Insights into the stereoselective BF3-catalyzed hetero Diels-Alder reaction of Garner's aldehyde with Danishefsky's diene

Article abstract of DOI:10.1016/j.tetasy.2010.02.028

A trans-2,6-disubstituted tetrahydropyranone was prepared in high yield via a BF₃-mediated hetero Diels-Alder reaction between Danishefsky's diene and Garner's aldehyde. Only two of the four possible reaction products were obtained, and excellent diastereoselectivity toward the exo-syn adduct was observed (de = 80%). The origin of this somewhat unusual selectivity can be attributed to the steric interactions between the bulky protecting groups present in the diene and dienophile.

Full text of DOI:10.1016/j.tetasy.2010.02.028

Tetrahedron: Asymmetry 21 (2010) 398–404
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Insights into the stereoselective BF3-catalyzed hetero Diels–Alder reaction
of Garner’s aldehyde with Danishefsky’s diene
Carolina Fontana a, Marcelo Incerti a, Guillermo Moyna a,b, Eduardo Manta a,
*
a Cátedra de Química Farmacéutica, Departamento de Química Orgánica, Facultad de Química, Universidad de la República, Avenida General Flores 2124, Montevideo 11800, Uruguay
b Department of Chemistry & Biochemistry, University of the Sciences in Philadelphia, Philadelphia, PA 19104, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 December 2009
Accepted 23 February 2010
A trans-2,6-disubstituted tetrahydropyranone was prepared in high yield via a BF3-mediated hetero
Diels–Alder reaction between Danishefsky’s diene and Garner’s aldehyde. Only two of the four possible
reaction products were obtained, and excellent diastereoselectivity toward the exo–syn adduct was
observed (de = 80%). The origin of this somewhat unusual selectivity can be attributed to the steric inter-
actions between the bulky protecting groups present in the diene and dienophile.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
phorboxazoles.6,7 Herein we report a high-yielding and stereose-
lective route for the preparation of key intermediates in the syn-
Phorboxazoles 1 and 2 (Scheme 1), natural products first iso-
lated by Searle and Molinski from the sponge Phorbas sp.,1 display
exceptional cytostatic activity against all 60 human tumor cell
lines in the National Cancer Institute test panel, with an average
IG50 below 0.9 nM. Recent studies with fluorescent phorboxazole
derivatives indicate that these molecules induce persistent associ-
ation between the extranuclear cytokeratin intermediate filaments
(KRT10) and the cyclin-dependent kinase 4 (CDK4), leading to dis-
ruption of the cellular cycle at the G1–S interphase.2 This novel
mechanism gives them enormous potential as antineoplastic
agents, and could also complement and enhance the activity of mi-
totic spindle poisons that cause arrest between the G2 and M
phases, such as discodermolide, paclitaxel, and the epothilones.3
In addition to their antitumor activity and unique mechanism of
action, the phorboxazoles present a variety of structural features
that have inspired widespread interest among synthetic chemists
and have led to several total and formal syntheses.4 On the other
hand, the number of structure–activity relationship (SAR) studies
available for the phorboxazoles is relatively small.5 Additional ef-
forts in this area are required to fully decipher the mechanism of
action of these molecules.
thesis of analogues of the C3–C17 oxazole oxane fragment of
these molecules (Scheme 1). The approach relies on the BF3-cata-
lyzed hetero Diels–Alder (HDA) reaction between Danishefsky’s
diene and Garner’s aldehyde,8,9 and leads to a trans-2,6-disubsti-
tuted tetrahydropyranone as the major product. Particular empha-
sis is made on the determination of the stereochemistry of the
R
1R2
Br
O
15
MeO
O
N
21
OMe
9
O
O
O
CH2
28
HO
O
HO
N
26
1
O
32
O
1 - R1 = H / R2 = OH
2 - R1 = OH / R2 = H
R
1R2
The synthesis of phorboxazole analogues suitable for SAR stud-
ies requires straightforward strategies for the preparation of sev-
eral structural elements found in these molecules. As part of our
ongoing efforts aimed toward the design of naturally inspired bio-
logically active compounds through novel methodologies, we have
recently detailed the synthesis and conformational evaluation of
analogues of the C15–C32 bis-oxazole oxane fragment of the
O
O
O
O
NH
O
NBoc
O
CH2
OPMB
HO
Scheme 1. Chemical structure and numbering of phorboxazoles
A
(1, R1 = H;
* Corresponding author. Tel.: +598 2 924 1805; fax: +598 2 924 1906.
E-mail address: emanta@fq.edu.uy (E. Manta).
R
2 = OH) and B (2, R1 = OH; R2 = H), and retrosynthetic analysis of the C3–C17
fragment.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.02.028

C. Fontana et al. / Tetrahedron: Asymmetry 21 (2010) 398–404
399
products, which was achieved via a combination of spectroscopic
and computational studies on the reaction products and rigid
derivatives.
