Matched and mismatched pairings in B-secotaxane construction: A structure elucidation study

Article abstract of DOI:10.1016/j.tetasy.2005.09.012

The synthesis of the basic B-seco taxoid skeleton was achieved through a C10-C11 coupling of the A-ring segment (14S)-1 with the C-ring segments (10S) and (10R)-α-alkoxyorganolithium reagents, prepared in situ from 2 and 6 through nBuLi mediated transmeta

Full text of DOI:10.1016/j.tetasy.2005.09.012

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 3436–3450
Matched and mismatched pairings in B-secotaxane construction:
a structure elucidation study
*
´
´
Imad Safir, Jose I. Candela Lena, Laure Finet, Nicolas Birlirakis and Simeon Arseniyadis
Institut de Chimie des Substances Naturelles, CNRS, F-91198 Gif-sur-Yvette, France
Received 19 September 2005; accepted 28 September 2005
Available online 21October 2005
Abstract—The synthesis of the basic B-seco taxoid skeleton was achieved through a C10–C11 coupling of the A-ring segment (14S)-
1 with the C-ring segments (10S) and (10R)-a-alkoxyorganolithium reagents, prepared in situ from 2 and 6 through nBuLi mediated
transmetallation. The matched reactions of (14S)-1 with (10S)-2 and (10S)-6 displays an outstanding diastereoselectivity providing
12 and 34, respectively, as single isomers and hence allowing a convenient entry to highly functionalized taxoid diterpene frame-
works. Significant mismatching was observed with the (10R)-epimer of 2 and 6 yielding little, if any, diastereoselectivity. The struc-
tures of B-secotaxanes were assigned on the basis of spatial proximity effects in the proton NMR spectrum. Assignment of the C10/
C11 stereochemistry was made possible through conversion of the B-secotaxoid frameworks, derived from the matched and mis-
matched adducts, to the corresponding cyclic acetals. Configurational stability of a-alkoxyorganolithium derivatives was verified
in all the cases investigated. Structure elucidation of these adducts was essential for the successful C1–C2 bonding via an intramo-
lecular aldol reaction, given the fact that adducts containing a b-MOM substituent at C10 would be disfavored for such an
endeavor.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
close to 5 and 8, respectively (Scheme 1). Our interest in
this topic resulted from the need of an effective scaleable
synthesis of the taxoid ABC-ring systems 4 and 8, valu-
able precursors in the preparation of taxoids possessing
medical applications other than oncological. First
accomplished using the enantiomerically pure organost-
annane (10S)-2 with racemic 1, the A+C coupling
revealed the existence of a high kinetic discrimination.
With the above mentioned successful construction of
the taxoid diterpene 4, we became particularly interested
in how reactions of (14S)-16 with (10S)-6 and (10R)-6
derived a-alkoxyorganolithium reagents would proceed
in leading to either matched or mismatched B-secotax-
anes, since, ultimately that could determine the aldol
outcome during the crucial B-ring closure. We expected,
from precedent in our work, to be able to generate 7-
deoxytaxane (7-nor taxoid) ABC framework 8 and be-
lieved that we would also be able to introduce the right
stereochemistry at C-11 by using the appropriate
matched segments.
Recently, our laboratory reported an efficient A+C
approach for assembling the taxoid ABC diterpene
framework1 based on StillÕs a-alkoxyorganolithium2
mediated fragment coupling and an intramolecular aldol
reaction for the crucial B-ring formation. This protocol
has been applied to the construction of close precursors
of all major taxoid representatives3 thus demonstrating
the suitability of the stannylation/destannylation-aldol
protocol to access the key substructure 4.
This approach was carried further using a five-step
sequence, which introduced the oxygen functionalities
at C-1and C-5 and reduced the existing at C-14, thus
transforming the key substructure 4 into the pivotal
intermediate 5. This resulted in the preparation of sev-
eral tricyclic taxoid diterpene frameworks, close precur-
sors of various representatives of the taxane family. The
most accessible was the hitherto unsynthesized taxu-
spine D 9,4 and 7-deoxytaxanes 10 (taiwanxan) and 11
(taxuyunnanine C),5 whose ABC substructures are quite
The two (10S)-a-alkoxyorganolithium reagents from 2
and 6 exhibited typical matched behavior with (14S)-1
affording single AC adducts 12 (Scheme 2) and 34
(Scheme 5), respectively. Additions of a-alkoxyorganoli-
thium reagents from (10R)-organostannanes, 2 and 6,
*
Corresponding author. Fax: +33 169 82 30 29; e-mail: Simeon.
Arseniyadis@icsn.cnrs-gif.fr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.09.012

