New 2-acyl-1,3-dioxane derivatives from (1R)-(-)-myrtenal: stereochemical effect on their relative ability as chiral auxiliaries

Article abstract of DOI:10.1016/j.tetasy.2007.10.047

Four 3,10-pinanediol derivatives 1a-d, prepared in 50-72% global yields from (1R)-(-)-myrtenal 2, were treated with (RO)₂CHCOR₃ (R₃ = CH₃, Ph) to afford 2-acyl-1,3-dioxanes 3a-f. The latter were submitted to nucleophilic additions using several Grignard reagents to mainly afford carbinols generated by re diastereofacial attack (85-99% yield, ≥88:12 dr). The lowest diastereoselectivity was observed when PhLi or hydrides were used as nucleophiles. Only an equatorial substituent at C-3 modifies the diastereoselectivity of the nucleophilic additions.

Full text of DOI:10.1016/j.tetasy.2007.10.047

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2727–2737
New 2-acyl-1,3-dioxane derivatives from (1R)-(ꢀ)-myrtenal:
stereochemical effect on their relative ability as chiral auxiliaries
a
a
a
Elvia Becerra-Mart ´ı nez, Pedro Vel a´ zquez-Ponce, Miguel A. S a´ nchez-Aguilar,
a
b
a
Alfredo Rodr ´ı guez-Hostegu ´ı n, Pedro Joseph-Nathan, Joaqu ´ı n Tamariz
a,
*
and L. Gerardo Zepeda
a
Departamento de Qu ı´ mica Org a´ nica, Escuela Nacional de Ciencias Biol o´ gicas, Instituto Polit e´ cnico Nacional,
Prol. de Carpio y Plan de Ayala, M e´ xico, DF 11340, Mexico
b
Departamento de Qu ı´ mica, Centro de Investigaci o´ n y de Estudios Avanzados del Instituto Polit e´ cnico Nacional,
Apartado 14-740, M e´ xico, DF 07000, Mexico
Received 23 June 2007; accepted 26 October 2007
Abstract—Four 3,10-pinanediol derivatives 1a–d, prepared in 50–72% global yields from (1R)-(ꢀ)-myrtenal 2, were treated with
RO) CHCOR (R = CH , Ph) to afford 2-acyl-1,3-dioxanes 3a–f. The latter were submitted to nucleophilic additions using several
(
2
3
3
3
Grignard reagents to mainly afford carbinols generated by re diastereofacial attack (85–99% yield, P88:12 dr). The lowest diastereo-
selectivity was observed when PhLi or hydrides were used as nucleophiles. Only an equatorial substituent at C-3 modifies the diastereo-
selectivity of the nucleophilic additions.
ꢀ
2007 Elsevier Ltd. All rights reserved.
1. Introduction
studies describing the synthesis of chiral 2-substituted-1,3-
1
,2,5
dioxanes from natural sources,
this being an encourag-
The preparation of enantiomerically pure 2-substituted-
,3-dioxanes continues to be a particular challenge in
asymmetric synthesis due to the scarce availability of chiral
,3-diols which normally are their immediate precursors.1,2
ing reason to prepare them in enantiomerically pure forms.
Accordingly, we visualized 3,10-pinanediols 1a–d as key
precursors for a variety of enantiomerically pure 2-substi-
tuted-1,3-dioxane derivatives, which might be of signifi-
1
1
2
The former are usually employed in diastereoselective
nucleophilic and electrophilic additions, both of which
are carried out on the pro-chiral center present in the
cance in asymmetric synthesis. Since such precursors can
easily be prepared from commercially available (1R)-(ꢀ)-
myrtenal 2, the present work deals with the construction
of 2-acyl-1,3-dioxane derivatives 3a–f from (1R)-(ꢀ)-myrt-
enal 2, and its treatment with several nucleophilic reagents,
this being the first application of pinane based 2-acyldiox-
1
,2
2
-substituent.
SN2-type reactions at the ketal/acetal
carbon, with concomitant dioxane ring cleavage, also
1
–4
occur.
A literature search revealed a scarce number of
chart 1
R1
R1
O
R3
R
OH
OH
S
O
O
R2
R2
O
O
1
1
1
1
a R1 = R2 = H
3a R1 = R2 = H; R3 = CH3
3b R1 = R3 = CH3; R2 = H
3c R = R = CH ; R = H
4a R = CH3
4b R = Ph
b R = CH ; R = H
1
3
2
c R = H; R = CH
1
2
3
2
3
3
1
d R1 = R2 = CH3
3d R = CH ; R = H; R = Ph
1
3
2
3
3
3
e R = H; R = CH ; R = Ph
1 2 3 3
f R1 = R2 = R3 = CH3
*
0
Corresponding author. Fax: +52 55 5396 3503; e-mail: lzepeda@woodward.encb.ipn.mx
957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.047

2728
E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
anes as chiral auxiliaries. In addition, the stereochemical
outcome of the nucleophilic addition on 3a–f allowed us
to compare their relative diastereoselectivities with those
obtained when using structurally analogous 2-acyl-1,3-oxa-
to afford an epimeric mixture of 10-methylmyrtenols
5b:5c (63:37) in 98% yield, from which the former com-
pound was efficiently purified by fractionated crystalliza-
tion and the latter by column chromatography. The
6
–8
thianes 4a and 4b.
above epimeric mixture was also oxidized with CrO in
3
pyridine to give 10-methylmyrtenone (82%), which was
subsequently treated with MeMgBr to yield tertiary carbi-
nol 5d (88%). Hydroboration–oxidation of alcohols 5b–d
gave diols 1b (80%), 1c (82%), and 1d (87%), respectively.
2
. Results and discussion
Our early synthesis started with the preparation of 3,10-
pinanediol 1a by hydroboration–oxidation of (1R)-(ꢀ)-
Suitable crystals of diols 1a,b,d were analyzed by X-ray dif-
fraction to give the ORTEP structures shown in Figure 1,
in which a trans relationship of the substituents at the
two newly formed stereogenic centers (C-2 and C-3) is visu-
alized. Unexpectedly, in the three cases, mutual interatomic
distances between the hydroxyl groups in the solid state
structures preclude any type of intramolecular hydrogen
bonding interaction.
9
,10
myrtenol 5a in 74% yield (Scheme 1), as described.
However due to the proven capability of BH to reduce
3
carbonyl groups, we decided to use (1R)-(ꢀ)-myrtenal 2
as the starting material to prepare 3,10-pinanediol 1a in a
one-pot protocol. Thus, the treatment of (1R)-(ꢀ)-myrte-
nal 2 with excess H BÆSMe in THF at rt for 24 h, followed
3
2
by oxidation with H O in the presence of NaOH, afforded
2
2
diol 1a in 78% yield as a white crystalline solid. This yield
was substantially higher than that described in a similar
To prepare 2-acyl-1,3-dioxanes 3a–f, a transacetalization
protocol was used. Thus, the initial treatment of 3,10-
pinanediol 1a with pyruvaldehyde dimethyl acetal in benz-
9
,10
protocol.
In turn, the preparation of diols 1b, 1c, and
1
d began by reacting (1R)-(ꢀ)-myrtenal 2 with MeMgBr
R1
1
) BH3 (4 eq)
R1
1) BH3 (1.5 eq)
2) H2O2, HO-
OH
OH
-
2
) H O , HO
2
2
OH
R2
O
to prepare 1a
R2
1
1
1
1
a R1 = R2 = H
2
5
5
5
5
a R1 = R2 = H
b R = CH ; R = H
1
3
2
b R = CH ; R = H
1
3
2
c R = H; R = CH
1
2
3
c R = H; R = CH
1
2
3
d R1 = R2 = CH3
d R1 = R2 = CH3
H
7
H
5
CCl4:C6H6 (8:1)
R1
O
(
RO)2CHCOR3
+
R3
H , 60 ºC
1
3 O
O
R2
R1
O
3
a: H-3ax (3%); H-7 (13%)
R3
3b: Me-ax (0.8%); H-7 (10%)
O
3
3
c: H-3ax (2.8%); H-7 (10.6%)
d: H-3ax (2%); H-7 (10%);
Horto (5%)
O
R2
Irradn.
of H-5
O
3a R1 = R2 = H; R3 = CH3
3
e: Me-ax (1%); H-7 (11%);
Horto (6%)
3
3
3
3
3
b R1 = R3 = CH3; R2 = H
c R2 = R3 = CH3; R1 = H
d R = R = H; R = Ph
2
3
f: Me-ax (0.5%); H-7 (10.5%)
1
2
3
e R1 = CH3; R2 = H; R3 = Ph
f R = R = R = CH
1
2
3
3
Scheme 1.
a
b
c
Figure 1. ORTEP X-ray projections of 3,10-pinanediols: (a) 1a, (b) 1b, and (c) 1d.

E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
2729
ene, using p-TsOH as the catalyst, at 75 ꢁC for 4 h gave
acetyldioxane 3a in 38% yield after silica gel column chro-
matography. To minimize the hydrolysis of the acetal
group, the silica gel should be previously alkalinized with
triethylamine. The low yield could be attributable to the
strong tendency of pyruvaldehyde dimethyl acetal to be
polymerized under the reaction conditions. The yield was
crystal of benzoyldioxane 3e (Fig. 2), where the C-3 (S)-
and C-5 (R)-configurations can be appreciated, and a
well-defined chair-like conformation of the dioxane ring
is evident.
The evaluation of 2-acetyl-1,3-dioxane 3a to induce diaste-
reofacial nucleophilic additions was tested using a repre-
sentative series of nucleophiles. The diastereoselective
ratios are presented in Table 1. As can be observed, the
nucleophilic addition proceeded in good to excellent chem-
ical yields at ꢀ78 ꢁC in THF as the solvent, giving carbinol
derivatives 6a–h and 7a–h. Concerning the stereoselectivity,
Grignard reagents (entries 1–7) were the most diastereo-
selective, followed by PhLi (entry 10), while reduction reac-
tions with LiAlH4 and NaBH4 (entries 8 and 9) lack
stereoselectivity. Additions of PhMgBr (entry 4) and PhLi
(entry 10) afforded epimer 6d as the major diastereoisomer,
denoting the same diastereofacial attack. In turn, the addi-
tion of MeMgBr to benzoyldioxane 3d gave carbinols 6d
and 7d in a 13:87 ratio (entry 13), which is essentially the
inverse ratio obtained by the addition of PhMgBr to acet-
yldioxane 3a (entry 4). The absolute configuration of the
new stereogenic center of major carbinol 7d is S as revealed
by X-ray diffraction analysis (Fig. 2), denoting the pre-
ferred re diastereofacial attack of the nucleophile.
significantly improved by using a benzene–CCl solvent
4
mixture and camphorsulfonic acid as the catalyst at 60 ꢁC
for 72 h, giving 3a in 54% yield after column chromatogra-
phy. Presumably, the lower polarity of CCl and its conse-
4
quent lower water-affinity, combined with the lower acidity
of camphorsulfonic acid, as compared to p-TsOH, might
contribute to the higher yield, since a lower degree of poly-
merization of pyruvaldehyde dimethyl acetal was notice-
able. A similar protocol was used to prepare dioxanes
3
b–f, whose yields were in the 35–60% range.
The stereochemical outcome of these transacetalization
reactions showed a very similar behavior than those ob-
6
,7
served in the preparation of 2-acyl-1,3-oxathianes, giving
in all cases a major predominance for the equatorial isomer
of acyldioxanes 3a–f, as was confirmed by NOE diff. exper-
1
iments (Scheme 1). As a result, the respective H NMR sig-
nals of H-3ax (2.0–3.5%) and H-7 (10–11%) were enhanced
upon irradiation of the acetalic hydrogen (H-5). The ste-
reochemical information obtained from NOE experiments
was further supported by X-ray diffraction analysis of a
To complement this, the addition of PhMgBr on acetyldi-
oxane 3b gave a mixture of carbinols 6i:7i (entry 11) almost
a
b
Figure 2. ORTEP X-ray projections of (a) benzoyldioxane 3e and (b) carbinol 7d.
Table 1. Chemical yields and diastereomeric ratios of 6:7 mixtures obtained from nucleophilic additions on acyldioxanes 3a–f (Scheme 2)
a
b
Entry
Acyldioxane
Reagent
R
4
Yield (%)
Ratio
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3b
3c
3d
3e
3f
EtMgBr
Et
90
86
70
82
73
85
80
95
93
95
90
90
98
88
95
92
98:02 (6a:7a)
90:10 (6b:7b)
85:15 (6c:7c)
89:11 (6d:7d)
80:20 (6e:7e)
80:20 (6f:7f)
83:17 (6g:7g)
50:50 (6h:7h)
50:50 (6h:7h)
70:30 (6d:7d)
88:12 (6i:7i)
67:33 (6j:7j)
13:87 (6d:7d)
11:89 (6i:7i)
77:23 (6k:7k)
50:50 (6k:7k)
i-PrMgBr
i-BuMgBr
PhMgBr
i-Pr
i-Bu
Ph
2
PhCH MgCl
PhCH
2
CH
CH
2
@CHMgBr
C„CMgBr
CH
CH
H
2
@CH
C„C
3
3
LiAlH
NaBH
PhLi
4
4
H
1
1
1
1
1
1
1
Ph
Ph
Ph
Me
Me
Ph
Ph
PhMgBr
PhMgBr
MeMgBr
MeMgBr
PhMgBr
PhLi
3f
a
Calculated after column chromatography purification as mixture of 6 and 7.
Determined by H NMR integration of H-5 on the crude reaction mixture.
b
1

2730
E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
in the same ratio as obtained by the addition of PhMgBr
on acetyldioxane 3a (entry 4). Furthermore, similar ratios
from the addition of MeMgBr on benzoyldioxanes 3d
other hand, in comparison with 2-acyl-1,3-oxathianes 4a
6
,7
and 4b, the lower diastereoselectivity observed in 2-acyl-
dioxanes 3a and 3d is due to a similar coordination capabil-
ity of the dioxane oxygen atoms for the metal of the
nucleophile, despite the aforementioned unequal substitu-
tion pattern. In addition, it is very stimulating to obtain
reasonable to good stereoinductions in good yields by
using non-sulfur containing molecules.
(
entry 13) and 3e (entry 14) were obtained. These results
clearly suggest that axial substituents at C-3 (or eventually
at C-7) do not affect the stereochemical course of the nucleo-
phile, essentially preserving the same diastereoisomeric
ratio of their corresponding carbinols as compared with
those obtained from acyldioxanes 3a or 3d unsubstituted
at the C-3 position. In contrast, the addition of PhMgBr
was noticeably lower when acetyldioxanes 3c (entry 12,
The diastereofacial preference of the nucleophile was con-
firmed by hydrolyzing some representative mixtures of car-
binols (Scheme 2). Thus, the mixtures of carbinols 6d:7d,
obtained by the addition of PhMgBr to 3a (entry 4), and
MeMgBr addition on 3d (entry 13), were hydrolyzed using
a catalytic amount of p-TsOH in a CH CN–H O mixture
6
j:7j 67:33) and 3f (entry 15, 6k:7k 77:23), both bearing
an equatorial methyl group at C-3, were used. In turn,
the addition of PhLi to 3f yielded the respective diastereo-
isomeric mixture in ca. 50:50 ratio (entry 16). These results
demonstrate the capability of the equatorial substituent in
3
2
to give 3,10-pinanediol 1a and aldehydes 8a and 8b, respec-
tively (Scheme 2). A similar protocol was followed to
hydrolyze the mixtures of carbinols 6i:7i obtained from
the addition of PhMgBr on 3b (entry 11), or MeMgBr
addition on 3d (entry 13), giving also aldehydes 8a and
8b, respectively. Finally, the mixture of carbinols 6i:7i, ob-
tained according to entry 14, was also hydrolyzed to give
aldehyde 8b as the major enantiomer. All the above crude
C-3 (R ) to modulate the diastereoselectivity of the nucleo-
2
philic addition.
The diastereoselectivity can be explained by considering a
Cram-type chelated transition state where the metal coor-
dination is shown between O4 (O2 in the X-ray structure)
and the oxygen of the carbonyl group (Fig. 3), as was de-
1
1
scribed by Bailey et al. in a similar series of 2-acyl-1,3-
dioxanes formed from 2,3-butanediol. In this sense, the
coordination capability of both dioxane oxygen atoms is
mainly differentiated by the unequal substitution pattern
placed at C-3 and C-7, where the equatorial substituent ex-
erts the decisive steric effect that drives the stereochemical
course of the incoming nucleophile (Scheme 2). On the
reaction mixtures were treated with NaBH in MeOH to
4
afford the more stable 1-phenyl-1,2-ethanodiols 9a and
9b, along with the corresponding 3,10-pinanediol. In turn,
these mixtures were separated by column chromatography
to provide (R)-(ꢀ)-9a as the major enantiomer (64–70%
yield, 72–76% ee from mixtures of entries 4 and 11, and
54% ee from entry 15), and (S)-(+)-9b (72% yield, 72% ee
from mixtures of entries 13 and 14), while the correspond-
ing pinanediols were recovered in good yield (70–80%)
preserving their original enantiomeric purity.
R1
2
R2
O6
R4 O4
Mg
3. Conclusions
O
R3
X
Herein we have reported a very easy protocol to synthesize
3
,10-pinanediols 1a–d from (1R)-(ꢀ)-myrtenal and show
Figure 3. Cram-type chelated transition state showing the preferred
coordination site of the Grignard reagents as well as the favored re face
attack on the carbonyl group.
for the first time their potential synthetic utility as chiral
auxiliaries. Although (R)-1,3-butanediol and (R,R)-2,4-
R1
O
Reagent
R1
R1
O
5
5
R3
R3
R3
R4
O
+
O
O
O
O
OH
R4
HO
R2
R2
R2
7a-k
3
3
3
3
3
3
a R1 = R2 = H; R3 = CH3
b R1 = R3 = CH3; R2 = H
c R2 = R3 = CH3; R1 = H
d R1 = R2 = H; R3 = Ph
e R1 = CH3; R2 = H; R3 = Ph
f R = R = R = CH
6a-k
p-TsOH MeCN:H2O
1
2
3
3
1
) LiAlH4, THF
CH3
O
HO
2) CC separation
1a-c
R3
+
Ph OH
H
R4 OH
(
(
R)-(-)-9a
S)-(+)-9b
R1
OH
OH
(R)-8a R3 = CH3; R4 = Ph
S)-8b R = Ph; R = CH
3
(
4
3
1
a-c
R2
Scheme 2.

E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
2731
pentanediol are two of the most preferred 1,3-diols to be
used as chiral auxiliaries, high costs seriously limit their uti-
lization in multigram scales. Therefore, 3,10-pinanediols
ring was continued for 2 h at the above temperature. Once
the reaction reached room temperature, 45 mL of 3 M
NaOH were added at once, followed by the dropwise addi-
tion of 30 mL of 30% H O over 30 min, the mixture was
1
a–d offer a practical alternative. Furthermore, X-ray
2
2
diffraction studies of carbinol 7d and chemical correlation
revealed that nucleophilic additions on acyldioxanes
proceeded mainly through the re-face of the carbonyl
group, a preference which is clearly modulated by the pres-
ence of equatorial substituents at C-3. The poorer diastere-
oselectivities found in acyldioxanes 3a and 3d, as compared
stirred for an additional 1.5 h. Excess THF was eliminated
in a rotary evaporator, the residue was extracted with
CH Cl (2 · 60 mL) and the organic layer was dried with
2
2
anhydrous Na SO , filtered, and evaporated to dryness.
2
4
The solid residue was washed with hexane (2 · 25 mL)
and dissolved in 250 mL of a mixture of hexane–CH Cl
2
2
6
–8
to acyloxathianes 4a and 4b, could be due to the similar
coordinating capability of both dioxane oxygen atoms for
the metal of the nucleophilic reagent. Despite the lower dia-
stereoselectivities obtained, as compared to those obtained
(3:1). The organic layer was washed with water
(5 · 20 mL), dried with anhydrous Na SO , and evapo-
2
4
rated to dryness. The solid was recrystallized from hex-
ane–CHCl , giving 8.75 g (78%) of 3,10-pinanediol 1 as
3
6
–8
using 3-acyl-1,3-oxathianes,
the present results are a
colorless crystals (mp 78–80 ꢁC; R 0.39, hexane–EtOAc
f
2
D
5
1
good approach for improving diastereoselectivities in myrt-
enal-derived acyldioxanes by implementing the proper
structural changes.
9:1). ½aꢁ ¼ þ14:4 (c 0.12, CHCl ). H NMR (CDCl ): d
3
3
4.31 (dt, 1H, J = 9.5, J = 5.1 Hz, H-3), 3.62–3.78 (m, 2H,
H-10a and H-10b), 2.37–2.58 (m, 3H, H-7e, H-2, H-4e),
1
.96 (m, 1H, H-5), 1.89 (br t, 1H, J = 5.5 Hz, H-1), 1.74
ddd, 1H, J = 13.8, 4.8, 2.4 Hz, H-4a), 1.65 (br s, 2H,
OH), 1.21 (s, 3H, Me-9), 1.14 (d, 1H, J = 9.6 Hz, H-7a),
(
4. Experimental
1
3
0
.88 (s, 3H, Me-8). C NMR (CDCl ): d 68.2 (C-3), 67.0
3
0
4
.1. General
(C-1 ), 55.4 (C-2), 43.4 (C-1), 41.8 (C-5), 38.0 (C-6), 37.7
(C-4), 34.1 (C-7), 27.4 (C-9), 23.9 (C-8). IR (CHCl3):
Melting points were determined on an electrothermal cap-
illary melting point apparatus and are uncorrected. Optical
rotations were measured at 589 nm using a 1 dm cell on a
JASCO DIP-370 polarimeter. Infrared spectra were
recorded on a Perkin–Elmer Spectrum 2000 spectrophoto-
3449, 3018, 2934, 1638, 1544, 1427, 1336, 1234, 1137,
ꢀ
1
933, 762, 453 cm . Anal. Calcd for C H O : C, 70.55;
1
0
18
2
H, 10.66. Found: C, 70.41; H, 10.50.
4.3. (1R)-10,10-Dimethylmyrtenol 5d
1
13
meter. H and C NMR spectra were recorded on a Varian
Mercury-300 spectrometer using CDCl3 as solvent and
TMS as the internal standard. Chemical shifts are reported
To a cooled solution (ꢀ78 ꢁC) of 2 g (12.17 mmol) of 10-
1
2
methylmyrtenone in 20 mL of anhydrous THF was
added 1.3 equiv of MeMgBr, and the resulting mixture
was stirred at the same temperature for 2 h under an N2
atmosphere. The crude reaction mixture was poured into
ice-water and was extracted (2 · 70 mL) with CH Cl ,
1
in parts per million (d) downfield from TMS for H, and
relative to the central line of the triplet of CDCl at
3
1
3
7
7.00 ppm for
C. The low-resolution mass spectra
(
LRMS) were recorded on a Varian Saturn 2000 GC/Ion
2
2
Trap Detector, using either EI (70 eV) or CI, as specified.
The high-resolution electron impact mass spectra (HRE-
IMS) were recorded on a VG 7070 high-resolution mass
spectrometer at the UCR Mass Spectrometry Facility, Uni-
versity of California, Riverside, CA. Thin-layer chromato-
grams were done on precoated TLC sheets of silica gel 60
F254 (E. Merck). Flash chromatography was carried out
using Merck silica gel (230–400 mesh). THF used in the
nucleophilic addition reactions was distilled from Na
immediately prior to use, and all other reagents were used
as received.
washed with brine, dried with anhydrous Na SO , filtered,
2 4
and concentrated to dryness. The residue was purified
through column chromatography (hexane–EtOAc 4:1) giv-
ing 1.93 g (88%) of carbinol 5d as a colorless syrup. R 0.36,
f
2
3
1
hexane–EtAOc 4:1. [a] = ꢀ38.3 (c 1.71, MeOH).
H
NMR (CDCl ): d 5.46 (m, 1H, H-3), 2.41 (m, 1H, H-
3
7eq), 2.33 (m, 1H, H-5), 2.26 (m, 2H, H-4eq, H4ax), 2.09
(m, 1H, H-1), 1.48 (s, 1H, OH), 1.30 (s, 3H, Me-9), 1.26–
1.25 (s, 6H, Me-11a, Me-11b), 1.13 (d, 1H, J = 8.8 Hz,
1
3
H-7ax), 0.82 (s, 3H, Me-8). C NMR (CDCl ): d 153.9
3
(C-10), 113.4 (C-3), 72.0 (C-2), 42.7 (C-5), 40.7 (C-1),
37.5 (C-6), 31.7 (C-7), 30.9 (C-4), 27.9 (C-11), 27.6 (C-
4
[
.2. (1S,2R,3S)-2-Hydroxymethyl-6,6-dimethylbicyclo-
3.1.1]heptan-3-ol 1a
12), 26.2 (C-9), 21.2 (C-8). MS m/z (rel. int.): 162
+
(M ꢀ18, 22), 147 (17), 133 (4), 119 (79), 105 (46), 91
(100), 77 (29), 65 (10), 53 (7), 41 (16), 27 (5). HRFABMS
A 500-mL oven-dried two-necked round-bottom flask,
equipped with a pressure-equalizing addition funnel, was
cooled in an ice-water bath and charged with 170 mL of
anhydrous THF and 10 mL (9.7 g, 65.7 mmol) of (1R)-
calcd for C H O+H 181.2945. Found 181.2939.
12 20
4.4. (1S,2R,3S,10S)-2-(1-Hydroxyethyl)-6,6-dimethylbi-
cyclo[3.1.1]heptan-3-ol 1b
(
ꢀ)-myrtenal 2 under a nitrogen atmosphere. A solution
of 13.5 mL of 10–10.2 M (136.4 mmol) BH –Et O in
Obtained as described in Section 4.2, in 50% yield, after
column chromatography, from the hydroboration–oxida-
tion of the epimeric mixture of 5b and 5c, as colorless crys-
3
2
3
0 mL of THF was added dropwise through the addition
funnel during 30 min. The resulting mixture was stirred
at 0–4 ꢁC for 3 h and further 24 h at room temperature.
The mixture was cooled again in an ice-water bath and
2
3
1
tals, mp 105–107 ꢁC. [a] = +30.4 (c 0.21, CHCl ). H
3
NMR (CDCl ): d 4.05 (dt, 1H, J = 10.8, 5.0 Hz, H-3),
3
1
0 mL of water was added dropwise over 30 min and stir-
3.81 (dc, 1H, J = 10.2, 7.0 Hz, H-10eq), 2.60–2.42 (m,

2732
E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
2
1
1
H, H-7eq, H-2), 2.30 (m, 1H, H-4eq), 1.95 (m, 1H, H-1),
0.93 mmol of diols 1a–d and 1.39 mmol of p-TsOH in
25 mL of anhydrous benzene, was placed in an oil bath
and warmed to 74–78 ꢁC. Then, 1.7 mmol of a,a-di-
alkoxyacetal were added dropwise, and the resulting mixture
was stirred at the above temperature under a nitrogen
atmosphere for 3.5 h. The reaction mixture was allowed
to reach room temperature and 40 mL of hexane was
added. The organic layer was washed with 10 mL of a
.75 (m, 2H, H-4a H-5), 1.35 (d, 3H, J = 7.0 Hz, Me-11),
.25 (s, 3H, Me-9), 1.09 (d, 1H, J = 10.5 Hz, H-7ax), 0.90
1
3
(
s, 3H, Me-8). C NMR (CDCl ): d 70.1 (C-3), 66.2
3
0
(
C-1 ), 50.8 (C-2), 42.0 (C-1), 41.6 (C-5), 38.3 (C-4), 37.8
(
C-6), 33.3 (C-7), 27.4 (C-9), 23.9 (C-8), 22.6 (C-11). IR
(
CHCl ): 3604, 3450, 3020, 2990, 2930, 1470, 1244, 1088,
3
ꢀ
1
7
88 cm . The structure of 1b was fully characterized by
single crystal X-ray analysis as shown in Figure 1.
5% aqueous solution of NaHCO , dried with anhydrous
3
Na SO , filtered, and evaporated to dryness in a rotary
2
4
4.5. (1S,2R,3S,10R)-2-(1-Hydroxyethyl)-6,6-dimethylbi-
cyclo[3.1.1]heptan-3-ol 1c
evaporator at 40–45 ꢁC under a reduced pressure. The oily
residue was purified by column chromatography using sil-
ica gel alkalinized with Et N and a mixture of hexane–
3
Obtained as described in Section 4.2, in 30% yield, after
column chromatography, from the hydroboration–oxida-
tion of the epimeric mixture of 5b and 5c, as colorless
EtOAc (99:1) to give acyldioxanes 3a–f.
4.7.2. Method B. In a 100 mL oven-dried two-necked
round-bottom flask equipped with a magnetic stirring
bar, thermometer, and condenser were dissolved 1.8 mmol
of diol 1a–c and 30 mg of camphorsulfonic acid in 6 mL of
benzene under gentle warming. A solution of 3.22 mmol of
2
3
1
needles, mp 58–59 ꢁC. [a] = +25.1 (c 1.0, CHCl ). H
3
NMR (CDCl ): d 4.47 (s, 1H, H-3), 3.84 (m, 1H, H-10),
3
3
.26 (s, 1H, –OH), 3.08 (s, 1H, –OH), 2.49 (m, 1H, H-
4
ec), 2.39 (M, H1-7ec), 1.99–1.90 (m, 2H, H-1, H-5), 1.78
(
m, 1H, H-4ax), 1.74 (m, 1H, H-2), 1.20 (s, 3H, Me-9),
a,a-dialkoxyacetal in 20 mL of CCl was added and the
4
1
0
6
3
.19 (d, 3H, J = 6 Hz, Me-11), 1.09 (d, 1H, J = 10 Hz),
resulting mixture was warmed at 60–62 ꢁC for 48 h. An
additional 0.2 mL (190 mg, 161.0 mmol) of pyruvic alde-
hyde dimethyl acetal was added and stirring continued at
the above temperature for further 24 h. After the reaction
mixture was allowed to reach room temperature, it was fil-
1
3
.89 (s, 3H, Me-8). C NMR (CDCl ): d 72.0 (C-10),
3
8.6 (C-3), 60.9 (C-2), 43.5 (C-1), 41.9 (C-5), 38.2 (C-6),
7.2 (C-4), 34.1 (C-7), 27.8 (C-9), 24.2 (C-8), 22.8 (C-11).
+
MS m/z (rel. int.): 285 (M +1, 0.3), 149 (10), 123 (179),
1
(
6
09 (10), 107 (41), 105 (22), 96 (20), 95 (35), 92 (23), 90
30), 80 (89), 79 (75), 78 (29), 77 (15), 71 (100), 70 (17),
9 (12), 67 (41), 55 (29), 43 (35), 41 (33), 39 (18). HRES-
I/APCI MS calcd for C H O +NH 202.1807. Found
tered through 2 g of silica gel alkalinized with Et N, which
3
was washed with 10 mL of hexane. The crude reaction mix-
ture was evaporated to dryness in a rotary evaporator at
40–45 ꢁC under reduced pressure. The residue was purified
by column chromatography packed with silica gel alkalin-
1
1
20
2
4
2
02.1804.
ized with Et N and using hexane–EtOAc 99:1 as mobile
3
4.6. (1S,2S,3S)-2-(1-Hydroxy-1-methylethyl)-6,6-dimethyl-
bicyclo[3.1.1]heptan-3-ol 1d
phase.
4
.7.3. (1S,2R,5R,7S,9R)-5-Acetyl-10,10-dimethyl-4,6-dioxa-
2
,7
Obtained as described in Section 4.2 in 87% yield by hyd-
tricyclo[7.1.1.0 ]undecane 3a. Obtained using either
roboration–oxidation of 5d, as colorless crystals, mp 60–
method A (38%) or method B (54%). Colorless syrup (Rf
2
3
1
25
6
1 ꢁC. [a] = +33.6 (c 1.28, MeOH). H NMR (CDCl ):
0.33, hexane–EtOAc 10:1). ½aꢁ ¼ ꢀ2:0 (c 0.4, CHCl ).
3
D
3
1
d 4.59 (dt, 1H, J = 7.7, 6.6 Hz, H-3), 3.14 ( s, 1H, OH),
.55 (m, 1H, H-7eq), 2.52 (m, 1H, H-4eq), 2.11 (dd, 1H,
J = 7.7 Hz, H-2), 1.98 (m, 2H, J = 6.6 Hz, H-1, H-5),
.73 (ddd, 1H, J = 13.2, 5.5, 6.6 Hz, H-4ax), 1.28 (s, 3H,
Me-9), 1.23–1.21 (s, 6H, H-11a, H-11b), 1.08 (d, 1H,
H NMR (CDCl ): d 4.97 (s, 1H, H-5), 4.45 (br q, 1H,
3
2
J = 9.3 Hz, H-7), 4.12 (dd, 1H, J = 12.0, 4.0 Hz, H-3eq),
3.80 (t, 1H, J = 12.0 Hz, H-3ax), 2.63 (m, 1H, H-11eq),
0
1
2.46–2.3 (m, 2H, H-8eq, H-2), 2.28 (s, 3H, Me-2 ), 2.14
(m, 1H, H-9), 1.94–1.83 (m, 2H, H-1, H-8ax), 1.30 (s,
3H, Me-13), 1.12 (s, 133H, Me-12), 1.08 (d, 1H,
1
3
J = 9.9 Hz, H-7ax), 0.97 (s, 3H, Me-8). C NMR (CDCl3):
d 74.1 (C-10), 65.6 (C-3), 62.7 (C-2), 44.5 (C-5), 42.5 (C-1),
J = 11.5 Hz, H-11ax).
C NMR (CDCl ): d 201.8
3
3
2
1
1
8.3 (C-6), 37.8 (C-7), 37.1 (C-4), 31.4 (C-9), 28.4 (C-12),
(C@O), 101.9 (C-5), 77.7 (C-7), 73.2 (C-3), 48.6 (C-2)
6.6 (C-11), 26.0 (C-8). IR (CHCl ): 3337, 2929, 1464,
43.7 (C-1), 43.1 (C-9), 40.4 (C-11), 38.9 (C-10), 32.9 (C-
3
ꢀ1
+
0
385, 1367 cm . MS m/z (rel. int.): 180 (M ꢀ18, 0.6),
8), 29.8 (C-13), 25.1 (C-12), 25.0 (C-2 ). IR (CHCl ):
3
65 (2), 147 (2), 137 (6), 129 (14), 107 (26), 95 (23), 79
2925, 1756, 1466, 1353, 1196, 1138, 1090, 996, 932, 881,
ꢀ
1
+
(100), 78 (44), 59 (73), 43 (53), 41 (51), 39 (20), 27 (9).
HRFABMS calcd for C H O +H 199.1698. Found
830, 769, 600 cm . MS m/z (rel. int.) 224 (M , 0.1), 181
(50), 135 (56), 107 (50), 105 (13), 93 (54), 91 (47), 81 (16),
79 (61), 67 (38), 53 (20), 43 (100), 39 (25).
1
2
22
2
1
99.1691.
4
3
.7. General procedure for the preparation of acyldioxanes
a–f
4.7.4. (1S,2R,3S,5R,7S,9R)-5-Acetyl-3,10,10-trimethyl-4,6-
3b. Obtained
2
,7
dioxatricyclo[7.1.1.0 ]undecane
using
2
3
method A (45%) as a colorless syrup. ½aꢁ ¼ ꢀ36 (c 0.15,
D
1
These compounds can be obtained using either of the fol-
lowing methods.
CHCl ). H NMR (CDCl ): d 5.17 (s, 1H, H-5), 4.70 (br
3
3
q, 1H, J = 9.7 Hz, H-7), 4.38 (dq, 1H, J = 6.3, 5.4 Hz, H-
3
), 2.71 (dd, 1H, J = 4.3, 9.7 Hz, H-2), 2.65 (m, 1H, H-
0
4
.7.1. Method A. A 100 mL oven-dried two-necked
11eq), 2.40 (m, 1H, H-8eq), 2.25 (s, 3H, Me-2 ), 2.13 (m,
1H, H-9), 1.85 (m, 2H, H-1, H-8ax), 1.35 (d, 3H,
J = 6.3 Hz, Me-14), 1.28 (s, 3H, Me-13), 1.12 (d, 1H,
round-bottom flask equipped with a Dean–Stark trap
and a magnetic stirring bar, containing a solution of

E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
2733
1
3
J = 7.8 Hz, H-11ax), 1.11 (s, 3H, Me-12). C NMR
4.7.8. (1S,2S,5R,7S,9R)-5-Acetyl-3,3,10,10-tetramethyl-4,6-
2
,7
(
CDCl ): d 202.5 (C@O), 95.9 (C-5), 74.6 (C-3), 70.0 (C-
), 51.5 (C-2), 44.2 (C-1), 43.4 (C-9), 41.5 (C-11), 39.4 (C-
0), 32.8 (C-8), 29.9 (C-13), 25.8 (C-12), 25.0 (C-2 ), 13.4
C-14). IR (CHCl ): 2925, 1721, 1190, 1145, 1088 cm
dioxatricyclo[7.1.1.0 ]undecane 3f. Obtained using meth-
3
25
7
1
(
od B (45%) as a colorless syrup. ½aꢁ ¼ þ16:5 (c 0.34,
D
0
1
CH OH). H NMR (CDCl ): d 5.09 (s,1H, H-5), 4.59 (br
3
3
ꢀ
1
.
q, 1H, J = 9.3 Hz, H-7), 2.67 (m 1H, H-11eq), 2.40 (m,
3
+
0
MS m/z (rel. int.): 237 (M +1, 0.1), 195 (32), 149 (40),
1H, H-8eq), 2.24 (m, 1H, H-2), 2,21 (s, 3H, Me-2 ), 2.11
1
07 (63), 91 (37), 79 (57), 43 (100).
(q, 1H, J = 6.1 Hz, H-9), 1.97 (t, 1H, J = 6.0 Hz, H-1),
1.83 (m, 1H, H-8ax), 1.30 (s, 3H, Me-15), 1.28 (s, 6H,
4
dioxatricyclo[7.1.1.0 ]undecane
.7.5. (1S,2R,3R,5R,7S,9R)-5-Acetyl-3,10,10-trimethyl-4,6-
3c. Obtained
Me-13, Me-14), 1.09 (s, 3H, Me-12), 1.08 (d, 1H,
2
,7
13
using
J = 9.6 Hz, H-11ax). C NMR (CDCl ): d 202.8 (C@O),
3
23
method A (63%) as a colorless syrup. ½aꢁ ¼ ꢀ28:4 (c
96.8 (C-5), 78.1 (C-3), 71.0 (C-7), 57.8 (C-2), 43.3 (C-1),
43.2 (C-9), 41.4 (C-11), 39.3 (C-10), 32.9 (C-8), 29.9 (C-
D
1
0
.44, CHCl ). H NMR (CDCl ): d 5.0 (s, 1H, H-5), 4.42
3 3
0
(
2
dd, 1H, H-7), 3.88 (m, 1H, H-3), 2.59 (m, 1H, H-11eq),
.39 (m, 1H, H-8eq), 2.26 (s, 3H, Me-16), 2.12 (m, 1H,
H-9), 2.02 (m, 1H, H-1), 1.89 (m, 2H, H-8ax, H-2), 1.29
13) 29.2 (C-15), 25.5 (C-12), 24.8 (C-2 ), 19.0 (C-14). IR
(CHCl ): 2926, 1736, 1457, 1389, 1234, 1148, 1078,
3
ꢀ
1
919 cm
.
(
3
s, 3H, Me-13), 1.25 (d, 3H, J = 6 Hz, Me-14), 1.10 (s,
H, Me-12), 1.02 (d, 1H, J = 9.6 Hz, H-11ax). C NMR
1
3
4.8. General procedure for the addition of Grignard reagents
to acyldioxanes 3a–e
(
CDCl ): d 202.3 (C-15), 101.9 (C-5), 79.4 (C-3), 76.8 (C-
3
7
1
1
1
2
), 55.3 (C-2), 43.2 (C-9), 43.1 (C-1), 40.2 (C-11), 39.1 (C-
0), 33.1 (C-8), 30.1 (Me-13), 25.4 (Me-12), 30.1 (Me-16),
To a solution of acyldioxanes 3a–f (1 equiv) in anhydrous
THF was added the Grignard reagent (1.5–2 equiv) at
8.7 (Me-14). IR (CHCl ): 2982, 2936, 1744, 1272, 1228,
3
ꢀ
1
+
+
174 cm . MS m/z (rel. int.): 239 (M +1, 66), 316 (M ,
ꢀ78 ꢁC in an N atmosphere. After stirring for 2 h at the
2
.26), 167 (30), 149 (100), 123 (8), 107 (13), 93 (13). HRES-
same temperature, the reaction mixture was allowed to
warm up to room temperature and stirred for a further
1 h. The reaction mixture was quenched with 10 mL of a
saturated solution of ammonium chloride, the THF was
eliminated by evaporation under reduced pressure, and
the remaining emulsion was extracted with ethyl ether.
The organic layer was washed with a saturated solution
of ammonium chloride, dried over anhydrous Na SO , fil-
I/APCI MS calcd for C H O +Na 261.1467. Found
1
4
22
3
2
61.1462.
4
.7.6. (1S,2R,5R,7S,9R)-5-Benzoyl-10,10-dimethyl-4,6-di-
2
,7
oxatricyclo[7.1.1.0 ]undecane 3d. Obtained using method
25
A (60%) as a colorless syrup. ½aꢁ ¼ ꢀ6:3 (c 0.74, CHCl ).
D
3
1
H NMR (CDCl ): d 8.14 (d, 2H, J = 7.1 Hz, H-ortho),
3
2
4
7
.60 (t, 1H, J = 7.4 Hz, H-para); 7.50 (t, 2H, J = 7.3 Hz,
tered, and evaporated to dryness, to give the corresponding
mixture of carbinols as colorless oils. Column chromato-
graphic separations were unsuccessful due to the very close
H-meta), 5.71 (s, 1H, H-5), 4.62 (br q, 1H, J = 9.4 Hz,
H-7), 4.22 (dd, 1H, J = 10.1, 3.7 Hz, H-3eq), 3.94 (t, 1H,
J = 10.1 Hz, H-3ax), 2.64 (m, 1H, H-11eq), 2.69–2.39 (m,
R of the resulting mixture of diastereoisomers; therefore,
f
2
2
H, H-8eq and H-2), 2.16 (m, 1H, H-9), 2.01–1.89 (m,
specific rotations are not reported. Only spectroscopic data
for the major diastereomers 6a–k, 7d, and 7i, obtained
from the spectra of their corresponding mixtures, are
described.
H, H-1 and H-8ax), 1.31 (s, 3H, CH -13), 1.18 (s, 3H,
3
1
3
CH -12), 1.13 (d, 1H, J = 9.8 Hz, H-11ax). C NMR
3
(
CDCl ): d 181.1 (C@O); 133.9 (C-ipso); 133.6 (C-para);
3
1
7
3
1
30.0 (C-ortho); 128.4 (C-meta), 102.0 (C-5), 78.5 (C-7),
0 0 0
(1S,2R,5R,7S,9R,2 R)-5-(2 -Hydroxybut-2 -yl)-
6a.
3.8 (C-3), 48.9 (C-2), 43.9 (C-1), 43.0 (C-9), 40.5 (C-11),
9.0 (C-10), 33.0 (C-8), 30.0 (C-12). IR (CHCl ): 2970,
719, 1595, 1460, 1384, 1255, 1177 cm . Anal. Calcd for
4.8.1.
10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
2
,7
3
ꢀ1
Obtained following the general procedure, compound 3a
(111 mg, 0.49 mmol) in anhydrous THF (10 mL) was trea-
ted with 3 M EtMgBr (0.49 mL, 1.48 mmol) in diethyl
ether. After workup 114 mg (90%) of a diastereoisomeric
mixture of carbinols 6a:7a (49:1) was obtained as a color-
C H O : C, 75.42; H, 7.74. Found: C, 75.29; H, 7.64.
1
8
22
3
4
4
.7.7.
(1S,2R,3S,5R,7S,9R)-5-Benzoyl-3,10,10-trimethyl-
2
,7
,6-dioxatricyclo[7.1.1.0 ]undecane 3e. Obtained using
1
method A (50%) as a colorless crystals, mp 85–86 ꢁC.
less syrup (R 0.44, hexane–EtOAc 9:1). H NMR (CDCl ):
f
3
2
D
8
1
½
aꢁ ¼ ꢀ36:4 (c 0.44, CHCl ). H NMR (CDCl ): d 8.14
d 4.55 (s, 1H, H-5), 4.35 (br q, 1H, J = 9.3 Hz, H-7), 4.02
(dd, 1H, J = 10.1, 3.8 Hz, H-3eq), 3.72 (dd, 1H, J = 10.1,
9.8 Hz, H-3ax), 2.61 (m, 1H, H-11eq), 2.33 (m, 1H, H-
8eq), 2.25–2.08 (m, 3H, H-2, OH, H-9), 1.88–1.80 (m,
3
3
(
d, 2H, J = 8.1 Hz, H-ortho), 7.56 ( t, 1H, J = 6.4 Hz, H-
meta), 7.45 (dd, 2H, J = 8.4, 6.4 Hz, H-para), 5.93 (s, 1H,
H-5), 4.85 (br q, 1H, J = 9.8 Hz, H-7), 4.48 (dq, 1H,
J = 7.1, 5.4 Hz, H-3), 2.89 (dd, 1H, J = 9.8, 5.4 Hz, H-2),
0
0
2H, H-1, H-8ax), 1.58 (m, 2H, H-3 a, H-3 b), 1.27 (s, 3H,
0
2
.68 (m, 1H, H-11eq), 2.44 (m, 1H, H-8eq), 2.25 (m, 1H,
Me-1 ), 1.16 (s, 3H, Me-13), 1.11 (s, 3H, Me-12), 1.04 (d,
H-9), 1.92 (s, 2H, H-1, H-8ax), 1.46 (d, 3H, J = 7.1 Hz,
Me-14), 1.30 (s, 3H, Me-13), 1.18 (d, 1H, J = 10.4 Hz, H-
1H, J = 9.7 Hz, H-11ax), 0.93 (t, 3H, J = 7.5 Hz, CH -
3
0
13
4 ). C NMR (CDCl ): d 106.5 (C-5), 77.4 (C-7), 73.6
3
1
3
0
1
1ax), 1.16 (s, 3H, M-12). C NMR (CDCl ): d 191.5
(C-2 ), 73.1 (C-3), 49.1 (C-2), 43.1 (C-1), 43.4 (C-9), 40.6
(C-11), 39.1 (C-10), 33.3 (C-8), 30.2 (C-1 ), 29.8 (C-3 ),
25.4 (C-12), 21.3 (C-13), 7.7 (C-4 ). IR (CHCl ): 3585,
2936, 1457, 1368, 1140, 1093 cm . MS m/z (rel. int.):
3
0
0
(
C@O), 133.9 (C-ipso). 133.4 (C-meta), 129.9 (C-para),
28.3 (C-ortho), 95.7 (C-5), 75.0 (C-3), 70.7 (C-7), 51.6
C-2), 44.3 (C-1), 43.4 (C-9), 41.5 (C-11), 39.4 (C-10),
2.8 (C-8), 29.9 (C-13), 25.8 (C-12), 13.4 (C-14). Anal.
Calcd for C H O : C, 75.97; H, 8.05. Found: C, 75.97;
0
1
(
3
3
ꢀ
1
+
254 (M +1, 1), 153 (24), 135 (100), 125 (14), 107 (12), 93
(8). HRCIMS calcd for C H O +NH 272.2226. Found
1
9
24
3
15 26
3
4
H, 8.14.
272.2227.

2734
E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
0
0
0
4
2
6
3
.8.2. (1S,2R,5R,7S,9R,2 R)-5-(3 -Methyl-2 -hydroxybut-
and the residue extracted with 70 mL of ethyl ether. The or-
ganic layer was washed with 5% aq HCl (3 · 30 mL) and
brine (1 · 30 mL), dried over anhyd Na SO , filtered, and
evaporated to dryness. The crude reaction outcome was
purified through a Chromatotron system using a mixture
of hexane–EtOAc (99:1) as the eluent to give 154 mg
(95%) of a mixture of 6d:7d (7:3) as a colorless syrup.
0
2,7
-yl)-10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
b. Obtained following the general procedure, compound
a (174 mg, 0.77 mmol) in anhydrous Et O (10 mL) was
treated with freshly prepared iPrMgBr (1.54 mmol) in
diethyl ether. After workup 179 mg (86%) of a diastereoiso-
meric mixture of carbinols 6b:7b (9:1) was obtained as a
colorless syrup (R 0.33, hexane–EtOAc 9:1). H NMR
2
4
2
1
f
(
CDCl ): d 4.65 (s, 1H, H-5), 4.36 (br q, 1H, J = 9.6 Hz,
4.8.4.2. Method B. Following the general procedure
described in 4.8, the addition of PhMgBr on acetyldioxane
3a gave an 82% of a mixture of 6d:7d (89:11) as a colorless
3
H-7), 4.04 (dt, 1H, J = 9.9, 3.3 Hz, H-3eq), 3.72 (br t,
1
1
J = 5.6 Hz, H-9), 1.95 (m, 1H, H-3 ), 1.90–1.80 (m, 2H,
H-1, H-8a), 1.27 (s, 3H, Me-1 ), 1.12 (s, 3H, Me-13), 1.10
(
J = 6.9 Hz, CH -4 ), 0.91 (d, J = 6.9 Hz, CH -5 ).
NMR (CDCl ): d 105.3 (C-5), 77.6 (C-7), 75.4 (C-2 ),
7
1
H, J = 10.0 Hz, H-3ax), 2.58 (m, 1H, H-11eq), 2.33 (m,
1
H, H-8eq), 2.26–2.16 (m, 2H, OH, H-2), 2.11 (br q, 1H,
syrup (R 0.37, hexane–EtOAc 9:1). H NMR (CDCl ): d
f
3
0
7.55 (d, 2H, J = 8.6 Hz, H-ortho), 7.34 (dd, 2H, J = 8.6,
7.2 Hz, H-meta), 7.27 (t, 1H, J = 7.2 Hz, H-para), 4.85
(s, 1H, H-5), 4.36 (br q, 1H, J = 9.4 Hz, H-7), 4.01 (dd,
1H, J = 10.0, 3.7 Hz, H-3eq), 3.69 (dd, 1H, J = 11.3,
10.2 Hz, H-3ax), 3.04 (s, 1H, OH), 2.58 (m, 1H, H-11eq),
2.40–2.20 (m, 2H, H-2, H-8eq), 2.11 (br q, 1H,
J = 5.6 Hz, H-9), 1.85 (m, 2H, H-8ax, H-1), 1.56 (s, 3H,
0
s, 3H, Me-12), 1.04 (d, 1H, J = 9.6 Hz, H-11ax), 0.96 (d,
0
0
13
C
3
3
0
3
3.2 (C-3), 49.2 (C-2), 44.0 (C-1), 43.4 (d, C-9), 40.7 (C-
0
0
1), 39.2 (C-10), 33.3 (C-8), 33.2 (C-3 ), 30.2 (C-1 ), 25.4
0
0
0
(
C-13), 18.1 (C-12), 17.0 (C-4 ), 16.9 (C-5 ). IR (CHCl ):
Me-2 ), 1.27 (s, 3H, Me-13), 1.09 (s, 3H, Me-12), 1.05 (d,
3
ꢀ
1
13
3
584, 2936, 1466, 1367, 1091, 919 cm . MS m/z (rel.
1H, J = 9.7 Hz, H-11ax). C NMR (CDCl ): d 144.6 (C-
3
+
int.): 269 (M +1, 0.1), 251 (1), 225 (3), 181 (37), 153 (8),
35 (98), 107 (41), 93 (52), 82 (100), 67 (22), 43 (25). HRE-
SIMS calcd for C H O +Na 291.1936. Found 291.1949.
ipso), 127.8 (C-meta), 126.7 (C-para), 125.5 (C-ortho),
0
1
106.1 (C-5), 77.2 (C-7), 74.8 (C-1 ), 73.0 (C-3), 48.7 (C-2),
43.7 (C-9), 43.1 (C-1), 40.3 (C-11), 38.9 (C-10), 32.9 (C-
1
6
28
3
0
8
), 29.9 (C-13), 25.1 (C-12), 25.0 (C-2 ). IR (CHCl ):
3
0
0
0
ꢀ1
4
2
6
3
.8.3. (1S,2R,5R,7S,9R,2 R)-5-(4 -Methyl-2 -hydroxypent-
3585, 2927, 1495, 1447, 1367, 1091, 699 cm . MS m/z
0
2,7
-yl)-10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
+
(rel. int.): 301 (M ꢀ1, 1), 285 (7), 181 (4), 135 (100), 133
c. Obtained following the general procedure, compound
a (148 mg, 0.66 mmol) in anhydrous THF (10 mL) was
(28), 107 (11), 93 (11), 67 (14), 55 (14). HRCIMS calcd
for C H O +NH 320.2226. Found 320.2228.
1
9
26
3
4
treated with iBuMgBr (0.99 mL, 1.98 mmol) in diethyl
ether. After workup 130 mg (70%) of a diastereoisomeric
mixture of carbinols 6c:7c (85:15) was obtained as a color-
0
0
4.8.5. (1S,2R,5R,7S,9R,2 R)-5-(2 -Hydroxy-3-phenylpro-
0
2,7
pane-2 -yl)-10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]unde-
cane 6e. Obtained following the general procedure,
compound 3a (210 mg, 0.93 mmol) in anhydrous THF
1
less syrup (R 0.39, hexane–EtOAc 9:1). H NMR (CDCl ):
f
3
d 4.49 (s, 1H, H-5), 4.34 (br q, 1H, J = 9.4 Hz, H-7), 4.02
dd, 1H, J = 10.0, 3.7 Hz, H-3eq), 3.71 (dd, 1H, J = 11.3,
(
(12 mL) was treated with PhCH MgCl (1.40 mL,
2
1
8
3
0.1 Hz, H-3ax), 2.58 (m, 1H, H-11eq), 2.33 (m, 1H, H-
eq), 2.25–2.15 (m, 3H, H-2, OH, H-9), 1.92–1.78 (m,
2.81 mmol) in diethyl ether. After workup 216 mg (73%)
of a diastereoisomeric mixture of carbinols 6e:7e (4:1)
0
0
0
H, H-1, H-8ax, H-4 ), 1.45 (m, 2H, H-3 a, H-3 b), 1.27
was obtained as a colorless syrup (R 0.39, hexane–EtOAc
f
0
1
(
s, 3H, CH -1 ), 1.19 (s, 3H, Me-13), 1.11 (s, 3H, Me-12),
9:1). H NMR (CDCl ): d 7.27 (m, 5H, Ar-H), 4.48 (s, 1H,
3
3
1
.05 (d, 1H, J = 9.7 Hz, H-11ax), 0.98 (d, 3H, J = 6.6 Hz,
H-5), 4.31 (br q, 1H, J = 9.4 Hz, H-7), 4.06 (dd, 1H,
0
0
13
CH -5 ), 0.95 (d, 3H, J = 6.7 Hz, CH -6 ). C NMR
J = 9.9, 3.9 Hz, H-3eq), 3.71 (dd, 1H, J = 11.2, 10.1 Hz,
3
3
0
0
(
CDCl ): d 106.9 (C-5), 77.2 (C-7), 73.8 (C-2 ), 72.9
H3ax), 2.85 (d, 1H, J = 13.5 Hz, H-3 a), 2.82 (d, 1H,
3
0
0
(
C-3), 48.9 (C-2), 44.9 (C-3 ), 43.8 (C-1), 43.2 (C-9), 40.4
J = 13.5 Hz, H-3 b), 2.59 (m, 1H, H-11eq), 2.29–2.19 (m,
0
(C-11), 38.9 (C-10), 33.0 (C-8), 29.9 (C-1 ), 25.1 (C-12), 25.1
3H, H-8eq, OH, H-2), 2.11 (m, 1H, H-9), 1.85 (m, 2H,
0
0
0
0
(
C-6 ), 24.5 (C-5 ), 23.5 (C-4 ), 21.8 (C-13). IR (CHCl ):
H-1, 8ax), 1.27 (s, 3H, Me-1 ), 1.14 (s, 3H, Me-13), 1.09
3
ꢀ
1
13
3
585, 2950, 1466, 1367, 1092, 958 cm . MS m/z (rel.
(s, 3H, Me-12), 1.04 (d, 1H, J = 9.8 Hz, H-11ax).
C
+
int.): 282 (M ꢀ1, 2), 181 (41), 135 (100), 107 (41), 93
48), 82 (76), 79 (39), 67 (13), 57 (10), 43 (13). HRESIMS
calcd for C H O +Na 305.2092. Found 305.2102.
NMR (CDCl ): d 137.6 (C-ipso), 131.0 (C-meta), 128.1
3
(
(C-ortho), 126.4 (C-para), 105.8 (C-5), 77.5 (C-7), 73.7
0
(C-2 ), 73.1 (C-3), 49.1 (C-2), 44.0 (C-1), 43.4 (C-9), 43.3
(
3
0
30
3
0
0
C-3 ), 40.7 (C-11), 39.2 (C-10), 33.3 (C-8), 30.2 (C-1 ),
0
0
0
2,7
4
1
6
.8.4. (1S,2R,5R,7S,9R,1 R)-5-(1 -Hydroxy-1 -phenyleth-
25.4 (C-12), 22.1 (C-13). IR (CHCl ): 3501, 2924, 1492,
3
0
ꢀ1
-yl)-10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
d. This compound was prepared according to the fol-
1454, 1367, 1140, 701 cm . MS m/z (rel. int.): 298
+
(M ꢀ18, 1), 224 (3), 135 (100), 107 (39), 91 (37), 67 (20),
lowing procedures.
43 (13), 41 (12), 39 (14). HRCIMS calcd for C H O +
2
0
28
3
NH 334.2382. Found 334.2389.
4
4
.8.4.1. Method A. A well-stirred cooled (ꢀ78 ꢁC)
0
0
0
0
solution of 120 mg (0.53 mmol) of acetyloxathiane 3a in
mL of anhydrous THF was treated with 0.89 mmol of
.8 M PhLi in cyclohexane and stirred under an N atmo-
4.8.6. (1S,2R,5R,7S,9R,2 R)-5-(2 -Hydroxy-3 -buten-2 -yl)-
6f.
2
10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
,7
8
1
Obtained following the general procedure, compound 3a
2
sphere for 2 h. The mixture was quenched with 1.5 mL of a
saturated soln. of ammonium chloride and allowed to
warm up to room temperature. The THF was evaporated
(120 mg, 0.53 mmol) in anhydrous THF (10 mL) was trea-
ted with CH @CHMgBr (1.60 mL, 1.52 mmol) in diethyl
2
ether. After workup 114 mg (85%) of a diastereoisomeric

E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
2735
mixture of carbinols 6f:7f (4:1) was obtained as a colorless
ized with triethylamine and a mixture of hexane–EtOAc
19:1 as eluent, yielding 172 mg (95%) of carbinols 6h:7h
(1:1) as a colorless syrup.
1
syrup (R 0.39, hexane–EtOAc 9:1). H NMR (CDCl ): d
f
3
0
.06 (dd, 1H, J = 17.4, 10.8 Hz, H-3 ), 5.38 (d, 1H,
6
0
0
J = 17.3 Hz, H-4 ), 5.15 (d, 1H, J = 10.8 Hz, H-4 ), 4.58
s, 1H, H-5), 4.36 (br q, 1H, J = 9.3 Hz, H-7); 4.04 (dd,
H, J = 10.8, 3.6 Hz, H-3eq), 3.72 (dd, 1H, J = 10.8 Hz,
H-3ax), 2.58 (m, 1H, H-11eq), 2.46 (br s, 1H, OH), 2.33
(
4.8.8.2. Method B. To a cooled (ꢀ78 ꢁC) solution of
120 mg (0.53 mmol) of acetyldioxane 3a in 10 mL of
1
MeOH was added 60 mg (1.58 mmol) of NaBH and the
4
(
1
1
m, 1H, H-8eq), 2.20 (m, 1H, H-2), 2.10 (m, 1H, H-9),
resulting mixture was stirred for 3 h. The reaction was
0
.86–1.80 (m, 2H, H-1 and H-8a), 1.28 (s, 3H, Me-1 ),
.27 (s, 3H, Me-13), 1.10 (s, 3H, Me-12), 1.04 (d, 1H,
quenched with 10 mL of a saturated solution of NH Cl,
4
stirred for 30 min, then methanol was added and the sol-
vents were evaporated. The crude reaction mixture was ex-
1
3
0
J = 9.6 Hz, H-11ax). C NMR (CDCl ): d 140.9 (C-3 ),
3
0
0
1
3
1
13.2 (C-4 ), 106.1 (C-5), 77.3 (C-7), 73.0 (C-2 ), 72.0 (C-
tracted with Et O (3 · 50 mL) and the solution washed
2
), 48.8 (C-2), 43.7 (C-1), 43.2 (C-9), 40.3 (C-11), 38.9 (C-
with water. The organic layer was dried with anhydrous
Na SO , filtered, and evaporated to dryness. The residue
0
1
0), 32.9 (C-8), 29.9 (C-13), 25.1 (C-12), 22.8 (C-1 ). IR
2
4
ꢀ
(
CHCl ): 3501, 2930, 1456, 1368, 1140, 1091 cm . MS
was purified by column chromatography (silica gel 230–
400 mesh) using hexane–AcOEt (99:1) as eluent, giving
172 mg (93%) of carbinols 6h:7h (1:1) as a colorless syrup.
3
+
m/z (rel. int.): 252 (M , 1), 234 (1), 181 (11), 136 (12),
35 (100), 107 (73), 93 (75), 82 (90), 67 (86), 55 (35), 43
55), 41 (40), 39 (39). HRCIMS calcd for C H O +H
1
(
1
(R 0.14, hexane–EtOAc 9:1). H NMR (CDCl ): d 4.57 (d,
1
5
24
3
f
3
2
53.1804. Found 253.1795.
1H, J = 2.3 Hz, H-5), 4.42 (br q, 1H, J = 9.3 Hz, H-7), 4.03
0
(dd, 1H, J = 9.9, 3.5 Hz, H-3eq), 3.74 (m, 1H, H-1 ), 3.73
0
0
0
4
1
.8.7. (1S,2R,5R,7S,9R,2 R)-5-(2 -Hydroxy-3-pentin-2 -yl)-
6g.
(t, 1H, J = 9.9 Hz, H-3ax), 2.58 (m, 1H, H-11eq), 2.36
(m, 2H, H-8eq, OH), 2.22 (m, 1H, H-2), 2.11 (br q, 1H,
J = 5.5 Hz, H-9), 1.89–1.75 (m, 2H, H-1 and H-8a), 1.28
2
0,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
,7
Obtained following the general procedure, compound 3a
149 mg, 0.61 mmol) in anhydrous THF (10 mL) was trea-
0
1
(
(s, 3H, Me-13), 1.21 (d, 3H, J = 6.3 Hz, Me-2 ), 1.11 (s,
3
ted with 0.5 M CH CCMgBr (3.69 mL, 1.84 mmol) in
diethyl ether. After workup 141 mg (80%) of a diastereoiso-
3H, Me-12), 1.04 (d, 1H, J = 9.6 Hz, H-11a). C NMR
3
0
(CDCl ): d 105.4 (C-5), 77.5 (C-7), 73.1 (C-1 ), 68.9 (C-
3
meric mixture of carbinols 6g:7g (83:17) was obtained as a
3), 49.2 (C-2), 44.0 (C-1), 43.4 (C-9) 40.7 (C-11), 39.2 (C-
1
0
colorless syrup (R 0.39, hexane–EtOAc 9:1). H NMR
10), 33.2 (C-8), 30.2 (C-13), 25.4 (C-12), 17.7 (C-2 ). IR
f
ꢀ
1
(
CDCl ): d 4.63 (s, 1H, H-5), 4.39 (br q, 1H, J = 9.4 Hz,
(CHCl ): 3479, 2928, 1456, 1367, 1141, 1091 cm . MS
3
3
+
H-7), 4.10 (dd, 1H, J = 10.0, 3.7 Hz, H-3eq), 3.80 (dd,
m/z (rel. int.): 225 (M ꢀ1, 1), 181 (5), 153 (14), 135
1
H, J = 11.3, 10.2 Hz, H-3ax), 2.80 (s, 1H, OH), 2.60 (m,
(100), 107 (32), 93 (23), 82 (30), 67 (27), 55 (9), 41 (16).
HRCIMS calcd for C H O +NH 244.1913. Found
1
H, H-11eq), 2.41–2.21 (m, 2H, H-2 and H-8eq), 2.12 (br
1
3
22
3
4
q, 1H, J = 5.5 Hz, H-9), 1.96–1.83 (m, 2H, H-1, 8ax);
244.1913.
0
0
1
1
1
.86 (s, 3H, Me-5 ), 1.47 (s, 3H, Me-1 ), 1.28 (s, 3H, Me-
0
0
0
3), 1.11 (s, 3H, Me-12), 1.07 (d, 1H, J = 9.7 Hz, H-
4.8.9. (1S,2R,3S,5R,7S,9R,1 R)-5-(1 -Hydroxy-1 -phenyl-
1
3
0
0
2,7
1ax). C NMR (CDCl ): d 105.3 (C-5), 80.5 (C-3 ), 80.5
eth-1 -yl)-3,10,10-trimethyl-4,6-dioxatricyclo[7.1.1.0 ]unde-
cane 6i. Obtained following the general procedure, com-
pound 3b (110 mg, 0.46 mmol) in anhydrous THF (10 mL)
was treated with 1 M PhMgBr (1.15 mL, 1.15 mmol) in
diethyl ether. After workup 131 mg (90%) of a diastereoiso-
3
0
0
(
C-4 ), 77.5 (C-7), 73.4 (C-3) 69.3 (C-2 ), 48.8 (C-2), 43.9
(
3
C-1), 43.4 (C-9), 40.5 (C-11), 39.2 (C-10), 33.1 (C-8),
0 0
0.4 (C-13), 25.4 (C-12), 25.1 (C-1 ), 4.2 (C-5 ). IR
(
CHCl ): 3501, 2920, 2250, 1456, 1367, 1141, 1092. MS
3
+
m/z (rel. int.): 263 (M ꢀ1, 3), 247 (3), 181 (35), 135
meric mixture of carbinols 6i:7i (22:3) was obtained as a
colorless oil. H NMR (CDCl ): d 7.50 (d, 2H, J =
1
(
100), 107 (49), 93 (61), 82 (89), 79 (53), 67 (31), 69 (32),
3
4
3 (19). HRESIMS calcd for C H O +Na 287.1623.
8.3 Hz, H-ortho), 7.30 (dd, 2H, J = 8.3, 6.2 Hz, H-meta),
1
6
24
3
Found 287.1619.
7.22 (d, 1H, J = 6.2 Hz, H-para), 5.14 (s, 1H, H-5), 4.70
(
br q, 1H, J = 9.3 Hz, H-7), 4.43 (dq, 1H, J = 6.9,
0
0
0
4
1
.8.8. (1S,2R,5R,7S,9R,1 S)-5-(1 -Hydroxyethane-1 -yl)-10,
5.4 Hz, H-3e), 2.61 (m, 2H, H-11e, H-2), 2.31 (m, 1H, H-
8e), 2.09 (m, 1H, H-9), 1.80 (m, 2H, H-8a, H-1), 1.50 (s,
3H, Me-2 ), 1.24 (s, 3H, Me-13), 1.22 (d, 3H, J = 6.9 Hz,
Me-14), 1.10 (d, 1H, J = 11.7 Hz, H-11a), 1.09 (s, 3H,
Me-12). C NMR (CDCl ): d 144.9 (C-ipso), 127.7 (C-
2
,7
0-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane 6h. This
compound was prepared according to the following
procedures.
0
1
3
3
4
.8.8.1. Method A. To a cooled (ꢀ78 ꢁC) suspension of
meta), 126.6 (C-para), 125.5 (C-ortho), 99.4 (C-5), 74.9
(C-3), 74.1 (C-1 ), 69.7 (C-7), 51.5 (C-2), 44.1 (C-1), 43.3
0
6
0 mg (1.58 mmol) of LiAlH in 5 mL of anhydrous THF
4
and under an N atmosphere was added a solution of
(C-9), 41.4 (C-11), 39.4 (C-10), 32.7 (C-8), 29.9 (C-13),
2
0
1
80 mg (0.80 mmol) of dioxane 3a in 5 mL of anhydrous
25.7 (C-12), 25.0 (C-2 ), 13.6 (C-14). MS m/z (rel. int.):
+
THF, and the resulting mixture was stirred at the above
temperature for 3 h. Then, 10 mL of a saturated solution
of ammonium chloride was added, the remaining THF
was evaporated and the crude reaction mixture was ex-
tracted (3 · 30 mL) with ethyl ether. The organic layer
was washed with brine, dried with anhydrous Na SO , fil-
315 (M , 0.1), 195 (33), 149 (54), 121 (34), 107 (100), 93
(33), 79 (47), 77 (25), 67 (15), 43 (73), 39 (7).
0
0
0
4.8.10. (1S,2R,5R,7S,9R,1 S)-5-(1 -Hydroxy-1 -phenyleth-
0
2,7
1 -yl)-10,10-dimethyl-4,6-dioxatricyclo[7.1.1.0 ]undecane
7d. Obtained following the general procedure, compound
3d (100 mg, 0.35 mmol) in anhydrous THF (10 mL) was
treated with MeMgBr (0.17 mL, 0.52 mmol) 3 M in diethyl
2
4
tered, and evaporated to dryness. The residue was purified
through column chromatography using silica gel alkalin-

2736
E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
ether. After workup 103 mg (98%) of a diastereoisomeric
mixture of carbinols 6d:7d (13:87) was obtained as a color-
less oil. A small amount of 7d was obtained as a white solid
76.5 (C-7), 75.0 (C-15), 55.4 (C-2), 43.3 (C-9), 43.1 (C-1),
40.1 (C-11), 39.1 (C-10), 33.2 (C-8), 30.2 (Me-13), 25.4
(Me-12), 24.7 (Me-16), 18.8 (Me-14). IR (CHCl ): 3494,
3
1
by crystallization from CH Cl –hexane, mp 75–76 ꢁC. H
2934, 1496, 1448, 1366, 1338, 1266, 1222, 1134, 1094,
2
2
ꢀ
1
+
NMR (CDCl ): d 7.5 (d, 2H, J = 8.4 Hz, H-ortho), 7.32
796 cm . MS m/z (rel. int.): 316 (M , 0.38), 299 (7), 195
(9), 165 (12), 149 (75), 121 (24), 107 (100), 105 (15), 93
(35), 91 (12), 79 (33), 43 (14). HRESI/APCI MS calcd for
C H O +Na 339.1936. Found 339.1935.
3
(
t, 2H, J = 8.4 Hz, H-meta), 7.27 (d, 1H, J = 8.4 Hz, H-
para); 4.79 (s, 1H, H-5), 4.35 (br q, 1H, J = 9.4 Hz, H-7),
.99 (dd,1H, J = 10.0, 3.7 Hz, H-3eq), 3.66 (t, 1H,
J = 10.0 Hz, H-3a), 2.91 (br s, 1H, OH), 2.56 (m, 1H, H-
3
2
0
28
3
0 0 0
4.8.13. (1S,2R,5R,7S,9R,1 R)-5-(1 -Hydroxy-1 -phenyleth-
1
1
1eq), 2.5 (m, 2H, H-2 and H-8eq), 2.08 (m, 1H, H-9),
0
0
2,7
.83 (m, 2H, H-8a and H-1), 1.56 (s, 3H, CH -2 ), 1.25
1 -yl)-3,3,10,10-tetramethyl-4,6-dioxatricyclo[7.1.1.0 ]und-
ecane 6k. Obtained using either procedure described in
Section 4.8.4.1 or 4.8.4.2. An enriched sample of 6k was
obtained by using the latter procedure as follows: com-
pound 3f (140 mg, 0.55 mmol) in anhydrous THF
(10 mL) was treated with 1 M PhMgBr (1.23 mL,
1.23 mmol) in diethyl ether. After workup 172 mg (95%)
3
(
s, 3H, CH -13), 1.06 (s, 3H, CH -12), 1.02 (d, 1H,
3 3
3
1
J = 9.6 Hz, H-11ax). C NMR (CDCl ): d 144.3 (C-ipso),
3
1
5
9
27.8 (C-meta), 126.9 (C-para), 126.0 (C-ortho), 106.5 (C-
), 77.1 (C-7), 75.0 (C-1 ), 73.0 (C-3), 48.9 (C-2), 43.8 (C-
0
), 43.3 (C-1), 40.6 (C-11), 39.0 (C-10), 33.2 (C-8), 30.0
0
(
q, C-2 ), 25.2 (q, C-12), 24.4 (q, C-13). IR (CHCl ):
3
ꢀ
1
3
450, 2930, 1603, 1450, 1370, 1140, 1090, 1005, 700 cm
.
of a diastereoisomeric mixture of carbinols 6k:7k (77:23)
1
MS m/z (rel. int.): 302 (M+1, 0.1); 181 (47); 135 (60); 122
8); 120 (75); 105 (80); 93 (70); 91 (64); 79 (100); 67 (50);
was obtained as a colorless oil. H NMR (CDCl ): d 7.54
3
(
(d, 2H, J = 8,47 Hz, H-ortho), 7.31 (dd, 2H, J = 7.04,
5
5 (30).
8.76 Hz, H-meta), 7.24 (d, 1H, J = 7.24 Hz, H-para), 4.92
(
s, 1H, H-5), 4.47 (br q, 1H, J = 8.70 Hz, H-7), 3.07 (s,
0
0
0
4
.8.11. (1S,2R,3S,5R,7S,9R,1 S)-5-(1 -Hydroxy-1 -phenyl-
1H, OH), 2.62 (m, 1H, H-11e), 2.30 (m, 1H, H-8e), 2.09
(m, 2H, H-2, H-9), 1.92 (t, 1H, J = 6.98 Hz, H-1), 1.78
(m, 1H, H-8a), 1.52 (s, 3H, Me-2 ), 1.24 (s, 3H, Me-15),
1.19 (s, 6H, Me-13, Me-14), 1.05 (d, 1H, J = 9.6 Hz, H-
11a), 1.04 (s, 3H, Me-12). C NMR (CDCl ): d 145.2
(C-ipso) 127.9 (C-meta), 126.8 (C-para), 126.2 (C-ortho),
100.5 (C-5), 77.5 (C-3), 74.9 (C-1 ), 71.1 (C-7), 58.1 (C-2),
43.6 (C-1), 43.5 (C-9), 41.7 (C-11), 39.6 (C-10), 33.2 (C-
0
2,7
eth-1 -yl)-3,10,10-trimethyl-4,6-dioxatricyclo[7.1.1.0 ]unde-
cane 7i. Obtained following the general procedure, com-
pound 3e (130 mg, 0.43 mmol) in anhydrous THF (10 mL)
was treated with MeMgBr (0.23 mL, 0.69 mmol) in diethyl
ether. After workup 120 mg (88%) of a diastereoisomeric
mixture of carbinols 6i:7i (11:89) was obtained as a color-
less oil. H NMR (CDCl ): d 7.52 (d, 2H, J = 8.3 Hz, H-
0
1
3
3
0
1
3
0
ortho), 7.33 (dd, 2H, J = 8.3, 6.2 Hz, H-meta), 7.25 (d,
8), 30.3 (C-15), 29.6 (C-13) 25.9 (C-12), 24.6 (C-2 ), 19.6
(C-14). MS m/z (rel. int.): 330 (M , 0.28), 163 (46), 135
(16), 121 (51), 107 (72), 91 (68), 79 (100), 67 (48).
+
1
1
3
1
1
H, J = 6.2 Hz, H-para), 5.06 (s, 1H, H-5), 4.62 (br q,
H, J = 9.4 Hz, H-7), 4.26 (dq, 1H, J = 7.0, 5.3 Hz, H-
e), 2.96 (s, 1H, OH), 2.62 (m, 2H, H-11e, H-2), 2.32 (m,
H, H-8e), 2.08 (m, 1H, H-9), 1.81 (m, 2H, H-8a, H-1),
4.9. General procedure for the hydrolysis of carbinols 6d and
7d
0
.53 (s, 3H, Me-2 ), 1.26 (s, 3H, Me-13), 1.25 (d, 3H,
J = 7.0 Hz, Me-14), 1.11 (d, 1H, J = 11.8 Hz, H-11a),
1
3
1
1
5
1
.08 (s, 3H, Me-12). C NMR (CDCl ): d 144.5 (C-ipso),
To a solution of carbinols 6d or 7d (0.33 mmol) in 10 mL of
CH CN–H O (9:1) was added 10 mg of p-TsOH and the
resulting mixture was stirred for 1 h. Then, 5 mL of a sat-
3
27.7 (C-meta), 126.7 (C-para), 125.8 (C-ortho), 99.7 (C-
), 75.0 (C-1 ), 73.9 (C-3), 69.8 (C-7), 51.6 (C-2), 44.1 (C-
), 43.3 (C-9), 41.5 (C-11), 39.3 (C-10), 32.8 (C-8), 29.9
C-13), 25.8 (C-12), 24.9 (C-2 ), 13.8 (C-14). MS m/z (rel.
int.): 315 (M , 0.1), 195 (33), 149 (54), 121 (34), 107
100), 93 (33), 79 (47), 77 (25), 67 (15), 43 (73), 39 (7).
3
2
0
urated solution of NaHCO was added and the mixture
3
0
(
stirred for 15 min. The organic layer was separated, the
aqueous layer was extracted with ethyl ether (3 · 20 mL)
and the combined organic layers were dried with anhy-
drous Na SO , filtered, and concentrated to dryness to give
+
(
2
4
0
0
0
1
4
.8.12. (1S,2R,3R,5R,7S,9R,1 R)-5-(1 -Hydroxy-1 -phenyl-
a colorless oil, whose H NMR spectrum showed the pres-
ence of aldehydes (R)-8a and (S)-8b. The crude reaction
mixture was submitted to reduction without further
purification.
0
2,7
eth-1 -yl)-3,10,10-trimethyl-4,6-dioxatricyclo[7.1.1.0 ]unde-
cane 6j. Obtained following the general procedure, com-
pound 3c (450 mg, 1.88 mmol) in anhydrous THF (20 mL)
was treated with PhMgBr (1.25 mL, 3.77 mmol) in diethyl
ether. After workup 537 mg (90%) of a diastereoisomeric
mixture of carbinols 6j:7j (67:33) was obtained as a color-
less oil. H NMR (CDCl ): d 7.54 (m, 2H, H-ortho), 7.32
4.10. General procedure for the preparation of diols 9a and
9b
1
3
(
5
2
m, 2H, H-meta), 7.23 (m, 1H, H-para), 4.79 (s, 1H, H-
), 4.32 (dd, 1H, J = 17, 9 Hz, H-7), 3.76 (m, 1H, H-3),
.96 (s, 1H, –OH), 2.56 (m, 1H, H-11eq), 2.29 (m, 1H,
The above crude reaction mixture was dissolved in anhy-
drous ethyl ether, cooled in an ice-water bath, treated with
4 equiv of LiAlH , and the resulting mixture stirred for
4
H-8eq), 2.07 (q, 1H, J = 5 Hz, H-9), 1.98 (t, 1H,
J = 6 Hz, H-1), 1.80 (m, 2H, H-8ax, H-2), 1.55 (s, 3H,
Me-16), 1.25 (s, 3H, Me-13), 1.17 (d, 3H, J = 6 Hz, Me-
1.5 h at room temperature. After the usual workup, a mix-
ture of pinanediol 1 and diols (S)-9a, or (R)-9b, was ob-
tained, which was separated by column chromatography
using hexane–EtOAc (5:1) as the mobile phase, giving the
title diols in 66–74% yield. All spectroscopic data of diols
(S)-9a and (R)-9b are in agreement with the published
1
4), 1.04 (s, 3H, Me-12), 0.99 (d, 1H, J = 10 Hz, H-11ax).
1
3
C NMR (CDCl ): d 144.6 (C-ipso), 127.8 (C-ortho),
3
1
26.9 (C-para), 126.1 (C-meta), 105.8 (C-5), 78.5 (C-3),

E. Becerra-Mart ı´ nez et al. / Tetrahedron: Asymmetry 18 (2007) 2727–2737
2737
data.13 Lit.13 ½aꢁ ¼ ꢀ5:8 (c 0.17, EtOH) for (R)-9b. Data
23
D
1.73–28.00ꢁ, unique reflections: 2538, observed reflections:
1603 with [I > 2r(I)], R = 8.2%, CCDC deposition no.
663931. Crystallographic data are deposited with the Cam-
bridge Crystallographic Data Center. Copies of the data
can be obtained, free of charge, on applications to the
Director, CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK. Fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk.
2
D
5
for (S)-9a: ½aꢁ ¼ þ4:1 (c 0.18, EtOH) obtained from mix-
25
ture 6d:7d (Table 1, entry 13). Data for (R)-9b: ½aꢁ ¼ ꢀ4:3
D
(
c 0.16, EtOH) obtained from a mixture of 6d:7d (Table 1,
25
entry 4) and ½aꢁ ¼ ꢀ3:2 (c 0.14, EtOH) from a mixture of
D
6
j:7j (Table 1, entry 15).
4
.11. X-ray analysis of 1a–c, 3e, and 7d
Crystal data were collected on a Siemens P4 diffractometer
using Mo Ka monochromated radiation (k = 0.71073 A),
Acknowledgments
˚
excepting 1c whose data were collected on a Nonius Bruker
L.G.Z. acknowledges CGPI/IPN (Grants 20030702 and
CAD4 diffractometer using Cu Ka monochromated radia-
20040199) and CONACyT-Mexico (Grant 44157-Q).
˚
tion (k = 1.54184 A). The structures were solved by direct
E.B.M. and M.A.S.A. thank CONACyT-Mexico (fellow-
ships 172521 and 126454, respectively) and CGPI/IPN
(PIFI) postgraduate fellowships. P.V.P. thanks Institu-
tional and PIFI fellowships (CGPI/IPN).
methods using SHELXS97. Data for 1a are: C H O ,
1
0
18
2
M = 170.25, monoclinic, space group P2 , a = 6.563(1),
1
b = 11.217(2), c = 13.829(2), b = 98.18(1)ꢁ, crystal size:
3
0
.21 · 0.52 · 0.68 mm, V = 1007.7(2), q
= 1.122 g/cm ,
calcd
ꢀ
Z = 4, F(000)e = 376. Collected reflections: 3213 within
a h range of 2.35–27.00ꢁ, unique reflections: 2546, observed
reflections: 2080 with [I > 2r(I)], R = 3.7%, CCDC deposi-
tion no. 663927. Data for 1b are: C H O , M = 184.27,
References
1
1
20
2
1
2
. Alexakis, A.; Mangeney, P. Tetrahedron: Asymmetry 1990, 1,
77.
. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmet-
ric Synthesis; Wiley Interscience: New York, USA, 1995.
orthorhombic, space group P2 2 2 , a = 6.8217(5), b =
1
1 1
4
1
1.6941(7), c = 13.62(1), crystal size: 0.6 · 0.6 · 0.9 mm,
3
ꢀ
V = 1086.3(2), q
= 1.127 g/cm , Z = 4, F(000)e =
calcd
4
2
1
6
08, collected reflections: 2018 within a h range of 2.30–
3. Ishihara, A.; Mori, A.; Arai, I.; Yamamoto, H. Tetrahedron
Lett. 1986, 27, 983.
8.50ꢁ, unique reflections: 1917, observed reflections:
649 with [I > 2r(I)], R = 5.3%, CCDC deposition no.
63928. Data for 1c are: C H O , M = 198.30, ortho-
4
. Yamamoto, K.; Ando, H.; Chikamatsu, H. J. Chem. Soc.,
Chem. Commun. 1987, 334.
1
2
22
2
5
. Kwang-Youn, K.; Jong-Yek, P. Bull. Korean Chem. Soc.
rhombic, space group P2 2 2 , a = 7.0330(6), b =
9
V = 1198.0(3), q
4
1
1 1
2
002, 23, 665.
.125(2), c = 18.668(1), crystal size: 0.42 · 0.40 · 0.38 mm,
3
ꢀ
6. Mart ´ı nez-Ramos, F.; Vargas-D ´ı az, M. E.; Chac o´ n-Garc ´ı a,
L.; Tamariz, J.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahe-
dron: Asymmetry 2001, 12, 3095.
= 1.099 g/cm , Z = 4, F(000)e =
calcd
40. Collected reflections: 925 within a h range of 4.74–
4.87ꢁ, unique reflections: 902, observed reflections: 883
5
7
. Vargas-D ´ı az, M. E.; Chac o´ n-Garc ´ı a, L.; Vel a´ zquez, P.;
Tamariz, J.; Joseph-Nathan, P.; Zepeda, L. G. Tetrahedron:
Asymmetry 2003, 14, 3225.
with [I > 2r(I)], R = 3.3%, CCDC deposition no. 663929.
Data for 3e are: C19 H O , M = 300.38, triclinic, space
24
3
group P1, a = 8.128(1), b = 9.5291(5), c = 11.0837(6),
8. Chac o´ n-Garc ´ı a, L.; Lagunas-Rivera, S.; P e´ rez-Estrada, S.;
Vargas-D ´ı az, M. E.; Joseph-Nathan, P.; Tamariz, J.; Zepeda,
L. G. Tetrahedron Lett. 2004, 45, 2141.
a = 91.843(5), b = 90.49(1), c = 107.58(1), V = 816.05(9),
3
ꢀ
qcalcd = 1.222 g/cm , Z = 2, F(000)e = 324 crystal size:
9
. Chretien-Bessiere, Y.; Boussac, G. Bull. Soc. Chim. Fr. 1967,
2, 4728.
0
.18 · 0.26 · 0.8 mm, collected reflections: 4185 within a h
1
range of 1.73–28.00ꢁ, unique reflections: 4184, observed
reflections: 3262 with [I > 2r(I)], R = 7.6%, CCDC deposi-
tion no. 663930. Data for 7d are: C H O , M = 302.40,
1
1
0. Chretien-Bessiere, Y. Bull. Soc. Chim. Fr. 1964, 9, 2182–2185.
1. Bailey, W. F.; Reed, D. P.; Clark, D. R.; Kapur, G. N. Org.
Lett. 2001, 3, 1865.
1
9
26
3
hexagonal, space group P6 , a = 13.580(1), b = 13.580(1),
3
12. Taber, D. F.; Balijepalli, B.; Liu, K. K.; Kong, S.; Rheingold,
A. L.; Askham, F. R. J. Org. Chem. 1999, 64, 4525.
13. Fujisawa, T.; Watai, T.; Sugiyama, T.; Ukaji, Y. Chem. Lett.
1989, 2045–2048, and references cited therein.
c = 18.130(2), c = 120ꢁ, V = 2895.5(4), q
= 1.041 g/
calcd
3
ꢀ
cm , Z = 6, F(000)e = 984, crystal size: 0.5 · 0.4 ·
.4 mm, collected reflections: 5908 within a h range of
0