Stereoselective synthesis of anamarine

Article abstract of DOI:10.1016/j.tet.2004.02.003

A stereoselective synthesis of the naturally occurring, α,β-unsaturated lactone anamarine is described. The key step was a highly stereoselective aldol reaction of a protected erythrulose derivative with a chiral aldehyde. Another relevant step was an asy

Full text of DOI:10.1016/j.tet.2004.02.003

Tetrahedron 60 (2004) 2979–2985
Stereoselective synthesis of anamarine
a
Santiago Dıaz-Oltra, Juan Murga, Eva Falomir, Miguel Carda and J. Alberto Marco
a
a
a
b
,
,
*
*
´
a
´
´
´
´
Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, E-12080 Castellon, Spain
´
Depart. de Q. Organica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
b
Received 12 November 2003; revised 2 February 2004; accepted 4 February 2004
Abstract—A stereoselective synthesis of the naturally occurring, a,b-unsaturated lactone anamarine is described. The key step was a highly
stereoselective aldol reaction of a protected erythrulose derivative with a chiral aldehyde. Another relevant step was an asymmetric aldehyde
allylation with a chiral allylborane. The lactone ring was made by means of a ring-closing metathesis.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
diastereoselective processes was found to depend on the
type of a-substituents (carbon vs heteroatom groups),
matched and mismatched cases being observed. As a matter
of fact, (S)-a-oxygenated aldehydes were found to react
with ketones 1 to yield aldols 3 with a high degree of
stereoselectivity, whereas those having the R configuration
turned out to give sluggish and nonstereoselective reactions
(Scheme 2). Mechanistic models were proposed to explain
these diverging results.8
The aldol reaction1 has proven to be a powerful and general
method for the stereocontrolled construction of carbon–
carbon bonds and has relevant application in the synthesis of
natural polyoxygenated molecules such as macrolide and
polyether antibiotics.2 Our current interest in the develop-
ment of erythrulose3 as a useful chiral building block for the
stereocontrolled construction of polyfunctionalized struc-
tures has led us to investigate the enolization of protected
derivatives thereof and the subsequent addition of the
resulting enolates to aldehydes. We recently reported that
L-erythrulose acetals with the general formula 1 (Scheme 1,
protecting group P¼silyl), readily prepared in two steps
from L-erythrulose,4 were transformed into boron enolates
provided that chlorodicyclohexylborane (Chx2BCl) was
used as the enolization reagent.5–7 The boron enolates were
then allowed to react with a range of achiral aldehydes to
yield aldol adducts of the general formula 2 with a high
degree of syn 1,2- and 1,3-induction (the 2,4-syn/4,5-syn
relationship in 2, diastereomeric ratio, d.r..19:1).
Scheme 2. Boron aldol reactions of erythrulose derivatives with chiral,
a-oxygenated aldehydes.
Scheme 1. Boron aldol reactions of erythrulose derivatives with achiral
aldehydes.
In order to show the synthetic utility of these aldol reactions,
we have now performed a total, stereoselective synthesis of
the naturally occurring lactone anamarine (Fig. 1). This
a,b-unsaturated lactone and several structural analogues
thereof such as spicigerolide, hyptolide and synrotolide
have been isolated from species of Hyptis and other
botanically related genera (natural configurations depicted
in Fig. 1).9 These compounds contain a polyoxygenated
chain connected with an a,b-unsaturated six-membered
lactone and show a range of pharmacological properties,
Very recently, we have shown that such aldol reactions can
be carried out with high stereoselectivity also in the case of
a-chiral aldehydes. The sense of induction of these doubly
Keywords: Erythrulose; Boron aldol reactions; Asymmetric allylboration;
Stereoselectivity; Ring-closing metathesis; Anamarine.
*
Corresponding authors. Tel.: þ34-96-3544337; fax: þ34-96-3544328;
e-mail address: alberto.marco@uv.es
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.003

´
S. Dıaz-Oltra et al. / Tetrahedron 60 (2004) 2979–2985
2980
published stereoselective syntheses of the natural enantio-
mers of spicigerolide and hyptolide.11
2. Results and discussion
The previous syntheses of both enantiomers of anamarine
were carbohydrate-based, with all stereogenic carbons
being already present in the chiral starting materials.10
Our synthesis relies upon the same general concept used in
our recent syntheses of structurally similar lactones, where
asymmetric allylations and ring-closing metatheses played a
key role.11 As shown in Scheme 3, the generic retrosynthetic
analysis for such lactones points to a 6-deoxyaldohexose as
the starting material. In our synthesis of spicigerolide, for
instance,11b we used to advantage the fact that the
polyoxygenated chain has the same absolute configuration
as L-rhamnose (6-deoxy-L-mannose), a commercially
available sugar. In the case of anamarine, however, the
same analysis leads to the nonavailable sugar 6-deoxy-L-
glucose. A synthesis for this compound in suitably protected
Figure 1. Naturally occurring g-pyrones isolated from Hyptis spp. and
related genera.
such as cytotoxicity against human tumor cells, antimicro-
bial or antifungal activity, etc. Pharmacological properties
of these types make these compounds interesting synthetic
goals. Efforts in this direction were limited for many years
to the syntheses of natural (þ)-anamarine (Fig. 1) and
its nonnatural (2)-enantiomer.10 Very recently, we have
Scheme 3. Retrosynthetic analysis for anamarine and related polyoxygenated lactones.