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3437
OMOM
O
19
R
R
HO
Bu3Sn
HO
OAc
OAc
18
10
7
HO
11
11
7
10
8
8 C
+
C
4
A
1
A 1
14
MOMO
"C10-C11"
2
2
5
14
4
20
OTBS
( )-1
TBSO
AcO
O
O
3
H
OCinnamoyl
H
(10S)-2R=OtBu
(1R=H0S)-6
R=OtBu
7R=H
OAc
20
9
"C1-C2"
Longest linear: 9-steps
AcO
OMOM
OMOM
R
HO
19 OtBu
HO
18
10
1
7
5
14
4
B
1
11
7
C
A
5
8
OR1
H
O
14
H
5
14
OAc
10
11
20
R2O
H
2
OAc
O
OH
H
R1=H, R2=2-Me-butanoyl
R1=R2=Ac
20
HO
4 R=OtBu
8 R=H
5
Scheme 1.
MOMO
O
OtBu
OtBu
Bu3Sn
10
HO
a
a
( )-1
11
10
+
12 + Dias
(7:1:1)
14
MOMO
(14S)-(-)-1
OTBS
(14R)-(+)-1
TBSO
(10S)-2
OTBS
TBSO
O
12
b
O
O
OtBu
OtBu
OtBu
10
O
10
O
O
10
11
c
11
11
d
TBSO
OTBS
OH OH
14
O
O
13
15
Scheme 2. Reagents and conditions: (a) nBuLi, THF, ꢀ78 ꢁC, 20 min; (b) TMSOTf, collidine, ꢀ30 to 0 ꢁC, 2 h; (c) TBAF–THF, 60 ꢁC, 2.5 h; (d)
Dess–Martin periodinane, dry CH2Cl2, py, 25 ꢁC, 1.5 h.
on the other hand, were significantly mismatched. In
each case, the adducts resulting from b-face attack
accounted for nearly one-half of the total AC products.
Since we were unable to obtain X-ray quality crystals
of B-secotaxane frameworks synthesized their corre-
sponding acetal derivatives proved ideal substrates for
NOEDIFF experiments, and we were able to obtain
excellent support for our assignments. This paper
describes a series of experiments addressing these issues.
with nucleophilic attack of the a-alkoxyorganolithium
species occurring exclusively at the C-11 electrophilic
terminus of 1.8
2.1. Linking of the subunits: preparation of B-secotaxanes
The matched double asymmetric reaction of Tin-MOM
acetal (10S)-2 with (14S)-1 proceeded with an outstand-
ing stereoselectivity and in excellent isolated yield (92%)
affording 12 as the sole detectable adduct. At this stage,
neither the C10 configuration of the organotin acetal
nor the stereochemistry at C10 relative to C11 and
C14 in 12 could be determined from NMR analysis.
Therefore, the assignment of the absolute configuration
of (10S)-2 was based on the relative stereochemistry of
the C-10 stereocenter in 4 (Scheme 1) and the assump-
tion of retentive transmetallation,9 which by inference,
proved the C-10 configuration of 2. We needed a more
direct and reliable method to assign the configurations
of the newly formed carbinol center at C11, resulting
from the segment coupling. This was achieved through
conversion of the B-secotaxoid frameworks to their cor-
responding acetals (e.g., 13–15).
2. Results and discussion
The synthesis of C-ring fragments such as a-alkoxy
stannanes 2 and 6 to be used as ÔC-10 NuꢀÕ and TBS-
protected phorenol 1 to be used as ÔC-11 E+Õ for the
synthesis of the B-seco taxane derivatives has been
described in previous work.7 To accomplish the key
fragment coupling (C10–C11), we opted to employ the
Still transmetallation, in view of the high regio- and ste-
reoselectivity this process is known to display. In each
case, the appropriate tin acetal was converted to its cor-
responding a-alkoxy stabilized carbanion, which in turn
was coupled with the A-ring precursor (14S)-1 to pro-
duce the desired B-secotaxane framework. In the present
study, we have used stereopure A and C-ring compo-
nents in order to facilitate product characterization. In
all cases investigated, this reaction was regioselective,
To check the reliability of the proposed structure corre-
lation, full stereochemical assignment of the known 12
was achieved following conversion to its corresponding
acetal 13 by treatment with TMSOTf in the presence