NMR data, an analysis of 3JHH coupling constants and NOE correla-
tions was undertaken. A peculiar phenomenon observed with
derivatives of Garner’s oxazolidines is that their NMR spectra
showed two sets of signals at 25 °C due to the slow dynamic equi-
librium between conformers generated by rotation about the car-
bamate group C–N bond.13 For this reason, most of the NMR
experiments were performed at 60 °C, well above the coalescence
temperature of the 1H signal pairs. In the case of compound 9a,
2. Results and discussion
One of the first routes to the C3–C17 fragment of the phorbox-
azoles was reported by Cink and Forsyth more than a decade ago.10
As depicted in Scheme 2, their strategy involved a BF3-catalyzed
HDA reaction between isopropylidene-(S)-glyceraldehyde 3 and
TES-protected Danishefsky’s diene 4, which afforded 5a as the ma-
jor product of a 16:4:1 mixture of diastereomers. The outcome of
the reaction was rationalized by the authors as the result of good
Felkin selectivity and stabilization of the endo transition state
through interactions of secondary orbitals.
Based on these results, and taking into account the well-docu-
mented use of Garner’s aldehyde in similar stereocontrolled HDA
cycloadditions,9,11,12 we decided to investigate the suitability of
oxazolidine 6 instead of acetonide 3 as the dienophile in the BF3-
catalyzed reaction. This route would lead to a precursor of the
C3–C17 fragment bearing an oxazolidine ring on C-15, which, as
we have recently shown,7 can be readily converted into the oxazole
moiety present in the parent compound. Thus, treatment of an
ether solution of 6 and TBS-protected diene 7 with a catalytic
amount of BF3ꢀOEt2 at ꢁ78 °C led exclusively to the formation of
two of the four possible diastereomeric silyl enol ethers, com-
pounds 8a and 8b, in 10:1 ratio (de = 80%) and an 82% combined
yield. Following chromatographic separation of the two isomers,
desilylation with TBAF in THF gave tetrahydropyranones 9a and
9b in 90% yield (Scheme 3).
3
both JHH couplings for H-11 are relatively small (3JH11–
3
H12a = 4.4 Hz and JH11–H12b = 6.0 Hz), suggesting that this proton
is gauche to both protons on C-12, and consequently equatorial
3
3
to the oxane ring. JH14a–H15 and JH14b–H15 vicinal coupling con-
stants of 1.8 and 10.0 Hz, respectively, indicate that H-15 is gauche
to H-14a, antiperiplanar to H-14b, and axial to the ring. The
H-10aMH-11 and H-10bMH-15 NOESY correlations confirm an
axial orientation for H-15 and the C-11 side chain (Table 1), and
3
the large JH11–H10b (10.1 Hz) indicates an antiperiplanar arrange-
ment of the H-11 and H-10b protons. These findings, summarized
in Figure 1, are in agreement with a chair conformation for the
oxane ring and a trans arrangement of its substituents. In addition,
these data allowed us to tentatively assign the configuration of the
C-11 and C-15 carbons as (R) and (S), respectively.
In order to obtain an accurate structural model for compound
9a that could satisfactorily explain the NMR data presented above,
the conformational space available to the molecule was thoroughly
sampled using simulated annealing.6,14 Apart from being an effec-
tive tool for the generation of large conformer ensembles, simu-
lated annealing is particularly well suited to overcome the
energy barriers that may preclude adequate sampling of the phase
space in cyclic systems. The most populated family of conformers
obtained following this approach, comprising of 50% of the low en-
ergy structures, corresponds with the chair conformation postu-
lated earlier (Fig. 1d), and validates our preliminary model.
The same approach was followed in the structural study of com-
We relied on a combination of NMR experiments and molecu-
lar-modeling simulations to determine the stereochemistries of
the two new stereogenic centers in compounds 9a and 9b. Follow-
ing the assignment of 1H and 13C NMR resonances for both mole-
3
3
pound 9b. In this case, the large JH14b–H15 (14.1 Hz) and JH11–H12a
cules (Tables
1 and 2), which was accomplished through
(11.6 Hz) coupling constants suggest that these protons have a
interpretation of 1D and 2D (COSY, NOESY, HMBC, and HSQC)
OTES
OTES
CHO
BF3⋅OEt2
Et2O, -78 ºC
+
+
5b + 5c
O
O
O
OPMB
16:4:1
(5a:5b:5c)
O
O
Me Me
OPMB
Me
5a
Me
3
4
Scheme 2. BF3-catalyzed HDA reaction of isopropylidene-(S)-glyceraldehyde 3 with Danisefsky’s diene 4 reported by Cink and Forsyth.8
OTBS
OTBS
OTBS
CHO
NBoc
a
+
+
O
O
OPMB
O
OPMB
10:1
(8a:8b)
O
O
NBoc
Me
NBoc
Me
Me
Me Me
OPMB
Me
8a
8b
6
7
O
O
O
O
13
b
9
15
17
8a or 8b
or
11
OPMB
OPMB
O
O
NBoc
Me
NBoc
Me
Me
9a
Me
9b
Scheme 3. BF3-catalyzed HDA reaction of Garner’s aldehyde 6 with Danisefsky’s diene 7. Reagents and conditions: (a) BF3ꢀEt2O, Et2O, ꢁ78 °C, 82%; (b) TBAF, THF, 90%. The
numbering scheme used for the C3–C17 fragment of the phorboxazoles is followed.

400
C. Fontana et al. / Tetrahedron: Asymmetry 21 (2010) 398–404
Table 1
Table 2
1H and 13C NMR assignments and relevant NOE correlations for compound 9a in
CDCl3 at 60 °Ca
1H and 13C NMR assignments and relevant NOE correlations for compound 9b in
CDCl3 at 60 °Ca
O
O
13
13
14
15
12
11
14
15
12
11
9
21
23
24
9
21
23
24
17
27
17
27
16
10
22
23
24
25
16
10
22
23
24
25
O
O
O
O
O
O
O
O
26
26
N
N
18
18
O
O
28
28
29
29
20
20
20
20
O
O
19
20
19
20
Position 1H (ppm)
13C
NOE
Position 1H (ppm)
13C
NOE
(ppm)
(ppm)
9
10
3.59 (m, 2H)
66.3
36.8
H-10a (s), H-10b (s)
—
—
H-10a (m), H-10b (m), H-12b
(m), H-15 (s)
H-10a (m), H-10b (m)
9
3.54 (m, 2H)
66.1
H-10a (s), H-10b (s), H-
11 (m)
H-9 (s), H-11 (s), H-12a
(m)
1.84 (Ha, m, 1H)
1.94 (Hb, m, 1H)
3.78 (m, 1H)
10
1.74 (Ha, dddd, 14.2, 7.8, 5.2,
5.2, 1H)
1.91 (Hb, dddd, 14.2, 10.1,
5.2, 5.2, 1H)
4.51 (dddd, 10.1, 6.0, 5.2,
4.4, 1H)
2.29 (Ha, dd, 15.0, 4.4, 1H)
2.67 (Hb, dd, 15.0, 6.0, 1H)
—
33.4
11
12
74.7
48.1
H-9 (s), H-15 (s)
2.28 (Ha, dd, 14.4,
11.6, 1H)
2.40 (Hb, m, 1H)
—
2.40 (m, 2H)
3.68 (dd, 14.1, 7.9,
1H)
11
12
70.9
46.3
H-9 (m), H-10a (s), H-
12a (m), H-12b (s)
H-10a (m), H-11 (m)
H-11 (s)
H-11 (m)
—
H-15 (s), H-17a (w), H-17b (w)
H-11 (s), H-14 (s), H-17b (m), H-
28 (w)
—
H-14 (w), H-29 (s)
13
14
15
207.3
45.7
77.6
13
14
207.6
44.8
—
2.40 (Ha, dd, 14.0, 1.8, 1H)
2.58 (Hb, dd, 14.0, 10.0, 1H)
4.03 (m, 1H)
H-15 (s)
—
H-10b (s), H-14a (s), H-
16
17
3.98 (m, 1H)
3.89 (Ha, dd, 8.9, 5.5,
60.9
65.3
15
71.1
1H)
28 (w)
4.07 (Hb, d, 8.9, 1H)
—
—
H-14 (w), H-15 (m), H-28 (w)
—
—
—
—
—
—
—
16
17
4.03 (m, 1H)
3.86 (Ha, dd, 9.0, 5.2, 1H)
4.09 (Hb, d, 9.0, 1H)
—
60.8
64.8
—
18
19
20
21
22
23
24
25
26
27
28
29
153.5
80.9
28.8
H-29 (s)
H-28 (w)
—
—
—
—
—
—
—
—
—
—
1.50 (s, 9H)
4.44 (s, 2H)
—
7.25 (d, 8.6, 2H)
6.90 (d, 8.6, 2H)
—
3.82 (s, 3H)
—
1.56 (s, 3H)
1.54 (s, 3H)
18
19
20
21
22
23
24
25
26
27
28
29
153.5
81.0
28.8
73.2
—
130.7
129.6
114.3
159.7
55.6
94.3
28.1
28.1
1.51 (s, 9H)
4.44 (s, 2H)
—
7.25 (d, 8.5, 2H)
6.89 (d, 8.5, 2H)
—
3.82 (s, 3H)
—
1.56 (s, 3H)
1.54 (s, 3H)
73.2
130.7
129.7
114.2
159.7
55.7
94.3
28.8
28.8
—
—
—
H-15 (w), H-17b (w)
H-17a (s)
H-15 (w), H-17b (w)
H-17a (s)
a
NOE correlations are classified as strong (s), medium (m), or weak (w).
a
NOE correlations are classified as strong (s), medium (m), or weak (w).
trans 1,2-diaxial arrangement (Fig. 2). Together with the strong
H-11MH-15 NOESY correlation (Table 3), these data are in agree-
ment with a cis-configuration of the oxane ring, and are also con-
sistent with (R)-configurations of both the C-11 and C-15 carbons.
A detailed structural model for compound 9b was also obtained
using simulated annealing. In this case, all the low energy con-
formers generated with this protocol corresponded with the chair
conformation postulated earlier (Fig. 2d). As for 9a, these simula-
tions corroborate our initial stereochemical assignments.
To further confirm the configuration of the stereogenic centers
in compound 9b, we set out to prepare a rigid derivative with no
rotation around the C-15–C-16 bond. This would allow the config-
uration of the C-16 carbon, originating from L-serine, to be used di-
rectly as reference to establish the stereochemistries of the newly
created stereogenic centers. This transformation was accomplished
by a series of steps summarized in Scheme 4. First, the treatment of
the cis-tetrahydropyranone with NaBH4 yielded an equatorial
alcohol as a result of the axial attack of the reducing agent on
the C-13 ketone group.15 Following acetylation of this alcohol
and acid-catalyzed removal of the isopropylidene moiety, the
C-17 hydroxyl group was oxidized to the carboxylic acid using
aqueous NaClO2 and a catalytic amount of TEMPO and NaClO.
The C-13 alcohol was then deacetylated, and the resulting hydroxy-
Figure 1. Coupling constant analysis for protons H-15 (a), H-11 (b), and H-10b (c),
relevant NOE correlations (in red), and heavy atom representation of the most
populated conformer family obtained for compound 9a through simulated anneal-
ing (d).
acid lactonized to give bicycle 10. In this compound, the C-15–C-16
bond is fixed, making it ideal for our purposes.

C. Fontana et al. / Tetrahedron: Asymmetry 21 (2010) 398–404
401
to confirm the absolute configuration of the C-11 and C-15 stereo-
genic centers proposed previously.
The conclusions derived from NOE data are also consistent with
the results obtained from the analysis of the vicinal coupling con-
stants. The 3JH11–H12a and 3JH11–H12b of 10.6 and 5.3 Hz, respectively,
indicate that H-11 is gauche to H-12a, antiperiplanar to H-12b, and
3
thus axial to the oxane ring (Fig. 4a). The JHH couplings for H-15
with both protons on C-14 are either small or undetectable
3
(3JH15–H14b = 5.6 Hz and JH15–H14a ꢂ 0), suggesting that this proton
is gauche to both protons on C-14 and consequently equatorial to
the oxane ring (Fig. 4b). Similarly, the coupling constants for H-13
with protons H-12a, H-12b, H-14a, and H-14b are small and could
not be detected experimentally, revealing that this proton is
gauche to protons on both C-12 and C-14 and also equatorial to
the oxane ring (Fig. 4c).
While the rigidity of 10 drastically reduces the number of confor-
mations that this compound can adopt, an accurate structural model
was obtained following the same approach employed for 9a and 9b.
The single conformer obtained is supported by the observed NOE
correlations. Furthermore, 3JHH coupling constants back-calculated
from this structure using the Haasnoot-de Leeuw-Altona equation
agree remarkably well with the experimental values (Table 3).16
The results described above allow us to draw conclusions
regarding the stereochemical outcome of the HDA reaction. First,
and in analogy to what was observed by Cink and Forsyth in the
cycloaddition of 3 with 4,10 Lewis acid chelation is precluded and
good Felkin control was achieved, leading only to the observed
syn products. Conversely, while the use of acetonide 3 led to an
endo adduct (cis product), the reaction with Garner’s aldehyde 6 af-
fords almost exclusively an exo adduct (trans product). Although
this selectivity is somewhat uncommon, it can be satisfactorily ex-
plained in terms of steric interactions between the –NBoc- and
–OTBS-protecting moieties present on oxazolidine 6 and diene 7
that would destabilize the endo transition state (Scheme 5).
Figure 2. Coupling constant analysis for protons H-11 (a), H-15 (b), proposed chair
conformation showing relevant NOE correlations (c), and heavy atom representa-
tion of the most populated conformer family obtained for compound 9b through
simulated annealing (d).
The stereochemistry of compound 10 was then studied using
1D-NOESY experiments. The strong dipolar coupling between H-
11 and H-14b, together with the medium H-11MH-15 correlation
(Fig. 3b and c), indicates that the oxane ring adopts a boat confor-
mation (Fig. 4d). This is also corroborated when the relative inten-
sities of these two NOE correlations are qualitatively compared
with the internuclear distances between these protons. These
observations are also in agreement with a cis,cis arrangement of
the C-13, C-15, and C-16 substituents on the lactone ring. Finally,
the NOE observed between H-14a and H-16 (Fig. 3a) allowed us
3. Conclusions
Table 3
3
Experimental and back-calculated JHH coupling constants for compound 10
In conclusion, we have presented a straightforward route to 2,6-
disubstituted tetrahydropyranones, key fragments in the prepara-
tion of analogues of the C3–C17 oxazole oxane fragment of the
phorboxazoles. It is worth noting that despite being highly stereo-
selective, our approach leads to a tetrahydropyranone with a trans
stereochemistry not found in the natural product. In principle, the
correct stereoisomer could be obtained using a chelating Lewis
Proton pair
Calculated dihedral
angles (°)
Back-calculated
Experimental
3JHH (Hz)
3JHH (Hz)
H-16–H-15
H-15–H-14a
H-13–H-14b
H-13–H-14a
H-13–H-14b
H-13–H-12a
H-13–H-12b
H-11–H-12a
H-11–H-12b
ꢁ57
75
ꢁ44
ꢁ56
62
2.5
0.6
6.1
4.2
1.6
0.7
7.9
11.2
4.2
1.6
ꢂ0
5.6
4.6
ꢂ0
96
ꢂ0
acid such as ZnCl2 and Garner’s aldehyde derived from D-serine
ꢁ21
ꢁ163
ꢁ45
7.1
10.6
5.3
as dienophile. Attack from the re-face of the oxazolidine-catalyst
complex would situate the –NBoc and –OTBS groups far from each
other in this case, thus not hindering the formation of the expected
O
OAc
a,b
c,d
O
OPMB
O
OPMB
O
O
NBoc
NBoc
Me
Me
Me
9b
Me
OAc
O
O
O
13
OH
e,f
16
9
BocHN
O
OPMB
15
11
O
OPMB
NHBoc
10
Scheme 4. Preparation of bicyclic lactone 10. Reagents and conditions: (a) NaBH4, MeOH; (b) Ac2O, pyridine, DMAP, CH2Cl2, 75% (both steps); (c) TsOHꢀH2O, dioxane; (d)
TEMPO, NaClO2, NaClO, phosphate buffer, MeCN, 53%; (e) NaBH4, MeOH; (f) EDCI, DMAP, CH2Cl2, 21% (both steps).

402
C. Fontana et al. / Tetrahedron: Asymmetry 21 (2010) 398–404
Figure 3. 1D-NOE spectra obtained for lactone 10 after selective inversion of protons H-16 (a), H-11 (b), and H-14b (c). The standard 1H NMR spectrum is shown for reference
*
(d). The ( ) indicates an impurity in the sample.
endo–syn transition state (Scheme 6). Work on this hypothesis is
currently ongoing and our findings will be reported in due course.
a
b
H11
H15
C13
O
H12b
H14b
H14a
C16
C10
4. Experimental
4.1. General
O
H12a
C13
3JH12a-H11 = 10.6 Hz
3JH12b-H11 = 5.3 Hz
3JH14a-H15 ~ 0 Hz
3JH14b-H15 = 5.6 Hz
Flash column chromatography purifications were carried out
using 230–400 mesh silica gel. Optical rotations were measured
on Perkin–Elmer 341 and Krüss Optronic P8000 polarimeters
equipped with 1.0 and 0.5 mL cells, respectively. IR spectra were
recorded on a Shimadzu 8101 FT-IR spectrophotometer. MS and
HRMS spectra were recorded on Shimadzu GC–MS QP 1100 EX
and VG AutoSpec Q mass spectrometers, respectively, using elec-
tron impact ionization in both cases. NMR experiments were car-
ried out on a Bruker AVANCE 400 spectrometer equipped with a
5 mm QXI probe and operating at 1H and 13C frequencies of
400.13 and 100.61 MHz, respectively. Chemical shifts (d) are re-
ported in ppm relative to the residual CDCl3 signal (7.28 ppm),
and couplings constants (J) are given in hertz. 1D-NOESY experi-
ments were performed with the DPFGSE-NOE pulse sequence of
Stott and co-workers,17 using Gaussian-shaped pulses for selective
proton inversion. A mixing time of 500 ms was employed for all 1D
and 2D NOESY experiments.
c
H13
H13
H12a
H14b
H14a
H12b
O
C12
O
C14
C11
C15
3JH14a-H13 = 4.6 Hz
3JH14b-H13 ~ 0 Hz
3JH12a-H13 ~ 0 Hz
3JH12b-H13 = 7.1 Hz
d
9
H
PMBO
Hb
14
Hb
Ha
11
H
O
O
13
Ha 15
BocHN
H
H
O
Figure 4. Coupling constant analysis for protons H-15 (a), H-11 (b), and H-13 (c),
and proposed bicycle conformation for compound 10 showing relevant NOE
correlations (d).
Molecular modeling studies were carried out using HyperChem
7.52 (HyperCube, Inc.). The low-energy conformers for compound

C. Fontana et al. / Tetrahedron: Asymmetry 21 (2010) 398–404
403
328 (5), 137 (8), 121 (100), 100 (17), 75 (8), 57 (23). HRMS: m/z
calcd for C31H51NO7Si: ([M]+): 577.3435, found 577.3406.
H
H
F
F
H
H
H
H
O
H
O
H
B
F
B
F
F
OPMB
F
O
N
O
OPMB
Me
Me
N
4.2.2. (S)-tert-Butyl 4-((2S,6S)-4-(tert-butyldimethylsilyloxy)
-6-(2-(4-methoxybenzyloxy)ethyl)-3,6-dihydro-2H-pyran-2-yl)-
2,2-dimethyloxazolidine-3-carboxylate 8b
Boc
Boc
Me
Me
TBSO
OTBS
Obtained as a colorless oil. Rf = 0.65 (EtOAc/hexanes 1:6). IR
(CHCl3, cmꢁ1): 2934, 2859, 1796, 1613, 1514, 1464, 1366, 1252,
1173, 1098, 1038, 837, 777. 1H NMR (60 °C): d 7.28 (d, J = 8.7,
2H), 6.88 (d, J = 8.7, 2H), 4.77 (s, 1H), 4.44 (s, 2H), 4.30 (m, 1H),
4.06 (d, J = 9.2), 3.88 (m, 1H), 3.86 (m, 1H), 3.82 (s, 3H), 3.68 (m,
1H), 3.57 (m, 2H), 2.22 (m, 1H), 1.91 (m, 1H), 1.79 (m, 2H), 1.54
(s, 3H), 1.51 (s, 3H), 1.47 (s, 9H), 0.93 (s, 9H), 0.14 (s, 6H). 13C
NMR (60 °C): d 159.6, 152.7, 149.3, 131.0, 129.6 (2), 114.2 (2),
106.8, 89.1, 80.5, 74.5, 73.1, 72.1, 66.9 (2), 60.6, 55.6, 44.8, 37.0,
28.8 (3), 26.0, 18.4, ꢁ3.9 (2). MS m/z (rel. int.): 577 ([M]+, 1), 504
(7), 478 (6), 456 (13), 400 (16), 377 (16), 328 (5), 137 (8), 121
(100), 100 (17), 57 (23). HRMS: m/z calcd for C31H51NO7Si:
([M]+): 577.3435, found 577.3400.
exo adduct
endo adduct
Scheme 5. Transition states leading to the observed syn HDA reaction products 8a
and 8b. Steric clashes between the –NBoc and –OTBS groups that can potentially
destabilize the endo adduct are shown.
t-BuO
ZnCl2
O
O
O
N
O
H
Me
O
OPMB
Me
H
H
OPMB
O
H
NBoc
Me
TBSO
Me
endo adduct
4.3. Preparation of tetrahydropyranones 9a and 9b
Scheme 6. Proposed endo–syn transition state for the ZnCl2-mediated HDA with
Garner’s aldehyde derived from -serine as dienophile.
D
A solution of silyl enol ether 8a (6.58 g, 11.4 mmol) in THF
(90 mL) at 0 °C was treated with a 1 M solution of TBAF in THF neu-
tralized with TsOHꢀH2O (11.4 mL). The resulting mixture was stir-
red for 10 min and diluted with Et2O (150 mL). The organic layer
was then washed with H2O (2 ꢃ 70 mL), brine (70 mL), and dried
over MgSO4. The solvent was removed under reduced pressure,
and the resulting oil was purified by flash chromatography
(EtOAc/hexanes, 1:2) to give 9a in 90% yield (4.75 g). Tetrahydro-
pyranone 9b was obtained from 8b following an analogous
procedure.
9a, 9b, and 10 were generated with a simulated annealing proto-
col.6,14 The MM2-based MM+ force field was employed for the sim-
ulations,18 using no non-bonded cutoffs and bond dipoles to
compute electrostatic interactions. Each simulated annealing cycle
consisted of 1 ps of equilibration at 800 K and annealing to 200 K
for a 0.8 ps period, followed by minimization of the resulting struc-
tures to an energy gradient below 0.001 Kcal/mol. From the total
1000 structures obtained through this process, a set of 50 low-en-
ergy conformers was selected for the analyses detailed above.
4.3.1. (S)-tert-Butyl 4-((2R,6S)-6-(2-(4-methoxybenzyloxy)
ethyl)-4-oxo-tetrahydro-2H-pyran-2-yl)-2,2-
dimethyloxazolidine-3-carboxylate 9a
4.2. Preparation of silyl enol ethers 8a and 8b
Obtained as a colorless oil. Rf = 0.50 (EtOAc/hexanes, 1:2).
½
a 2D0
ꢄ
¼ ꢁ42:7 (c 1.0, CHCl3). IR (CHCl3, cmꢁ1): 3006, 2979, 2870,
BF3ꢀOEt2 (183
lL, 1.5 mmol) was added to a solution of 6
1720, 1613, 1514, 1457, 1308, 1250, 1173, 1098, 758. 1H and 13C
NMR: see Table 1. 13C NMR: see Table 1. MS m/z (rel. int.): 462
([M+H]+, 1), 406 (10), 364 (7), 200 (6), 144 (8), 121 (100), 100
(32), 57 (40). HRMS: m/z calcd for C25H37NO7 462.2492 ([M+H]+),
found 462.2646.
(3.43 g, 15.0 mmol) and 7 (4.64 g, 13.3 mmol) in Et2O (90 mL) at
ꢁ78 °C, and the resulting mixture was stirred for 2 h. The reaction
was then quenched with saturated aqueous NaHCO3 (10 mL), the
mixture was diluted with EtOAc (120 mL), and washed with H2O
(40 mL) and brine (50 mL). The aqueous layer was subsequently
extracted with EtOAc (2 ꢃ 25 mL), and the combined organic layers
were dried with MgSO4 and evaporated to dryness under reduced
pressure. The resulting yellow oil was purified by flash chromatog-
raphy with silica gel previously neutralized with triethylamine
(EtOAc/hexanes, 1:5) to afford silyl enol ethers 8a and 8b in a
10:1 ratio (6.3 g, 82% combined yield).
4.3.2. (S)-tert-Butyl 4-((2R,6R)-6-(2-(4-methoxybenzyloxy)
ethyl)-4-oxo-tetrahydro-2H-pyran-2-yl)-2,2-
dimethyloxazolidine-3-carboxylate 9b
Obtained as a colorless oil, Rf = 0.50 (EtOAc/hexanes, 1:2),
½
a 2D0
ꢄ
¼ ꢁ27:9 (c 1.0, CHCl3), IR (CHCl3, cmꢁ1): 3007, 2940, 2875,
1717, 1698, 1517, 1387, 1306, 1248, 1173, 759. 1H and 13C NMR:
see Table 2. MS m/z (rel. int.): 462 ([M+H]+, 1), 406 (20), 364 (7),
144 (6), 137 (7), 121 (100), 57 (37). HRMS: m/z calcd for
C25H37NO7 462.2492 ([M+H]+), found 462.2481.
4.2.1. (S)-tert-Butyl 4-((2S,6R)-4-(tert-butyldimethylsilyloxy)
-6-(2-(4-methoxybenzyloxy)ethyl)-3,6-dihydro-2H-pyran-2-yl)-
2,2-dimethyloxazolidine-3-carboxylate 8a
Obtained as a colorless oil. Rf = 0.60 (EtOAc/hexanes 1:6). IR
(CHCl3, cmꢁ1): 2934, 2859, 1797, 1613, 1514, 1474, 1310, 1252,
4.4. Preparation of bicyclic lactone 10
1204, 1175, 1096, 1053, 835. 1H NMR (60 °C):
d 7.26 (d,
J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.82 (s, 1H), 4.48 (m, 1H),
4.44 (s, 2H), 4.07 (d, J = 8.1 Hz, 1H), 4.04 (m, 1H), 3.95 (m, 1H),
3.87 (m, 1H), 3.82 (s, 3H), 3.57 (m, 2H), 2.23 (m, 1H), 1.90 (m,
2H), 1.90 (m, 1H), 1.60 (s, 3H), 1.53 (s, 3H), 1.15 (s, 9H), 0.93 (s,
9H), 0.15 (s, 6H). 13C NMR (60 °C): d 159.6, 152.0, 148.1, 131.0,
129.6 (2), 114.2 (2), 106.2, 94.5, 80.5, 73.2, 73.1, 70.4, 70.2, 67.3,
60.4, 55.6, 45.3, 35.1, 28.8 (3), 26.0, 18.4, –4.2 (2). MS m/z (rel.
int.): 577 ([M]+, 1), 504 (7), 478 (6), 456 (13), 400 (16), 377 (16),
NaBH4 (23 mg, 0.61 mmol) was added in portions to a solution
of 9b (235 mg, 0.51 mmol) in MeOH (5 mL) at 0 °C. The mixture
was stirred for 30 min, diluted with water (10 mL), and extracted
with EtOAc (3 ꢃ 10 mL). The organic layer was dried over MgSO4
and the solvent was removed under reduced pressure. The crude
alcohol was resuspended in CH2Cl2 (12 mL) and treated with
Ac2O (69
lL, 0.73 mmol), pyridine (57 lL, 0.73 mmol), and a cata-
lytic amount of DMAP. The mixture was stirred for 1 h, diluted

404
C. Fontana et al. / Tetrahedron: Asymmetry 21 (2010) 398–404
with water (10 mL), and extracted with EtOAc (3 ꢃ 10 mL). The or-
ganic layer was dried over MgSO4 and the solvent was removed
under reduced pressure. Purification of the crude product by flash
chromatography (EtOAc/hexanes, 1:2) gave the corresponding ace-
tate in 75% yield (190 mg).
Acknowledgments
We acknowledge the Facultad de Química, the Programa de
Desarrollo de las Ciencias Básicas and the Fondo Clemente Estable
(Grant FCE/2004/10050) for financial support (C.F., M.I., E.M.). G.M.
recognizes funding from the Agencia Nacional de Investigación e
Innovación, the Camille and Henry Dreyfus Foundation (Award
TH-08-004), the Comision Sectorial de Investigación Científica,
and the Royal Society of Chemistry. We also wish to thank Profes-
sor Graciela Mahler for insightful discussions.
The above product (175 mg, 0.35 mmol) was dissolved in diox-
ane (6 mL) and treated with p-TsOHꢀH2O (19 mg, 0.10 mmol). The
mixture was then diluted with water (10 mL) and extracted with
EtOAc (3 ꢃ 10 mL). The organic extract was dried over MgSO4
and the solvent was removed under reduced pressure. A solution
of this crude primary alcohol (40 mg, 0.086 mmol) in MeCN
(0.5 mL) and phosphate buffer (0.67 M, pH 6.7, 0.35 mL) was
heated to 35 °C and treated with TEMPO (1 mg). This was followed
by the simultaneous addition of aqueous solutions of NaClO2
(20 mg in 0.1 mL) and NaOCl (2 mg in 0.05 mL). The resulting mix-
ture was stirred at 35 °C until the starting material was consumed,
and then cooled to RT. Water (0.5 mL) and 2 M NaOH (0.05 mL)
were added, and the reaction was then quenched by pouring into
a Na2SO3 solution. The mixture was acidified to pH 3-4 with 5%
HCl and extracted with EtOAc (3 ꢃ 5 mL). The organic layer was
dried over MgSO4 and the solvent was removed under reduced
pressure to give the crude acid in 53% yield (20 mg).
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The material obtained from the previous steps (20 mg,
0.043 mmol) was dissolved in MeOH (5 mL) and treated with
NaBH4 in portions until deacetylation was confirmed by TLC.
Water (5 mL) was then added, and the mixture was extracted
with EtOAc (3 ꢃ 5 mL). The organic layer was dried with MgSO4
and the solvent was evaporated under reduced pressure. Without
purification,
the
resulting
crude
hydroxyacid
(18 mg,
0.043 mmol) was dissolved in CH2Cl2 (5 mL) and treated with
EDCI (16 mg, 0.086 mmol) and a catalytic amount of DMAP at
0 °C. Following consumption of the starting material brine
(1 mL) was added, and the resulting mixture was extracted with
CH2Cl2 (3 ꢃ 2 mL). The organic layer was dried with MgSO4, the
solvent removed under vacuum, and the crude oil purified by
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oil in 21% yield (4 mg).
4.4.1. tert-Butyl (1S,4R,5R,7R)-7-(2-(4-methoxybenzyloxy)ethyl)
-3-oxo-2,6-dioxa-bicyclo[3.3.1]nonan-4-ylcarbamate 10
Rf = 0.50 (EtOAc/hexanes, 2:1). ½a D20
ꢄ
¼ þ10:6 (c 0.6, CHCl3). 1H
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NMR (30 °C): d 5.36 (d, J = 8.7, 1H), 7.26 (d, J = 8.6, 2H), 6.90 (d,
J = 8.6, 2H), 4.91 (dd, J = 7.1, J = 4.6, 1H), 4.46 (dd, J = 5.6, J = 1.6,
1H), 4.44 (s, 2H), 4.35 (dd, J = 8.7, J = 1.6, 1H), 3.97 (dddd, J = 10.6,
J = 6.9, J = 5.3, J = 5.3, 1H), 3.83 (s, 3H), 3.59 (m, 1H), 3.52 (m, 1H),
2.42 (dd, J = 14.1, J = 5.6, 1H), 2.14 (dd, J = 14.1, J = 4.6, 1H), 2.10
(ddd, J = 15.5, J = 7.1, J = 5.3, 1H), 1.92 (dd, J = 15.5, J = 10.6, 1H),
1.74 (m, 2H), 1.50 (s, 9H). 13C NMR: d 170.8, 159.7, 156.1, 130.8,
129.7 (2), 114.2 (2), 80.9, 73.8, 73.1, 69.3, 66.2, 65.9, 58.7, 55.7,
39.0, 36.5, 28.7 (3), 27.3. HRMS: m/z calcd for C22H31NO7
422.2173 ([M+H]+), found 422.2187.
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