´
S. Dıaz-Oltra et al. / Tetrahedron 60 (2004) 2979–2985
2981
Scheme 4. Synthesis of (þ)-anamarine. Reaction conditions: (a) Chx2BCl, Et3N, Et2O, 0 8C, then 5, from 278 8C to 0 8C, 5 h, then LiBH4, 278 8C, 2 h (75%
of 7); (b) MOMCl, DIPEA, 4 days, K (72%); (c) PPTS, aq MeOH, rt, overnight (70%); (d) Pb(OAc)4, CH2Cl2, rt, 1 h, then (EtO)2POCH2COOEt, LiCl, DIPEA,
MeCN, rt, overnight (88% overall); (e) DIBAL, hexane–toluene, 0 8C, 4 h, (82%); (f) PCC, celite, CH2Cl2, rt, 1.5 h (90%); (g) allylBIpc2 [from (þ)-DIP-Cl
and allylmagnesium bromide], Et2O, 278 8C, 3 h (88:12 diastereoisomer mixture, 74% of pure 13 after chromatography); (h) cinnamoyl chloride, Et3N, cat.
DMAP, CH2Cl2, rt, 12 h (81%); (i) catalyst A (10%), CH2Cl2, reflux, 3 h (98%); (j) BF3·Et2O, SMe2, 210 8C, 30 min; (k) aq HF, rt, 7 h; (l) Ac2O, Et3N, cat.
DMAP, CH2Cl2, rt, overnight (62% overall for the three steps). Abbreviations: Chx, cyclohexyl; MOMCl, methoxymethyl chloride; DIPEA, ethyl
N,N-diisopropylamine; PPTS, pyridinium p-toluenesulfonate; DIP-Cl, diisopinocampheylboron chloride; PCC, pyridinium chlorochromate; DMAP,
N,N-dimethylaminopyridine; DIBAL, diisobutylaluminum hydride.
form was then designed with reliance on our aldol
methodology with erythrulose derivatives (Scheme 3).
3. Conclusions
Erythrulose derivatives are able to give highly stereoselec-
tive aldol reactions with a-oxygenated aldehydes provided
that the configurations of both chiral components are
suitably matched (doubly diastereoselective process). The
synthetic utility of these reactions has been shown here with
the stereoselective synthesis of the naturally occurring,
pharmacologically active lactone (þ)-anamarine. Further
applications of this methodology to the synthesis of natural
products are being currently developed by our group and
will be described in near future.
As we have recently reported, the reaction between the
boron enolate of ketone 1 (P¼TBS) and the (S)-lactaldehyde
derivative 5 generates with high diastereoselectivity the
boron aldolate 6 which, by means of an oxidative hydrolytic
work-up, gives rise to the corresponding aldol adduct
(Scheme 4).8 In the present case, however, aldolate 6 was
reduced in situ with LiBH4 to yield the syn-1,3-diol 7.12
After protection of the hydroxyl groups and hydrolytic
cleavage of the acetonide ring,13 diol 9 was oxidatively
cleaved to an intermediate a-alkoxy aldehyde (not depicted)
which, without purification, was olefinated by means of a
modified Horner–Emmons reaction14 to conjugated ester
10. Standard functional group manipulations afforded
conjugated aldehyde 12, which was then subjected to
asymmetric allylation15 to alcohol 13. Acylation of the
latter with cinnamoyl chloride,16 followed by ring-closing
metathesis in the presence of the second-generation
Grubbs ruthenium catalyst A,17 provided conjugated lactone
15. Finally, cleavage of all protecting groups and per-
acetylation furnished synthetic (þ)-anamarine, identical in
its physical and spectral properties9a to the natural product
(Scheme 4). The overall yield was about 8% (based on
ketone 1), a figure which compares well with the previous
synthetic efforts.10
4. Experimental
4.1. General
NMR spectra were measured at 400 or 500 MHz in CDCl3
solution at 25 8C. The signals of the deuterated solvent
(CDCl3) were taken as the reference (the singlet at d 7.25 for
1H NMR and the triplet centered at 77.00 ppm for 13C NMR
data). The multiplicities of the 13C NMR signals were
determined with the DEPT pulse sequence. Mass spectra
were run by the electron impact (EIMS, 70 eV) or with the
fast atom bombardment mode (FABMS, m-nitrobenzyl
alcohol matrix) on a VG AutoSpec mass spectrometer. IR

´
S. Dıaz-Oltra et al. / Tetrahedron 60 (2004) 2979–2985
2982
data are given only for compounds with relevant functions
(OH, CvO) and were recorded as oily films on NaCl plates
(oils) or as KBr pellets (solids). Optical rotations were
measured at 25 8C. Reactions which required an inert
atmosphere were carried out under N2 with flame-dried
glassware. Et2O was freshly distilled from sodium-benzo-
phenone ketyl. Dichloromethane was freshly distilled from
CaH2. Tertiary amines were freshly distilled from KOH.
Toluene was freshly distilled from sodium wire. Commer-
cially available reagents were used as received. Unless
detailed otherwise, ‘work-up’ means pouring the reaction
mixture into 5% aq NaHCO3 (if acids had been utilized in
the reaction) or into satd aq NH4Cl (if bases had been
utilized), then washing again the organic layer with brine,
drying over anhydrous Na2SO4 or MgSO4 and elimination
of the solvent in vacuo. When solutions were filtered
through a Celite pad, the pad was additionally washed with
the same solvent, and the washing liquids incorporated into
the main organic layer. The obtained material was then
chromatographed on a silica gel column (Su¨d-Chemie AG,
60–200 m) with the indicated eluent. Reagent acronyms are
explained in the caption of Scheme 4.
(tert-butyldiphenylsilyloxy)-3,5-bis(methoxymethoxy)-
heptane-1,2-diol, 9. Acetonide 8 (1.354 g, 2 mmol) was
dissolved in MeOH (20 mL) and treated with a solution of
pyridinium p-toluenesulfonate (12 mg, 0.05 mmol) in water
(1 mL). The solution was stirred overnight at room
temperature and then carefully neutralized with aq
Na2CO3. After removal of all volatiles in vacuo, the residue
was subjected to column chromatography on silica gel
(hexanes–EtOAc, 70:30) to furnish diol 9 (892 mg, 70%):
oil, [a]D¼þ7.3 (c 0.9; CHCl3); IR nmax (cm21) 3400 (br,
OH); 1H NMR (500 MHz) d 7.70–7.60 (4H, m), 7.40–7.30
(6H, m), 4.87 (2H, AB system, J¼6 Hz), 4.48 (2H, AB
system, J¼6.5 Hz), 4.08 (1H, br q, J¼6.5 Hz), 3.94 (1H, br
d, J¼6 Hz), 3.72 (2H, m), 3.55 (2H, m), 3.47 (3H, s), 3.44
(1H, t, J¼5 Hz), 3.25 (3H, s), 2.60 (1H, d, J¼5 Hz, OH),
2.50 (1H, t, J¼6 Hz, OH), 1.08 (3H, d, J¼6.5 Hz), 1.05
(9H, s), 0.84 (9H, s), 0.03 (3H, s), 0.02 (3H, s); 13C NMR
(125 MHz) d 134.5, 133.9, 19.1, 18.4 (C), 136.1, 135.9,
129.6, 129.5, 127.6, 127.4, 81.5, 80.8, 73.0, 70.2, 69.9 (CH),
98.2, 97.7, 64.1 (CH2), 56.1 (£2), 27.1 (£3), 26.0 (£3), 18.0,
24.6, 24.8 (CH3). HR FABMS m/z 659.3393 (MþNa)þ,
calcd for C33H56NaO8Si2, 659.3411. Anal. Calcd for
C33H56O8Si2: C, 62.23; H, 8.86. Found, C, 62.03; H, 9.02.
4.1.1. (1R,2S,3S,4S)-2-(tert-Butyldimethylsilyloxy)-4-(tert-
butyldiphenylsilyloxy)-1-((4S)-2,2-dimethyl-[1,3]dioxo-
lan-4-yl)-pentane-1,3-diol (7). The aldol reaction of ketone
1 with aldehyde 5 promoted by Chx2BCl, followed by in situ
LiBH4 reduction was performed as previously reported8 to
yield 7 in 75% overall yield: oil, IR nmax (cm21) 3400 (br,
OH); 1H NMR (500 MHz) d 7.75–7.65 (4H, m), 7.45–7.35
(6H, m), 4.25 (1H, br q, J¼6.5 Hz), 4.10 (1H, dd, J¼8,
4.5 Hz), 4.00–3.80 (3H, m), 3.55–3.45 (2H, m), 1.43 (3H,
s), 1.36 (3H, s), 1.07 (9H, s), 1.07 (3H, d, J¼6.5 Hz, over-
lapped), 0.86 (9H, s), 0.12 (3H, s), 0.03 (3H, s); 13C NMR
(125 MHz) d 134.0, 133.8, 109.2, 19.2, 19.1 (C), 135.9,
135.8, 129.7, 129.6, 127.7, 127.5, 76.0, 74.4, 72.5, 70.2,
68.2 (CH), 66.3 (CH2), 27.1 (£3), 26.7, 26.0 (£3), 25.8,
18.2, 24.2, 24.5 (CH3).
4.1.4. Ethyl (2E,4R,5S,6S,7S)-5-(tert-butyldimethylsilyl-
oxy)-7-(tert-butyldiphenylsilyloxy)-4,6-bis(methoxy-
methoxy)-oct-2-enoate, 10. Lead tetraacetate (488 mg,
1.1 mmol) was added to a solution of diol 9 (636 mg, ca.
1 mmol) in CH2Cl2 (10 mL). The solution was stirred for
1 h at room temperature, then filtered through a Celite pad
and evaporated in vacuo. The residue was redissolved in
Et2O, cooled in an ice bath and stirred with powdered
K2CO3 (1.38 g, 10 mmol) for 30 min. The mixture was then
filtered and evaporated in vacuo. The oily residue was
dissolved in dry acetonitrile (45 mL) and treated with
DIPEA (610 mL, 3.5 mmol), LiCl (212 mg, 5 mmol) and
(EtO)2POCH2COOEt (790 mL, 4 mmol). The reaction
mixture was then stirred overnight at room temperature
and worked up (extraction with Et2O). Solvent removal in
vacuo and column chromatography of the residue on silica
gel (hexanes–EtOAc, 90:10) provided ethyl ester 10
(594 mg, 88%): oil, [a]D¼222.5 (c 1; CHCl3); IR nmax
4.1.2. (4S)-4-[(1R,2S,3S,4S)-2-(tert-Butyldimethylsilyl-
oxy)-4-(tert-butyldiphenylsilyloxy)-1,3-bis(methoxy-
methoxy)pentyl]-2,2-dimethyl-[1,3]dioxolane, 8. Diol 7
(2.355 g, 4 mmol) was dissolved in dry CH2Cl2 (100 mL)
and treated dropwise with DIPEA (8 mL, 46 mmol) and
MOM chloride (3 mL, ca. 40 mmol). The reaction was then
stirred at reflux for 4 days. Work-up (extraction with
CH2Cl2) and column chromatography on silica gel (hex-
anes–EtOAc, 95:5) afforded compound 8 (1.95 g, 72%): oil,
[a]D¼225.5 (c 0.9; CHCl3); 1H NMR (500 MHz) d 7.70–
7.60 (4H, m), 7.40–7.30 (6H, m), 4.86 (2H, AB system,
J¼6.2 Hz), 4.60 (1H, d, J¼6.7 Hz), 4.40 (1H, d, J¼6.7 Hz),
4.20 (1H, br q, J¼6.5 Hz), 3.95–3.90 (2H, m), 3.85 (1H, m),
3.77 (1H, br d, J¼8 Hz), 3.56 (1H, dd, J¼8, 3.6 Hz), 3.49
(1H, dd, J¼8, 3.7 Hz), 3.48 (3H, s), 3.20 (3H, s), 1.31 (3H,
s), 1.20 (3H, s), 1.07 (9H, s), 1.02 (3H, d, J¼6.5 Hz), 0.87
(9H, s), 0.04 (3H, s), 0.00 (3H, s); 13C NMR (125 MHz) d
134.2, 134.1, 108.2, 19.1, 18.0 (C), 136.1, 135.9, 129.6,
129.5, 127.5, 127.4, 80.8, 80.1, 76.5, 73.7, 70.1 (CH), 97.7,
97.0, 65.8 (CH2), 56.1, 55.6, 27.1 (£3), 26.8, 26.0 (£3),
25.7, 17.7, 24.7, 25.0 (CH3). Anal. Calcd for C36H60O8Si2:
C, 63.87; H, 8.93. Found, C, 64.01; H, 9.00.
1
(cm21) 1724 (CvO); H NMR (500 MHz) d 7.70–7.60
(4H, m), 7.40–7.30 (6H, m), 7.00 (1H, dd, J¼16, 4.5 Hz),
5.86 (1H, dd, J¼16, 1.7 Hz), 4.84 and 4.76 (2H, AB system,
J¼6 Hz), 4.35 (2H, AB system, J¼6.6 Hz), 4.17 (3H, m),
3.98 (1H, dq, J¼2, 6.5 Hz), 3.68 (1H, dd, J¼7.7, 2 Hz), 3.60
(1H, dd, J¼7.7, 4.5 Hz), 3.46 (3H, s), 3.20 (3H, s), 1.29 (3H,
t, J¼7 Hz), 1.04 (9H, s), 1.02 (3H, d, J¼6.5 Hz), 0.88 (9H,
s), 0.05 (6H, s); 13C NMR (125 MHz) d 165.9, 134.7, 133.8,
19.1, 18.0 (C), 144.5, 136.1, 136.0, 129.5, 129.4, 127.5,
127.4, 122.2, 81.5, 77.5, 74.1, 70.1 (CH), 97.8, 95.3, 60.3
(CH2), 56.1, 55.8, 27.1 (£3), 25.9 (£3), 18.1, 14.2, 24.5,
25.0 (CH3). HR FABMS m/z 697.3599 (MþNa)þ, calcd for
C36H58NaO8Si2, 697.3562. Anal. Calcd for C36H58O8Si2: C,
64.06; H, 8.66. Found, C, 64.03; H, 8.88.
4.1.5. (2E,4R,5S,6S,7S)-5-(tert-Butyldimethylsilyloxy)-7-
(tert-butyldiphenylsilyloxy)-4,6-bis(methoxymethoxy)-
oct-2-en-1-ol, 11. DIBAL (2.4 mL of a 1 M solution in
toluene, 2.4 mmol) was added to an ice-cooled solution
of ester 10 (540 mg, 0.8 mmol) in hexanes (10 mL). The
solution was stirred for 4 h at 0 8C and quenched with satd
4.1.3. (2S,3R,4S,5S,6S)-4-(tert-Butyldimethylsilyloxy)-6-

´
S. Dıaz-Oltra et al. / Tetrahedron 60 (2004) 2979–2985
2983
aq NH4Cl. After filtering through a Celite pad, the solution
was evaporated in vacuo. Column chromatography of the
residue on silica gel (hexanes–EtOAc, 80:20) afforded
alcohol 11 (415 mg, 82%): oil, [a]D¼237.8 (c 1.7; CHCl3);
IR nmax (cm21) 3430 (br, OH); 1H NMR (500 MHz) d
7.70–7.60 (4H, m), 7.40–7.30 (6H, m), 5.70 (1H, dt, J¼16,
5.2 Hz), 5.55 (1H, dd, J¼16, 5.5 Hz), 4.86 and 4.73 (2H,
AB system, J¼6.2 Hz), 4.38 and 4.26 (2H, AB system,
J¼6.6 Hz), 4.02 (2H, m), 3.96 (2H, m), 3.78 (1H, dd, J¼7.5,
2 Hz), 3.50 (1H, dd, J¼7.5, 4 Hz), 3.46 (3H, s), 3.16 (3H, s),
1.04 (9H, s), 1.03 (3H, d, J¼6.5 Hz), 0.87 (9H, s), 0.03 (6H,
s); 13C NMR (125 MHz) d 134.4, 134.3, 19.1, 18.1 (C),
136.1, 136.0, 132.3, 129.5, 127.5, 127.4, 80.0, 77.8, 74.1,
70.4 (CH), 97.2, 94.4, 63.1 (CH2), 55.9, 55.5, 27.1 (£3),
25.9 (£3), 17.7, 24.5, 24.9 (CH3). HR FABMS m/z
655.3475 (MþNa)þ, calcd for C34H56NaO7Si2, 655.3462.
Anal. Calcd for C34H56O7Si2: C, 64.51; H, 8.92. Found, C,
64.44; H, 8.80.
mixture was present. A careful column chromatography on
silica gel (hexanes–EtOAc, 90:10) afforded pure alcohol 13
(299 mg, 74%): oil, [a]D¼247.6 (c 1.8; CHCl3); IR nmax
1
(cm21) 3450 (br, OH); H NMR (400 MHz) d 7.70–7.60
(4H, m), 7.40–7.30 (6H, m), 5.77 (1H, m), 5.62 (1H, ddd,
J¼15.7, 5.4, 1 Hz), 5.47 (1H, ddd, J¼15.7, 6.6, 1 Hz),
5.15–5.10 (2H, m), 4.86 and 4.75 (2H, AB system, J¼
6.2 Hz), 4.37 and 4.22 (2H, AB system, J¼6.6 Hz), 4.05
(1H, dq, J¼2.2, 6.5 Hz), 4.00 (2H, m), 3.76 (1H, dd, J¼7.5,
2.2 Hz), 3.53 (1H, dd, J¼7.5, 4.3 Hz), 3.46 (3H, s), 3.17
(3H, s), 2.20 (2H, m), 1.70 (1H, br s, OH), 1.05 (3H, d,
J¼6.5 Hz), 1.04 (9H, s), 0.86 (9H, s), 0.03 (3H, s), 0.02 (3H,
s); 13C NMR (100 MHz) d 134.5, 134.3, 19.1, 18.1 (C),
136.5, 136.1 (£2), 134.3, 129.6, 129.5, 127.6, 127.5, 126.1,
80.6, 78.2, 74.4, 70.8, 70.4 (CH), 118.2, 97.5, 94.1, 41.7
(CH2), 56.0, 55.5, 27.1 (£3), 26.0 (£3), 18.0, 24.5, 24.8
(CH3). HR FABMS m/z 695.3757 (MþNa)þ, calcd for
C37H60NaO7Si2, 695.3775. Anal. Calcd for C37H60O7Si2: C,
66.03; H, 8.99. Found, C, 65.93; H, 9.08.
4.1.6. (4R,5S,6S,7S)-5-(tert-Butyldimethylsilyloxy)-7-
(tert-butyldiphenylsilyloxy)-4,6-bis(methoxymethoxy)-
oct-2E-enal, 12. PCC (194 mg, 0.9 mmol) and Celite
(180 mg) were added to a solution of alcohol 11 (380 mg,
0.6 mmol) in dry CH2Cl2 (6 mL). The solution was stirred
for 1.5 h at room temperature, then filtered through a Celite
pad and evaporated in vacuo. The oily residue was subjected
to column chromatography on silica gel (hexanes–EtOAc,
90:10) to provide aldehyde 12 (341 mg, 90%): oil, [a]D¼
4.1.8. (4R,7R,8S,9S,10S)-8-(tert-Butyldimethylsilyloxy)-
10-(tert-butyldiphenylsilyloxy)-7,9-bis(methoxy-
methoxy)-undeca-1,5E-dien-4-yl (E)-3-phenylacrylate,
14. Alcohol 13 (270 mg, 0.4 mmol) was dissolved in dry
CH2Cl2 (8 mL) and treated with triethyl amine (140 mL,
1 mmol), (E)-cinnamoyl chloride (133 mg, 0.8 mmol) and
DMAP (5 mg, ca. 0.04 mmol). The mixture was then stirred
overnight at room temperature and worked up (extraction
with CH2Cl2). Column chromatography on silica gel
(hexanes–EtOAc, 95:5) provided ester 14 (260 mg, 81%):
oil, [a]D¼260.4 (c 3; CHCl3); IR nmax (cm21) 1716
1
210.8 (c 1.5; CHCl3); IR nmax (cm21) 1697 (CvO); H
NMR (500 MHz) d 9.40 (1H, d, J¼8 Hz), 7.70–7.60 (4H,
m), 7.40–7.30 (6H, m), 6.82 (1H, dd, J¼16, 4.3 Hz), 6.10
(1H, ddd, J¼16, 8, 1 Hz), 4.80 and 4.76 (2H, AB system,
J¼6 Hz), 4.39 (2H, AB system, J¼6.7 Hz), 4.28 (1H, m),
4.00 (1H, br q, J¼6.5 Hz), 3.70–3.60 (2H, m), 3.43 (3H, s),
3.20 (3H, s), 1.06 (3H, d, J¼6.5 Hz), 1.05 (9H, s), 0.87 (9H,
s), 0.04 (3H, s), 0.03 (3H, s); 13C NMR (125 MHz) d 193.1,
134.5, 133.8, 18.1, 18.0 (C), 153.5, 136.0, 135.9, 132.3,
129.7, 129.5, 127.6, 127.4, 81.3, 77.6, 74.2, 70.2 (CH), 97.7,
95.7 (CH2), 56.1, 55.9, 27.0 (£3), 25.9 (£3), 19.1, 24.6,
25.0 (CH3). HR FABMS m/z 653.3325 (MþNa)þ, calcd for
C34H54NaO7Si2, 653.3305.
1
(CvO); H NMR (500 MHz) d 7.70–7.60 (5H, m), 7.50
(3H, m), 7.40–7.30 (8H, m), 6.42 (1H, d, J¼16 Hz), 5.78
(1H, m), 5.66 (1H, dd, J¼15.7, 5.1 Hz), 5.62 (1H, dd,
J¼15.7, 6.5 Hz), 5.45 (1H, m), 5.15–5.10 (2H, m), 4.84 and
4.76 (2H, AB system, J¼6.2 Hz), 4.43 and 4.28 (2H, AB
system, J¼6.6 Hz), 4.07 (1H, dq, J¼2.2, 6.5 Hz), 4.03 (1H,
m), 3.79 (1H, dd, J¼7.2, 2.5 Hz), 3.58 (1H, dd, J¼7.5,
4.7 Hz), 3.45 (3H, s), 3.20 (3H, s), 2.22 (2H, m), 1.06 (9H,
s), 1.05 (3H, d, J¼6.5 Hz), 0.86 (9H, s), 0.04 (3H, s), 0.02
(3H, s); 13C NMR (125 MHz) d 165.9, 134.8, 134.5, 134.1,
18.3, 18.1 (C), 144.8, 136.0, 135.9, 133.3, 132.2, 130.2,
129.6, 129.4, 128.8, 128.4, 128.1, 127.6, 127.4, 118.4, 80.8,
78.2, 74.2, 72.8, 70.6 (CH), 118.0, 97.6, 94.2, 39.0 (CH2),
56.0, 55.5, 27.1 (£3), 26.0 (£3), 19.1, 24.4, 24.8 (CH3).
Anal. Calcd for C46H66O8Si2: C, 68.79; H, 8.28. Found, C,
68.93; H, 8.10.
4.1.7. (4R,7R,8S,9S,10S)-8-(tert-Butyldimethylsilyloxy)-
10-(tert-butyldiphenylsilyloxy)-7,9-bis(methoxy-
methoxy)-undeca-1,5E-dien-4-ol, 13. Allylmagnesium
bromide (commercial 1 M solution in Et2O, 750 mL,
0.75 mmol) was added dropwise via syringe to a solution of
(þ)-diisopinocampheylboron chloride (289 mg, 0.9 mmol)
in dry Et2O (5 mL) cooled in a dry ice–acetone bath. After
replacing the latter by an ice bath, the mixture was stirred
for 1 h. The solution was then allowed to stand, which
caused precipitation of magnesium chloride. The super-
natant solution was then carefully transferred to another
flask via canula. After cooling this flask at 278 8C, a
solution of aldehyde 12 (378 mg, 0.6 mmol) in dry Et2O
(5 mL) was added dropwise via syringe. The resulting
solution was further stirred at the same temperature for 3 h.
The reaction mixture was then quenched through addition of
phosphate pH 7 buffer solution (2 mL), MeOH (3 mL) and
30% H2O2 (2 mL). After stirring for 30 min, the mixture
was poured onto satd aq NaHCO3 and worked up as usual
(extraction with Et2O). An NMR examination of the crude
reaction product revealed that an 88:12 diastereoisomer
4.1.9. (6R)-6-[(3R,4S,5S,6S)-4-(tert-Butyldimethylsilyl-
oxy)-6-(tert-butyldiphenylsilyloxy)-3,5-bis(methoxy-
methoxy)-hept-1-enyl]-5,6-dihydropyran-2-one,
15.
Ester 14 (240 mg, 0.3 mmol) and ruthenium catalyst A
(26 mg, 0.03 mmol) were dissolved in dry, degassed
CH2Cl2 (42 mL) and heated under N2 at reflux until
consumption of the starting material (3–4 h, TLC monitor-
ing!). Solvent removal under reduced pressure was followed
by column chromatography on silica gel (hexanes–EtOAc,
4:1) to yield a,b-unsaturated lactone 15 (206 mg, 98%): oil,
[a]D¼215.2 (c 1.5; CHCl3); IR nmax (cm21) 1733 (CvO);
1H NMR (500 MHz) d 7.75–7.65 (4H, m), 7.40–7.30 (6H,
m), 6.74 (1H, m), 6.00 (1H, br d, J¼10 Hz), 5.74 (1H, dd,
J¼16, 5.1 Hz), 5.64 (1H, dd, J¼16, 5.5 Hz), 4.83 and 4.76
(2H, AB system, J¼6.2 Hz), 4.70 (1H, m), 4.36 and 4.26

´
S. Dıaz-Oltra et al. / Tetrahedron 60 (2004) 2979–2985
2984
(2H, AB system, J¼6.5 Hz), 4.04 (2H, m), 3.70 (1H, dd,
J¼7.7, 1.5 Hz), 3.53 (1H, dd, J¼7.5, 4.5 Hz), 3.46 (3H, s),
3.16 (3H, s), 2.15 (2H, m), 1.06 (3H, d, J¼6.5 Hz), 1.04
(9H, s), 0.86 (9H, s), 0.03 (6H, s); 13C NMR (125 MHz) d
163.8, 134.4, 134.3, 19.1, 18.1 (C), 144.6, 136.0, 135.9,
130.3, 129.6, 129.5, 129.3, 127.5, 127.4, 121.5, 80.7, 77.6,
77.4, 74.0, 70.2 (CH), 97.5, 94.7, 29.5 (CH2), 55.9, 55.5,
27.0 (£3), 25.9 (£3), 17.9, 24.5, 25.0 (CH3). FABMS m/z
721 (MþNa)þ, calcd for C38H58NaO8Si2, 721. Anal. Calcd
for C38H58O8Si2: C, 65.29; H, 8.36. Found, C, 65.23; H,
8.16.
References and notes
1. (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem.
1982, 13, 1–115. (b) Mukaiyama, T. Org. React. 1982, 28,
203–331. (c) Masamune, S.; Choy, W.; Petersen, J. S.; Sita,
L. R. Angew. Chem., Int. Ed. Engl. 1985, 24, 1–30.
(d) Heathcock, C. H.; Masamune, S.; Choy, W.; Petersen,
J. S.; Sita, L. R. Angew. Chem., Int. Ed. Engl. 1985, 24,
111–212. (e) Heathcock, C. H. Aldrichim. Acta 1990, 23,
99–111. (f) Comprehensive organic synthesis; Trost, B. M.,
Fleming, I., Winterfeldt, E., Eds.; Pergamon: Oxford, 1993;
Vol. 2. (g) Mekelburger, H. B.; Wilcox, C. S. Comprehensive
organic synthesis; Trost, B. M., Fleming, I., Winterfeldt, E.,
Eds.; Pergamon: Oxford, 1993; Vol. 2, pp 99–131.
(h) Heathcock, C. H. Comprehensive organic synthesis;
Trost, B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon:
Oxford, 1993; Vol. 2, pp 133–179, see also pp 181–238.
(i) Kim, B. M.; Williams, S. F.; Masamune, S. Comprehensive
organic synthesis; Trost, B. M., Fleming, I., Winterfeldt, E.,
Eds.; Pergamon: Oxford, 1993; Vol. 2, pp 239–275. (j) Rathke,
M. W.; Weipert, P. Comprehensive organic synthesis; Trost,
B. M., Fleming, I., Winterfeldt, E., Eds.; Pergamon: Oxford,
1993; Vol. 2, pp 277–299. (k) Paterson, I. Comprehensive
organic synthesis; Trost, B. M., Fleming, I., Winterfeldt, E.,
Eds.; Pergamon: Oxford, 1993; Vol. 2, pp 301–319.
(l) Franklin, A. S.; Paterson, I. Contemp. Org. Synth. 1994,
1, 317–338. (m) Braun, M. Houben-Weyl’s methods of
organic chemistry, stereoselective synthesis; Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Georg
Thieme: Stuttgart, 1996; Vol. 3, pp 1603–1666, see also pp
1713–1735.
4.1.10. (6R)-6-[(3R,4S,5S,6S)-3,4,5,6-Tetraacetoxyhept-
1-enyl]-5,6-dihydropyran-2-one, Anamarine. Lactone 15
(196 mg, 0.28 mmol) was dissolved in SMe2 (3 mL) and
cooled to 210 8C. Then, BF3·Et2O (710 mL, 5.6 mmol) was
added to the solution, which was stirred at the same
temperature for 30 min. Work-up (extraction with CH2Cl2)
and solvent removal under reduced pressure gave an oily
material which was dissolved in MeCN (5 mL) and treated
at room temperature with 48% aq HF (115 mL, 2.8 mmol).
After stirring at room temperature for 7 h, the reaction
mixture was worked up (extraction with CH2Cl2) and
evaporated in vacuo. The oily residue was then dissolved in
dry CH2Cl2 (10 mL) and treated with Et3N (310 mL,
2.2 mmol), acetic anhydride (190 mL, 2 mmol) and DMAP
(4 mg, 0.03 mmol). After stirring overnight, the reaction
mixture was worked up (extraction with CH2Cl2) and
chromatographed on a silica gel column (hexanes–EtOAc,
1:1) to give (þ)-anamarine (74 mg, 62% overall): white
crystals, mp 110–111 8C (from Et2O), lit.9a for natural
anamarine, mp 110–112 8C; [a]D¼þ14.5 (c 0.06; CHCl3);
lit.9a for natural anamarine, [a]D¼þ28.2 (c 0.52; CHCl3),
value later revised to þ18.8; lit.10b for synthetic (þ)-ana-
marine, [a]D¼þ15.9 (c 0.8; CHCl3); lit.10c for synthetic
2. (a) In Recent progress in the chemical synthesis of antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer: Berlin, 1990.
(b) Tatsuta, K. In Recent progress in the chemical synthesis
of antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin,
1990; pp 1–38. (c) Blizzard, T.; Fisher, M.; Mrozik, H.; Shih,
T. In Recent progress in the chemical synthesis of antibiotics;
Lukacs, G., Ohno, M., Eds.; Springer: Berlin, 1990; pp
65–102. (d) Isobe, M. In Recent progress in the chemical
synthesis of antibiotics; Lukacs, G., Ohno, M., Eds.; Springer:
Berlin, 1990; pp 103–134. (e) Beau, J.-M. In Recent progress
in the chemical synthesis of antibiotics; Lukacs, G., Ohno, M.,
Eds.; Springer: Berlin, 1990; pp 135–182. (f) Yonemitsu, O.;
Horita, K. In Recent progress in the chemical synthesis of
antibiotics; Lukacs, G., Ohno, M., Eds.; Springer: Berlin,
1990; pp 447–466. (g) Norcross, R. D.; Paterson, I. Chem.
Rev. 1995, 95, 2041–2114.
(2)-anamarine, [a]D¼215 (c 0.02; CHCl3); IR nmax (cm21
)
1738 (CvO); 1H NMR (500 MHz) d 6.88 (1H, ddd, J¼10,
5.2, 3 Hz), 6.04 (1H, dt, J¼10, 1.5 Hz), 5.85–5.75 (2H, m),
5.36 (1H, dd, J¼7, 6.5 Hz), 5.30 (1H, dd, J¼7, 3.5 Hz), 5.17
(1H, dd, J¼7, 3.5 Hz), 4.95 (1H, m), 4.90 (1H, quint,
J¼6.5 Hz), 2.45 (2H, m), 2.12 (3H, s), 2.07 (3H, s), 2.06
(3H, s), 2.02 (3H, s), 1.17 (3H, d, J¼6.5 Hz); 13C NMR
(125 MHz) d 170.0, 169.8, 169.7, 169.6, 163.4 (C), 144.5,
133.0, 125.7, 121.6, 75.9, 71.9, 71.7, 70.5, 67.4 (CH), 29.2
(CH2), 21.0, 20.9, 20.8, 20.6, 15.8 (CH3).
´
´
3. Marco, J. A.; Carda, M.; Gonzalez, F.; Rodrıguez, S.; Castillo,
E.; Murga, M. J. Org. Chem. 1998, 63, 698–707, and
references cited therein.
Acknowledgements
Financial support has been granted by the Spanish Ministry
of Education and Science (project BQU2002-00468), by the
4. For an improved preparation of silylated L-erythrulose
acetonides 1 (P¼TES, TBS, TPS) from L-erythrulose hydrate,
´
`
Fundacio Caixa Castello-Univ. Jaume I (project PI-1B2002-
06) and by the AVCyT (project Grupos03/180). One of the
authors (J.M.) thanks the Spanish Ministry of Science and
´
see: (a) Carda, M.; Rodrıguez, S.; Murga, J.; Falomir, E.;
¨
Marco, J. A.; Roper, H. Synth. Commun. 1999, 29,
2601–2610. For the preparation of protected D- and
L-erythrulose derivatives using chiral precursors other than
´
Technology for a Ramon y Cajal fellowship. S.D.-O. thanks
´
`
the Consellerıa de Educacio de la Generalitat Valenciana for
a predoctoral fellowship. The authors further thank Dr.
H. Roeper, Cargill TDC Food Europe, Cerestar Vilvoorde
R&D Centre, Belgium, for a very generous supply of
´
erythrulose itself, see: (b) Marco, J. A.; Carda, M.; Gonzalez,
´
F.; Rodrıguez, S.; Murga, J. Liebigs Ann. Chem. 1996,
1801–1810.
5. For a general review of boron aldol reactions: Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 1–200.
L-erythrulose, and Dr. S. Valverde, from the Instituto de
1
´
Q. Organica General, CSIC, Madrid, for the sending of a H
NMR spectrum of anamarine.
6. For the enolization of ketones with Chx2BCl/tertiary amine to
yield E boron enolates, see, for example: (a) Brown, H. C.;

´
S. Dıaz-Oltra et al. / Tetrahedron 60 (2004) 2979–2985
2985
´
R.; Fragoso-Serrano, M.; Cerda-Garcıa-Rojas, C. M. J. Org.
Chem. 2003, 68, 5672–5676.
Ganesan, K.; Dhar, R. K. J. Org. Chem. 1993, 58, 147–153.
(b) Paterson, I.; Nowak, T. Tetrahedron Lett. 1996, 37,
8243–8246.
12. Paterson, I.; Channon, J. A. Tetrahedron Lett. 1992, 33,
797–800.
´
7. (a) Falomir, E. Ph.D. Thesis, University of Castellon, Spain,
1998. (b) Marco, J. A.; Carda, M.; Falomir, E.; Palomo, C.;
Oiarbide, M.; Ortiz, J. A.; Linden, A. Tetrahedron Lett. 1999,
40, 1065–1068. (c) Carda, M.; Murga, J.; Falomir, E.;
13. When the synthesis was started with lactaldehyde protected
with a TBS group, the latter did not resist the acidic conditions
of acetonide cleavage (step c in Scheme 4). The internal and
more hindered TBS group survived, however, these
conditions.
´
Gonzalez, F.; Marco, J. A. Tetrahedron 2000, 56, 677–683.
´
8. Marco, J. A.; Carda, M.; Dıaz-Oltra, S.; Murga, J.; Falomir, E.;
Roeper, H. J. Org. Chem. 2003, 68, 8577–8582.
´
9. (a) Alemany, A.; Marquez, C.; Pascual, C.; Valverde, S.;
14. Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183–2186.
´
Martınez-Ripoll, M.; Fayos, J.; Perales, A. Tetrahedron Lett.
1979, 20, 3583–3586. (b) Pereda-Miranda, R.; Fragoso-
´
Serrano, M.; Cerda-Garcıa-Rojas, C. M. Tetrahedron 2001,
15. The allylborane used in step (g) was prepared as described in
the literature from allylmagnesium bromide and (þ)-diiso-
pinocampheylboron chloride. See: Ramachandran, P. V.;
Chen, G.-M.; Brown, H. C. Tetrahedron Lett. 1997, 38,
2417–2420. For a very recent review on asymmetric
allylborations, see: Ramachandran, P. V. Aldrichim. Acta
2002, 35, 23–35.
57, 47–53. (c) Achmad, S. A.; Høyer, T.; Kjær, A.; Makmur,
L.; Norrestam, R. Acta Chem. Scand. 1987, 41B, 599–609.
(d) Coleman, M. T. D.; English, R. B.; Rivett, D. E. A.
Phytochemistry 1987, 26, 1497–1499.
10. (a) Lichtenthaler, F.; Lorenz, K.; Ma, W. Tetrahedron Lett.
1987, 28, 47–50. (b) Lorenz, K.; Lichtenthaler, F.
Tetrahedron Lett. 1987, 28, 6437–6440. (c) Valverde, S.;
16. Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R. J. Org.
Chem. 2002, 67, 7547–7550. We have previously used this
acyl residue in cases where acryloyl chloride did not react
´
´
´
Hernandez, A.; Herradon, B.; Rabanal, R. M.; Martın-Lomas,
M. Tetrahedron 1987, 43, 3499–3504, The overall yield in
these rather lengthy syntheses was less than 1%.
´
efficiently: Garcıa-Fortanet, J.; Murga, J.; Carda, M.; Marco,
J. A. Org. Lett. 2003, 5, 1447–1449.
´
11. (a) Murga, J.; Garcıa-Fortanet, J.; Carda, M.; Marco, J. A.
Tetrahedron Lett. 2003, 44, 1737–1739. (b) Falomir, E.;
Murga, J.; Ruiz, P.; Carda, M.; Marco, J. A.; Pereda-Miranda,
17. Trnka, T.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29,
The standard ruthenium catalyst PhCHvRuCl2(PChx3)2
proved ineffective in this case.