3438
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
of collidine (TMSOTf, collidine, ꢀ30 to 0 ꢁC, 2 h, 97%).
The added rigidity in the molecule accompanying this
transformation allowed for the successful measuring of
proximity effects using NOE difference experiments
(see below). This material was converted to enone-alde-
hyde 15 in a straightforward two-step sequence. First,
acetal 13 was desilylated (nBu4NF–THF, 60 ꢁC, 2 h) to
yield diol 14 (96%), which was then subjected to Dess–
Martin oxidation (Dess–Martin periodinane, dry
CH2Cl2, py, 25 ꢁC, 1.5 h) to give 15 (85%).
be introduced as a methoxymethyl ether, in a form
suitable for subsequent elaboration into the taxoid
diterpene framework. Similarly, the oxidation of the
mixture 19+20 according to Dauben–Michno protocol,
delivered enone 21 in 83% yield. These results show that
reasonably high levels of control in face selectivity can
be achieved with the TBS-protected derivative of phore-
nol 1 (both racemic and 14S forms).
While the matched double asymmetric reaction of (14S)-
1 with (10S)-2 proceeded with excellent stereoselectivity
affording a single diastereomer, significant mismatching
was observed with the (10R)-epimer of 2, yielding mod-
erate diastereoselectivity, with a slight reversal in facial
selectivity. With the configurational assignments of 12
secured by spatial proximity studies on the cyclic acetal
derivatives, and the inherent facial selectivity of 1 found
to be roughly 7:1, we went on to determine the identity
of the AC adducts 22 and 23. Hence, we set out on the
sequence displayed in Scheme 4. Thus, proceeding under
the same conditions as above, the mismatched reaction
of (14S)-1 with (10R)-2 did not display any significant
diastereoselectivity affording 22 and 23, in 84% com-
bined yield and in a 1:1.3 ratio (Scheme 4), easily sepa-
rable by column chromatography on silica gel.
With the outstanding match effect observed in the above
reaction, we went on to check the inherent facial selec-
tivity of (14S)-1 with achiral organolithium reagents
such as nBuLi and Bu3SnCH2OMOM. The latter was
readily prepared using literature procedures from the
corresponding aldehyde by condensation of lithium tri-
butylstannylate followed by protection of the resulting
alcohol using chloromethyl methyl ether in the presence
of HunigÕs base.10 As portrayed in Scheme 3, the reac-
tant 1 [racemic and (S)-form] in its reactions with achiral
reaction partners revealed a 7:1inherent diastereoselec-
tivity. Furthermore, these reactions, like that of (10S)-2
with (14S)-1 (Scheme 2) were regioselective, with nucle-
ophilic attack of the a-alkoxy carbanion occurring
exclusively at the C-11 electrophilic terminus.
This reaction, like that of (10S)-2 is regioselective with
nucleophilic attack of a-alkoxy carbanion occurring
exclusively at the C-11 electrophilic terminus. At that
point, spectral analysis could not tell us, which of the
two possible B-secotaxanes, C11(S)-22 or C11(R)-23,
was preferentially formed. To determine the identity of
the AC adducts, we prepared as above, the correspond-
ing acetals 24 and 25, respectively in 82% yield. Further,
removal of both TBS protecting groups (TBAF–THF,
60 ꢁC, 2.5 h) in 24 and 25 gave the corresponding diols
26 (91%) and 27 (94%), respectively. Oxidation of the
diol thus obtained with Dess–Martin periodinane (dry
CH2Cl2, py, 25 ꢁC, 1.5 h) afforded the intramolecularly
linked aldol partners 28 (87%) and 29 (87%), on which
we performed NOE studies. On the other hand, cleavage
of the TBS-protected ethers 22 and 23 with TBAF and
subsequent exposure of the derived diols 30 (80%) and
31 (83%) to Dess–Martin periodinane afforded the
required enone-aldehydes 32 (84%) and 33 (86%),
respectively.
OMOM
OMOM
OMOM
O
SnBu3
HO
HO
11
OMOM
a
b
+
O
7 : 1
OTBS
(14S)-(-)-1
TBSO
TBSO
TBSO
17
18
16
O
(CH2)3Me
HO
(CH2)3Me
b
HO
(CH2)3Me
+
11
c
O
7 : 1
OTBS
(14S)-(-)-1
TBSO
TBSO
TBSO
21
20
19
Scheme 3. Reagents and conditions: (a) nBuLi, Bu3SnCH2OMOM,
THF, ꢀ78 ꢁC, 20 min; (b) PCC, 4 A MS, CH2Cl2, 25 ꢁC, 12 h; (c)
˚
nBuLi, THF, ꢀ78 ꢁC, 20 min.
The reaction between enone (14S)-1 and a-alkoxy-
organolithium derived from Bu3SnCH2OMOM via trans-
metallation with nBuLi (nBuLi, Bu3SnCH2OMOM,
THF, ꢀ78 ꢁC, 20 min) gave a mixture of two diastereo-
meric products, 16 and 17 (84% in 7:1ratio), which were
separated by SiO2 flash chromatography and isolated
pure. Reaction between enone (14S)-1 and nBuLi pro-
ceeded analogously (nBuLi, THF, ