
2.01Ϫ2.47 (m, 3 H, cyclohexyl CH2 and cyclohexyl CHH), 2.68
(d, J ϭ 17.1 Hz, 1 H, CCHAHBCO), 2.85 (d, J ϭ 17.1 Hz, 1 H,
CCHAHBCO), 4.38 (d, J ϭ 10.1 Hz, 1 H, CHAHBO), 4.50 (d, J ϭ
10.1 Hz, 1 H, CHAHBO), 4.71 (br. s, 1 H, OH), 7.18Ϫ7.42 (m, 5 H,
arom. CH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 21.6 (cyclohexyl
CH2), 22.0 (cyclohexyl CH2), 29.4 (cyclohexyl CH2), 34.9 (cyclo-
hexyl CH2), 36.9 (CH2CO), 65.1 (CH2O), 81.2 (C), 106.7 (OCOH),
127.7 (2 arom. CH), 128.2 (arom. CH), 129.0 (2 arom. CH), 136.9
(arom.C), 171.8 (CO) ppm.
(2R,3aR)-3a-Benzyloxy-2,3,3a,4,5,6-hexahydrobenzofuran-2-carbo-
nitrile (16). Swern Route: Dry dimethyl sulfoxide (156 µL,
2.16 mmol) was added dropwise, under nitrogen and at Ϫ60 °C, to
a solution of oxalyl chloride (128 µL, 1.44 mmol) in dry CH2Cl2
(2.6 mL). The reaction mixture was stirred at Ϫ60 °C for 10 mi-
nutes, and a solution of hemiacetal 10 (100 mg, 0.36 mmol) in dry
CH2Cl2 (1 mL) was added. The reaction mixture was kept at Ϫ40
°C for 2.5 hours, dry triethylamine was added (0.49 mL, 3.6 mmol),
and the resulting mixture was allowed to warm up and was stirred
for 30 minutes at room temperature. The solvent was removed in
vacuo and the residue was taken up with EtOAc (10 mL). The solu-
tion was filtered through Celite and concentrated in vacuo. The
residue was purified by column chromatography (cyclohexane/
EtOAc, 6:1) to give enol ether 16 as a white solid (51 mg, 55%).
(1R,2R)- and (1S,2R)-2-Benzyloxy-2-(2Ј-hydroxyethyl)cyclohexanols
(20): Sodium borohydride (48 mg, 1.26 mmol) was added portion-
wise to a solution of Michael adduct 6 (200 mg, 0.63 mmol) in
ethanol (5 mL). The reaction mixture was stirred at room tempera-
ture for 3 hours. An aqueous solution of HCl (0.5 , 4 mL) was
added, and the resulting mixture was extracted with EtOAc (3 ϫ
20 mL). The combined organic layers were dried (MgSO4) and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (cyclohexane/EtOAc, 3:1) to give the diols 20 as a white solid
(58 mg, 37%, 3:1 mixture of diastereomers at C-1, ratio determined
1
by H NMR). MS: m/z (ESI) found 273.1453 [MNaϩ], C15H23O3
1
(M, 250.4) requires 273.1467. IR (neat): ν˜ ϭ 3385 cmϪ1. H NMR
(400 MHz, CDCl3, major diastereomer): δ ϭ 1.23Ϫ1.34 (m, 2 H,
Burgess’ Salt Route:
A solution of hemiacetal 10 (150 mg, cyclohexyl CH2), 1.39Ϫ1.48 (m, 2 H, cyclohexyl CH2), 1.64Ϫ1.83
0.55 mmol) in dry toluene (3 mL) was added under nitrogen to a
suspension of Burgess’ salt (133 mg, 0.59 mmol) in dry toluene
(2 mL). The reaction mixture was stirred at 50 °C for two days and
concentrated in vacuo. The residue was taken up in water (10 mL)
(m, 4 H, CHAHBCH2OH, cyclohexyl CH2 and cyclohexyl CHH),
2.04 (m, 1 H, cyclohexyl CHH), 2.12 (ddd, J ϭ 15.5, 6.1, 3.3 Hz,
1 H, CHAHBCH2OH), 2.40Ϫ3.20 (br. s, 2 H, OH), 3.53 (dd, J ϭ
9.9, 4.1 Hz, 1 H, CHOH), 3.64 (ddd, J ϭ 11.4, 6.9, 3.3 Hz, CHAH-
and CH2Cl2 (25 mL), and the aqueous layer was separated and BOH), 3.82 (ddd, J ϭ 11.4, 6.1, 3.9 Hz, 1 H, CHAHBOH), 4.31 (d,
extracted with CH2Cl2 (3 ϫ 25 mL). The combined organic layers
were dried (MgSO4) and concentrated in vacuo. The residue was
purified by column chromatography (cyclohexane/EtOAc, 9:1) to
J ϭ 10.7 Hz, 1 H, CHAHBO), 4.43 (d, J ϭ 10.7 Hz, 1 H,
CHAHBO), 7.24Ϫ7.36 (m, 5 H, arom. CH) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ ϭ 20.9 (cyclohexyl
Eur. J. Org. Chem. 2003, 2488Ϫ2497
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2493

L. Keller, F. Dumas, J. d’Angelo
FULL PAPER
CH2), 23.9 (cyclohexyl CH2), 30.6 (cyclohexyl CH2), 32.6 (cyclo-
°C for 50 hours and the solvent was removed in vacuo. The residue
hexyl CH2), 39.2 (CH2CH2OH), 57.7 (CH2CH2OH), 62.4 (CH2O),
was taken up in water (5 mL) and EtOAc (20 mL), and the aqueous
74.4 (CHOH), 77.2 (C), 127.4 (2 arom. CH), 128.3 (3 arom. CH), layer was separated and extracted with EtOAc (3 ϫ 25 mL). The
138.6 (arom. C) ppm.
combined organic layers were washed with brine (2 ϫ 30 mL),
dried (MgSO4), and concentrated in vacuo. The residue was puri-
fied by column chromatography (cyclohexane/EtOAc, 2:1) to give
α-hydroxy lactones 24 as a white solid (280 mg, 71%, 3:1 mixture
of diastereomers at C-8a, ratio determined by 1H NMR). These
diastereomers could be separated by column chromatography
(cyclohexane/EtOAc, 3:1). MS: m/z (ESI) found 299.1251 [MNaϩ],
C16H20O4 (M, 276.4) requires 299.1259. IR (neat): ν˜ ϭ 3249 and
1733 cmϪ1. 1H NMR (400 MHz, CDCl3, major diastereomer): δ ϭ
1.27 (m, 1 H, cyclohexyl CHH), 1.36 (m, 1 H, cyclohexyl CHH),
1.52 (m, 2 H, cyclohexyl CH2), 1.76 (t, J ϭ 12.5 Hz, 1 H,
CHAHBCHOH), 1.85 (m, 2 H, cyclohexyl CH2), 2.10 (ddd, J ϭ
16.7, 12.1, 3.9 Hz, 1 H, cyclohexyl CHH), 2.22 (dd, J ϭ 15.1,
1.6 Hz, 1 H, cyclohexyl CHH), 2.74 (dd, J ϭ 12.5, 7.1 Hz, 1 H,
CHAHBCHOH), 3.03 (br. s, 1 H, OH), 4.21 (dd, J ϭ 12.1, 4.3 Hz,
1 H, CHOCO), 4.36 (dd, J ϭ 12.5, 7.1 Hz, CHOH), 4.42 (d, J ϭ
11.2 Hz, 1 H, CHAHBO), 4.52 (d, J ϭ 11.2 Hz, 1 H, CHAHBO),
7.28Ϫ7.38 (m, 5 H, arom. CH) ppm. 13C NMR (100 MHz, CDCl3,
major diastereomer): δ ϭ 19.7 (cyclohexyl CH2), 23.7 (cyclohexyl
CH2), 26.1 (cyclohexyl CH2), 30.9 (cyclohexyl CH2), 35.7
(CCH2CH), 62.3 (CH2O), 65.4 (CHOH), 73.4 (C), 85.9 (CHOCO),
126.9 (2 arom. CH), 127.5 (arom. CH), 128.4 (2 arom. CH), 137.7
(arom. C), 173.9 (CO) ppm.
(3aR,1aR)-3a-Benzyloxyhexahydrobenzofuran-7a-ol
(21)
and
(3aR,1aS)-3a-benzyloxyhexahydrobenzofuran-2-one (22): A solution
of periodic acid (130 mg, 0.57 mmol) and chromium trioxide (2 mg,
0.02 mmol) in CH3CN (1.3 mL) and water (0.1 mL) was added
dropwise at 0 °C to a solution of diols 20 (58 mg, 0.23 mmol) in
CH3CN (3 mL). The reaction mixture was stirred at 5 °C for 1
hour and quenched with aqueous NaH2PO4 (1 , 4 mL). The aque-
ous layer was separated and extracted with EtOAc (10 mL). The
combined organic layers were successively washed with brine (2 ϫ
5 mL), a saturated aqueous solution of NaHSO3 (5 mL), and brine
(5 mL), dried (MgSO4), and concentrated in vacuo. The residue
was purified by column chromatography (cyclohexane/EtOAc, 2:1
to 1:1) to give an inseparable 1.5:1 mixture of hemiacetal 21 and
lactone 22 as a white solid (36 mg, 64% combined yield). IR (neat):
ν˜ ϭ 3526 and 1781 cmϪ1. H NMR (400 MHz, CDCl3): 21 (perti-
1
nent signals): δ ϭ 3.46 (br. s, 1 H, OH), 3.91 (dd, J ϭ 8.4, 1.3 Hz,
1 H, CH2CHAHBO), 4.14 (ddd, J ϭ 12.8, 8.4, 4.2 Hz, 1 H,
CH2CHAHBO), 4.40 (d, J ϭ 11.1 Hz, 1 H, CHAHBO), 4.60 (d, J ϭ
11.1 Hz, 1 H, CHAHBO) ppm; 22 (pertinent signals): δ ϭ 2.35 (d,
J ϭ 16.6 Hz, 1 H, CHAHBCO), 2.85 (d, J ϭ 16.6 Hz, 1 H,
CHAHBCO), 4.10 (J ϭ 12.3, 4.0 Hz, 1 H, CHOCO), 4.35 (d, J ϭ
11.3 Hz, 1 H, CHAHBO), 4.45 (d, J ϭ 11.3 Hz, 1 H, CHAHBO)
ppm. 13C NMR (100 MHz, CDCl3): 21 (pertinent signals): δ ϭ
32.4 (CH2CH2O), 64.3 (CH2CH2O), 66.8 (CH2O), 82.5 (C), 102.6
(HOCO) ppm; 22 (pertinent signals): δ ϭ 39.2 (CH2CO), 63.8
(CH2O), 79.8 (C), 86.5 (CHOCO) 175.2 (CO) ppm.
(2R)-N-{2-Benzyloxy-2-[2Ј-(dimethylhydrazono)ethylcyclo-
hexanone]}-NЈ,NЈ-dimethylhydrazone (25): 1,1-Dimethylhydrazine
(0.29 mL, 3.8 mmol) was added to a solution of Michael adduct 6
(300 mg, 0.95 mmol) in dry ethanol (3 mL). The reaction mixture
was heated at reflux under nitrogen in the presence of anhydrous
powdered molecular sieves for 12 hours. The reaction mixture was
filtered through Celite and concentrated in vacuo, and the residue
was purified by column chromatography (cyclohexane/EtOAc/
Et3N, 40:7:1) to give bis-hydrazone 25 as a pale yellow oil (105 mg,
34%). MS: m/z (ESI) found 353.2301 [MNaϩ], C19H30N4O (M,
(2R,1ЈR,2ЈR)- and (2R,1ЈR,2ЈS)-2-Acetoxy-2-(1Ј-benzyloxy-2Ј-
hydroxycyclohexyl)propionitriles (23): Zinc borohydride (2 mL of a
0.17  solution in Et2O, 0.34 mmol), was added dropwise at 0 °C
under nitrogen to a solution of Michael adduct 6 (500 mg,
1.58 mmol) in dry Et2O (5 mL). The reaction mixture was stirred
at 0 °C for 30 minutes, hydrolyzed with water (5 mL) and aqueous
HCl (1 , 1 mL), and extracted with Et2O (4 ϫ 10 mL). The com-
bined organic layers were dried (MgSO4) and concentrated in va-
cuo to give 23 as a colorless oil (450 mg, 90% (crude), 3:1 mixture
of diastereomers at C-2Ј, ratio determined by 1H NMR). This
crude material was used directly in the next step. These dia-
stereomers could be separated by column chromatography (cyclo-
330.6) requires 353.2317. IR (neat): ν˜ ϭ 1607 cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 1.38Ϫ1.56 (m, 3 H, cyclohexyl CHH and
cyclohexyl CH2), 1.83Ϫ1.90 (m, 1 H, cyclohexyl CHH), 1.95 (m, 1
H, cyclohexyl CHH), 2.05 (td, J ϭ 13.4, 5.3 Hz, 1 H, cyclohexyl
CHH), 2.12Ϫ2.20 (m, 1 H, cyclohexyl CHH), 2.47 (s, 6 H, CH3),
2.68 (dd, J ϭ 14.8, 5.8 Hz, CHAHBCHϭN), 2.71 (s, 6 H, CH3),
2.98 (dd, J ϭ 14.8, 5.8 Hz, CHAHBCHϭN), 3.11 (m, 1 H, cyclo-
hexyl CHH), 4.20 (d, J ϭ 11.5 Hz, 1 H, CHAHBO), 4.49 (d, J ϭ
11.5 Hz, 1 H, CHAHBO), 6.77 (t, J ϭ 5.8 Hz, 1 H, CHϭN),
7.26Ϫ7.34 (m, 5 H, arom. CH) ppm. 13C NMR (100 MHz, CDCl3):
δ ϭ 20.7 (cyclohexyl CH2), 25.9 (cyclohexyl CH2), 26.3 (cyclohexyl
CH2), 37.0 (CH2CHϭN), 37.9 (cyclohexyl CH2), 43.4 (2 CH3), 47.8
(2 CH3), 63.9 (CH2O), 78.9 (C), 127.3 (2 arom. CH), 128.3 (3 arom.
CH), 136.9 (arom. C), 139.1 (CHϭN), 167.7 (CϭN) ppm.
hexane/EtOAc, 10:1). IR (neat): ν˜ ϭ 3521, 2246 and 1750 cmϪ1
.
1H NMR (400 MHz, CDCl3, major diastereomer): δ ϭ 1.28Ϫ1.53
(m, 3 H, cyclohexyl CH2 and cyclohexyl CHH), 1.76 (m, 3 H,
cyclohexyl CH2 and cyclohexyl CHH), 1.96 (s, 3 H, CH3CO), 2.04
(m, 1 H, cyclohexyl CHH), 2.19 (m, 2 H, cyclohexyl CH2), 2.29
(dd, J ϭ 15.4, 6.3 Hz, 1 H, CCHAHBCH), 2.47 (dd, J ϭ 15.4,
6.3 Hz, 1 H, CCHAHBCH), 3.60 (m, 1 H, CHOH), 4.42 (d, J ϭ
11.1 Hz, 1 H, CHAHBO), 4.50 (d, J ϭ 11.1 Hz, 1 H, CHAHBO),
5.76 (t, J ϭ 6.3 Hz, 1 H, CHCN), 7.26Ϫ7.38 (m, 5 H, arom. CH)
ppm. 13C NMR (100 MHz, CDCl3, major diastereomer): δ ϭ 20.2
(CH3CO), 20.9 (cyclohexyl CH2), 23.1 (cyclohexyl CH2), 30.6
(cyclohexyl CH2), 31.7 (cyclohexyl CH2), 38.1 (CCH2CH), 58.4
(CHCN), 62.8 (CH2O), 73.9 (CHOH), 76.5 (C), 117.8 (CN), 127.1
(2 arom. CH), 127.6 (arom. CH), 128.5 (2 arom. CH), 138.1 (arom.
C), 168.9 (CO) ppm. C18H23NO4 (317.4), calcd. C 68.12, H 7.30,
N 4.41; found C 67.72, H 7.12, N 4.37.
(2R,1ЈR)-2-Acetoxy-3-(1Ј-benzyloxy-1ЈЈ,4ЈЈ-dioxaspiro[4.5]-
decyl)propionitrile (28): A solution of Michael adduct 6 (3.2 g,
10.1 mmol) in dry CH2Cl2 (13 mL) was added dropwise, under ni-
trogen and at Ϫ78 °C, to a solution of trimethylsilyl triflate
(0.51 mL, 3 mmol) and 1,2-bis(trimethylsilyloxy)ethane (4.8 mL,
20.3 mmol) in dry CH2Cl2 (13 mL). The reaction mixture was al-
lowed to warm up, was stirred for 6 hours at room temperature,
and was quenched with dry pyridine (2 mL). A saturated aqueous
solution of sodium hydrogen carbonate (25 mL) was added and the
(3S,4aR,8aR)- and (3R,4aR,8aR)-4a-Benzyloxy-3-hydroxyoctahyd-
rochromen-2-ones (24): An aqueous solution of HCl (1 , 15.2 mL) mixture was extracted with CH2Cl2 (3 ϫ 25 mL). The combined
was added at room temperature to a solution of crude 23 (450 mg, organic layers were dried (MgSO4) and concentrated in vacuo. The
1.42 mmol) in THF (7 mL). The reaction mixture was stirred at 50 oily residue was taken up in hot ethanol (20 mL) and recrystallized
2494
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2003, 2488Ϫ2497

Enantioselective Synthesis of the Ester Side Chain of Homoharringtonine
FULL PAPER
at Ϫ20 °C to give ketal 28 as a white solid (2.91 g, 80%); m.p. 138
°C. [α]2D0 ϭ ϩ106.0 (c ϭ 2.15, CHCl3). IR (neat): ν˜ ϭ 2250 and
acid 29 (3 g, 9.8 mmol) in dry Et2O (50 mL). The resulting mixture
was stirred at room temperature for 4 hours and the excess of di-
1743 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 1.41Ϫ1.73 (m, 4 H, azomethane was destroyed by addition of acetic acid. The reaction
cyclohexyl CH2), 1.88 (m, 1 H, cyclohexyl CHH), 1.95Ϫ1.98 (m, 4
mixture was taken up in Et2O (50 mL) and the resulting organic
H, cyclohexyl CHH and CH3CO), 2.16 (dd, J ϭ 15.9, 5.2 Hz, 1 H, layer was washed with brine (50 mL), dried (MgSO4), and concen-
CHAHBCHCN), 2.65 (dd, J ϭ 15.9, 5.2 Hz, 1 H, CHAHBCHCN), trated in vacuo to give methyl ester 30 as a colorless oil (3.1 g, 75%,
1
4.01 (m, 3 H, OCH2CHHO), 4.18 (m, 1 H, OCH2CHHO), 4.49 (d, 3 steps from 28). IR (neat): ν˜ ϭ 1733 cmϪ1. H NMR (200 MHz,
J ϭ 11.4 Hz, CHAHBO), 4.55 (d, J ϭ 11.4 Hz, 1 H, CHAHBO), CDCl3): δ ϭ 1.27Ϫ1.61 (m, 5 H, cyclohexyl CH2 and cyclohexyl
5.72 (t, J ϭ 5.2 Hz, 1 H, CHCN), 7.27Ϫ7.34 (m, 5 H, arom. CH)
CHH), 1.67Ϫ1.88 (m, 2 H, cyclohexyl CH2), 1.96Ϫ2.12 (m, 1 H,
cyclohexyl CHH), 2.52 (d, J ϭ 13.7 Hz, 1 H, CHAHBCO2CH3),
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 20.1 (CH3CO), 20.4
(cyclohexyl CH2), 22.5 (cyclohexyl CH2), 29.8 (cyclohexyl CH2), 2.73 (d, J ϭ 13.7 Hz, 1 H, CHAHBCO2CH3), 3.55 (s, 3 H,
32.2 (cyclohexyl CH2), 34.8 (CH2CHCN), 58.1 (CHCN), 63.7 CO2CH3), 3.75Ϫ3.98 (m, 4 H, OCH2CH2O), 4.54 (d, J ϭ 11.3 Hz,
(CH2O), 64.1 (OCH2CH2O), 64.4 (OCH2CH2O), 78.6 (C), 110.3
1 H, CHAHBO), 4.64 (d, J ϭ 11.3 Hz, 1 H, CHAHBO), 7.11Ϫ7.38
(OCO), 118.3 (CN), 126.8 (2 arom. CH), 127.2 (arom. CH), 128.3 (m, 5 H, arom. CH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 20.2
(2 arom. CH), 138.4 (arom. C), 168.9 (CO) ppm. C20H25NO5 (M, (cyclohexyl CH2), 22.9 (cyclohexyl CH2), 30.5 (cyclohexyl CH2),
359.5), calcd. C 66.83, H 7.01, N 3.89; found C 66.89, H 7.14,
N 3.92.
32.6 (cyclohexyl CH2), 35.8 (CH2CO2CH3), 51.3 (CO2CH3), 64.1
(OCH2CH2O), 64.5 (OCH2CH2O), 65.2 (CH2O), 79.9 (C), 110.9
(OCO), 126.9 (arom. CH), 127.3 (2 arom. CH), 128.1 (2 arom.
CH), 139.4 (arom. C), 171.6 (CO2CH3) ppm.
(R)-2-(1Ј-Benzyloxy-1ЈЈ,4ЈЈ-dioxaspiro[4.5]decyl)ethanoic Acid (29):
An aqueous solution of LiOH (1 , 31.6 mL, 31.6 mmol) was ad-
ded dropwise to a solution of ketal 28 (5.68 g, 15.8 mmol) in THF
(100 mL). The reaction mixture was vigorously stirred at room tem-
perature for 1 hour and the solvent was removed in vacuo. The
residue was taken up in water (50 mL) and EtOAc (75 mL), and
the aqueous layer was separated and extracted with EtOAc (3 ϫ
50 mL). The combined organic layers were washed with brine (3
ϫ 50 mL), dried (MgSO4), and concentrated in vacuo to give an
intermediary aldehyde as a pale yellow oil, which was used without
further purification in the next step.
Methyl (R)-(1Ј-Benzyloxy-2-oxocyclohexyl)acetate (3): Sodium
iodide (0.53 g, 3.4 mmol) and cerium trichloride heptahydrate
(7.95 g, 14.3 mmol) were successively added to a solution of ketal
30 (3.8 g, 11.9 mmol) in acetonitrile (120 mL). The reaction mix-
ture was stirred at reflux overnight and partitioned between a 0.5
 aqueous solution of HCl (150 mL) and EtOAc (150 mL). The
aqueous layer was separated and extracted with EtOAc (3 ϫ
75 mL). The combined organic layers were washed with a saturated
aqueous solution of sodium hydrogen carbonate (2 ϫ 60 mL) and
a 0.4  aqueous solution of sodium thiosulfate (2 ϫ 50 mL), dried
(MgSO4) and concentrated in vacuo. The residue was purified by
column chromatography (cyclohexane/EtOAc, 20:1) to give keto es-
ter 3 as a colorless oil (2.8 g, 85%). MS: m/z (ESI) found 299.1252
2-Methyl-2-butene (9.5 mL, 91.6 mmol) and an aqueous solution
of sodium hydrogen phosphate (1 , 19.7 mL, 19.7 mmol) were ad-
ded successively to the solution of crude aldehyde (4.59 g) in tert-
butyl alcohol (63 mL). Sodium chlorite (5.1 g, 45.8 mmol) was ad-
ded portionwise at 0 °C, and the reaction mixture was then vigor-
[MNaϩ], C16H20O4 (M, 276.4) requires 299.1259. [α]2D0 ϭ ϩ131.4
ously stirred at room temperature for 24 hours. The solvent was (c ϭ 0.73, CHCl3). IR (neat): ν˜ ϭ 1735 and 1715 cmϪ1. H NMR
1
removed in vacuo. The residue was taken up in water (75 mL) and
CH2Cl2 (125 mL), and the aqueous layer was extracted with
CH2Cl2 (3 ϫ 75 mL). The combined organic layers were dried
(MgSO4) and concentrated in vacuo to give carboxylic acid 29 as
a colorless oil. This material was used without further purification
(400 MHz, CDCl3): δ ϭ 1.44Ϫ2.08 (m, 5 H, cyclohexyl CH2 and
cyclohexyl CHH), 2.16Ϫ2.44 (m, 2 H, cyclohexyl CH2), 2.49Ϫ2.74
(m, 2 H, cyclohexyl CHH and CHAHBCO2CH3), 2.92 (d, J ϭ
14.9 Hz, 1 H, CHAHBCO2CH3), 3.57 (s, 3 H, CO2CH3), 4.02 (d,
J ϭ 10.8 Hz, 1 H, CHAHBO), 4.57 (d, J ϭ 10.8 Hz, 1 H,
1H CHAHBO), 7.15Ϫ7.38 (m, 5 H, arom. CH) ppm. 13C NMR
(50 MHz, CDCl3): δ ϭ 20.3 (cyclohexyl CH2), 27.6 (cyclohexyl
in the next step. IR (neat): ν˜ ϭ 3500Ϫ2500 and 1702 cmϪ1
NMR (200 MHz, CDCl3): δ ϭ 1.39Ϫ2.17 (m, 8 H, cyclohexyl
.
CH2), 2.63 (d, J ϭ 15.9 Hz, 1 H, CHAHBCO2H), 2.94 (d, J ϭ CH2), 36.7 (CH2CO2CH3), 38.2 (cyclohexyl CH2), 39.1 (cyclohexyl
15.9 Hz, 1 H, CHAHBCO2H), 4.00 (br. s, 4 H, OCH2CH2O), 4.58
CH2), 51.5 (CO2CH3), 65.7 (CH2O), 81.2 (C), 127.4 (2 arom. CH),
(s, 2 H, CH2O), 7.26Ϫ7.39 (m, 5 H, arom. CH) ppm. 13C NMR 127.5 (arom. CH), 128.3 (2 arom. CH), 137.7 (arom. C), 170.8
(50 MHz, CDCl3): δ ϭ 20.3 (cyclohexyl CH2), 22.7 (cyclohexyl (CO2CH3), 210.4 (CO) ppm.
CH2), 30.4 (cyclohexyl CH2), 32.4 (cyclohexyl CH2), 37.2
Methyl
(R)-[1Ј-Benzyloxy-2-(trimethylsilanoxy)cyclohex-2-enyl]-
(CH2CO2H), 64.3 (OCH2CH2O), 64.6 (CH2O), 65.0 (OCH2CH2O),
79.8 (C), 110.8 (OCO), 127.6 (2 arom. CH), 128.2 (3 arom. CH),
138.2 (arom. C), 174.4 (CO2H).
acetate (31): Dry triethylamine (1.12 mL, 8.1 mmol), trimethylsilyl
chloride (0.86 mL, 7 mmol), and a solution of anhydrous sodium
iodide (940 mg, 6.3 mmol) in dry acetonitrile (20 mL) were added
successively to a solution of keto ester 3 (1.86 g, 6.7 mmol) in dry
acetonitrile (20 mL). The reaction mixture was stirred under nitro-
gen at room temperature for 20 hours and taken up in dry Et2O
(40 mL). The resulting organic solution was washed with a cold
aqueous solution of potassium carbonate (1%, 20 mL), dried
(K2CO3), and concentrated in vacuo to give silyl enol ether 31 as
a colorless oil. This material was used without further purification
in the next step. IR (neat): ν˜ ϭ 1737, 1655 and 841 cmϪ1. 1H NMR
(200 MHz, CDCl3): δ ϭ 0.11 [s, 9 H, Si(CH3)3], 1.40Ϫ2.06 (m, 6
H, cyclohexyl CH2), 2.61 (d, J ϭ 13.9 Hz, 1 H, CHAHBCO2CH3),
2.78 (d, J ϭ 13.9 Hz, 1 H, CHAHBCO2CH3), 3.56 (s, 3 H,
CO2CH3), 4.39 (d, J ϭ 11.5 Hz, 1 H, CHAHBO), 4.49 (d, J ϭ
11.5 Hz, 1 H, CHAHBO), 4.91 (t, J ϭ 3.9 Hz, 1 H, CHϭ),
Methyl
(R)-2-(1Ј-Benzyloxy-1ЈЈ,4ЈЈ-dioxaspiro[4.5]decyl)acetate
(30). From Protected Cyanohydrin 28: Activated manganese dioxide
(24 g, 0.28 mol), and sodium cyanide (3.4 g, 69.5 mmol) were added
to a solution of 28 (5 g, 13.9 mmol) in absolute methanol (200 mL).
The resulting suspension was stirred for 3 days at room tempera-
ture, and Et2O (400 mL) was then added, causing the precipitation
of the excess of sodium cyanide. The reaction mixture was filtered
through Celite. The filter pad was washed with Et2O (3 ϫ 100 mL)
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (cyclohexane/EtOAc, 20:1) to give
methyl ester 30 as a colorless oil (2.7 g, 61%).
From Carboxylic Acid 29: A solution of diazomethane in Et2O (0.5
, 50 mL) was added at 0 °C to the solution of crude carboxylic
Eur. J. Org. Chem. 2003, 2488Ϫ2497
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2495

L. Keller, F. Dumas, J. d’Angelo
FULL PAPER
7.06Ϫ7.31 (m, 5 H, arom. CH) ppm. 13C NMR (50 MHz, CDCl3):
was added to a suspension of pyridinium chlorochromate (736 mg,
δ ϭ 0.1 [Si(CH3)3], 19.0 (cyclohexyl CH2), 24.2 (cyclohexyl CH2), 2.67 mmol) in dry CH2Cl2 (15 mL). The reaction mixture was vig-
33.5 (cyclohexyl CH2), 40.9 (CH2CO2CH3), 51.2 (CO2CH3), 65.7 orously stirred overnight at room temperature, taken up in Et2O,
(CH2O), 76.1 (C), 107.0 (CHϭC), 126.3 (arom. CH), 127.3 (2 and filtered through a short pad of silica gel. The filtrate was con-
arom. CH), 128.0 (2 arom. CH), 139.8 (arom. C), 149.0 (CHϭC), centrated in vacuo and the residue was purified by column chroma-
171.3 (CO2CH3) ppm.
tography (cyclohexane/EtOAc, 4:1) to give ketone 34 as a colorless
oil (420 mg, 80%). MS: m/z (MALDI-TOF) found 359.1457
[MNaϩ], C18H24O6 (M, 336.4) requires 359.1471. IR (neat): ν˜ ϭ
Dimethyl (2R,6R)- and (2R,6S)-2-Benzyloxy-6-hydroxyheptane-1,2-
dicarboxylate (33): Oxygen containing ca. 5% (v/v) ozone was
bubbled through a sinter glass at Ϫ78 °C into a solution of silyl
enol ether 31 (2 g, 5.7 mmol) in methanol (20 mL) and CH2Cl2
(60 mL) in the presence of a pinch of sodium hydrogen carbonate.
The gas flow was stopped when TLC analysis of the mixture
showed the total conversion of the starting material. Ozone in ex-
cess was flushed out with an oxygen flow, and dimethyl sulfide
(2.45 mL, 40.7 mmol) was added at Ϫ78 °C. The reaction mixture
was allowed to warm up and was stirred at room temperature for
5 hours. The solvents were removed in vacuo, the residue was taken
up in EtOAc (120 mL), and the resulting organic solution was
washed with brine (3 ϫ 30 mL), dried (MgSO4), and concentrated
in vacuo to give a sensitive aldehyde 32 as a yellow oil (not charac-
terized), which was used without further purification.
1733 and 1714 cmϪ1 1H NMR (200 MHz, CDCl3): δ ϭ 1.62
.
(quint., J ϭ 7.3 Hz, 2 H, CH2CH2CH2C), 1.92 (t, J ϭ 7.3 Hz, 2
H, CH2CH2CH2C), 2.09 (s, 3 H, CH3CO), 2.42 (t, J ϭ 7.3 Hz, 2
H, CH2CH2CH2C), 2.94 (s, 2 H, CH2CO2CH3), 3.64 (s, 3 H,
CO2CH3), 3.76 (s, 3 H, CO2CH3), 4.53 (s, 2 H, CH2O), 7.14Ϫ7.38
(m, 5 H, arom. CH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 17.4
(CH2CH2CH2C), 29.7 (CH3CO), 34.4 (CH2CH2CH2C), 39.7
(CH2CO2CH3), 43.0 (CH2CH2CH2C), 51.6 (CO2CH3), 52.1
(CO2CH3), 66.4 (CH2O), 80.6 (C), 127.4 (arom. CH), 127.5 (2
arom. CH), 128.1 (2 arom. CH), 138.0 (arom. C), 170.0 (CO2CH3),
172.6 (CO2CH3), 207.9 (CO) ppm.
Dimethyl
(R)-2-Benzyloxy-6-hydroxy-6-methylheptane-1,2-dicar-
boxylate (35): Methylmagnesium bromide (1.25 mL of a 1  solu-
tion in di-n-butyl ether, 1.25 mmol) was added dropwise (15 min),
under nitrogen and at Ϫ30 °C, to a solution of ketone 34 (420 mg,
1.25 mmol) in dry THF (14 mL). The reaction mixture was stirred
at Ϫ30 °C for 90 minutes, hydrolyzed successively with a saturated
aqueous solution of ammonium chloride (2 mL) and water (2 mL),
and taken up in Et2O (10 mL). The aqueous layer was separated
and extracted with EtOAc (3 ϫ 15 mL). The combined organic
layers were washed with brine (10 mL), dried (MgSO4), and con-
centrated in vacuo. The residue was purified by column chromatog-
raphy (cyclohexane/EtOAc, 9:1 to 1.5:1) to give the tertiary alcohol
35 as a colorless oil (183 mg, 42%). MS: m/z (MALDI-TOF) found
375.1795 [MNaϩ], C19H28O6 (M, 352.5) requires 375.1784. IR
(neat): ν˜ ϭ 3522 and 1733 cmϪ1. 1H NMR (200 MHz, CDCl3): δ ϭ
1.17 [s, 6 H, (CH3)2COH], 1.31Ϫ1.51 (m, 4 H, CH2CH2CH2C and
Methylmagnesium bromide (11.5 mL of a 1  solution in di-n-butyl
ether, 11.5 mmol) was added dropwise (30 minutes), under nitrogen
and at Ϫ40 °C, to a solution of the crude aldehyde 32 (1.62 g) in
dry THF (40 mL). The reaction mixture was stirred at Ϫ40 °C for
a further 10 minutes and was then hydrolyzed by successive ad-
dition of a saturated aqueous solution of ammonium chloride
(4 mL) and water (6 mL). Solvents were removed in vacuo, the resi-
due was acidified with an aqueous solution of HCl (0.1 , 75 mL),
and the aqueous layer was extracted with EtOAc (5 ϫ 25 mL). The
combined organic layers were dried (MgSO4) and concentrated in
vacuo to give an hydroxy acid as a yellow oil (not characterized).
This material was used without further purification in the next
step.
CH2CH2CH2C), 1.55 (br. s,
1 H, OH), 1.93 (m, 2 H,
A solution of diazomethane in Et2O (0.5 , 20 mL) was added at
0 °C to a solution of the crude hydroxy acid (1.8 g) in dry Et2O
(70 mL). The resulting mixture was stirred at room temperature for
2 hours and the excess of diazomethane was destroyed with acetic
acid. The reaction mixture was taken up in EtOAc (60 mL), and
the resulting organic layer was washed with brine (3 ϫ 25 mL),
dried (MgSO4), and concentrated in vacuo. The residue was puri-
fied by column chromatography (cyclohexane/EtOAc, 9:1 to 1.5:1)
to give dimethyl esters 33 as a colorless oil (687 mg, 35%, 4 steps
from γ-keto ester 3, 1:1 mixture of diastereomers at C-7). MS:
m/z (MALDI-TOF) found 361.1641 [MNaϩ], C18H26O6 (M, 338.5)
CH2CH2CH2C), 2.94 (m, 2 H, CH2CO2CH3), 3.64 (s, 3 H,
CO2CH3), 3.76 (s, 3 H, CO2CH3), 4.48 (d, J ϭ 11.0 Hz, 1 H,
CHAHBO), 4.56 (d, J ϭ 11.0 Hz, 1 H, CHAHBO), 7.17Ϫ7.38 (m,
5 H, arom. CH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 18.0
(CH2CH2CH2C), 29.1 [(CH3)2COH], 35.7 (CH2CH2CH2C), 39.8
(CH2CO2CH3), 43.6 (CH2CH2CH2C), 51.6 (CH2CO2CH3), 52.1
(CH2CO2CH3), 66.4 (CH2O), 70.5 [(CH3)2COH], 80.9 (C), 127.3
(arom. CH), 127.4 (2 arom. CH), 128.1 (2 arom. CH), 138.1 (arom.
C), 170.1 (CO2CH3), 172.8 (CO2CH3) ppm.
Dimethyl (R)-2,6-Dihydroxy-6-methylheptane-1,2-dicarboxylate (2):
Palladium on charcoal (10%, 67 mg) was added to a solution of
tertiary alcohol 35 (183 mg, 0.52 mmol) in methanol (36 mL). The
suspension was vigorously stirred under hydrogen (1 bar) at room
temperature for 2 hours and then filtered through Celite. The filter
pad was washed several times with methanol, and the filtrate was
concentrated in vacuo. The resulting solid was recrystallized from
pentane at 0 °C to give diol 2 as a colorless solid (140 mg, 100%);
m.p. 34 °C (ref.[3] m.p. 34Ϫ35 °C). [α]2D0 ϭ Ϫ14.0 (c ϭ 0.71, CHCl3)
{ref.[3] [α]2D0 ϭ Ϫ18.0 (c ϭ 0.71, CHCl3)}. IR (neat): ν˜ ϭ 3501 and
1
requires 361.1627. IR (neat): ν˜ ϭ 3447 and 1733 cmϪ1. H NMR
(200 MHz, CDCl3): δ ϭ 1.08 (d, J ϭ 6.1 Hz, 3 H, CH3CHOH)
and 1.09 (d, J ϭ 6.1 Hz, 3 H, CH3CHOH), 1.23Ϫ1.67 (m, 4 H,
CH2CH2CH2C and CH2CH2CH2C), 1.75Ϫ2.00 (m,
2 H,
CH2CH2CH2C), 2.87 (m, 2 H, CH2CO2CH3), 3.57 (s, 3 H,
CO2CH3), 3.69 (s, 3 H, CO2CH3), 4.41 and 4.43 (2 d, J ϭ 10.9 Hz,
1 H, CHAHBO), 4.44 (m, 1 H, CHOH), 4.50 and 4.52 (2 d, J ϭ
10.9 Hz, 1 H, CHAHBO), 7.11Ϫ7.36 (m, 5 H, arom. CH) ppm. 13
C
NMR (50 MHz, CDCl3): δ ϭ 19.4 and 19.5 (CH2CH2CH2C), 23.4
(CH3CHOH), 35.1 (CH2CH2CH2C), 38.9 and 39.0
(CH2CH2CH2C), 39.5 and 39.8 (CH2CO2CH3), 51.8 (CO2CH3),
52.2 (CO2CH3), 66.5 (CH2O), 67.4 and 67.5 (CHOH), 80.9 and
81,0 (C), 127.5 (2 arom. CH), 128.2 (3 arom. CH), 138.1 (arom.
C), 170.2 and 170.3 (CO2CH3), 172.9 (CO2CH3) ppm.
1733 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 1.19 [s, 7 H,
.
(CH3)2COH and OH], 1.24 (m, 1 H, CH2CHHCH2C), 1.41Ϫ1.57
(m, 3 H, CH2CH2CH2C and CH2CHHCH2C), 1.71 (m, 2 H,
CH2CH2CH2C), 2.70 (d, J ϭ 16.3 Hz, 1 H, CHAHB CO2CH3), 2.92
(d, J ϭ 16.3 Hz, 1 H, CHAHB CO2CH3), 3.67 (s, 3 H, CO2CH3),
3.72 (br. s, OH), 3.80 (s, 3 H, CO2CH3) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 18.0 (CH2CH2CH2C), 29.0 [CH3C(OH)CH3], 29.2
Dimethyl (R)-2-Benzyloxy-6-oxoheptane-1,2-dicarboxylate (34): A
solution of alcohol 33 (530 mg, 1.57 mmol) in dry CH2Cl2 (10 mL)
2496
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2488Ϫ2497

Enantioselective Synthesis of the Ester Side Chain of Homoharringtonine
FULL PAPER
M. Tori, C. Makino, K. Hisazumi, M. Sono,
[8l]
6, 289Ϫ298.
[CH3C(OH)CH3], 39.5 (CH2CH2CH2C), 43.3 (CH2CO2CH3), 43.5
(CH2CH2CH2C), 51.7 (CO2CH3), 52.8 (CO2CH3), 70.6
[(CH3)2COH], 75.2 (C), 171.2 (CO2CH3), 175.5 (CO2CH3) ppm.
C12H22O6 (262.3): calcd. C 54.94, H 8.45; found C 54.97, H 8.55.
K. Nakashima, Tetrahedron: Asymmetry 2001, 12, 301Ϫ307.
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L. Keller, C. Camara, A. Pinheiro, F. Dumas, J. d’Angelo,
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´
M. Nour, K. Tan, R. Jankowski, C. Cave, Tetra-
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[8p]
[8q]
See ref.[7b]
J.
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www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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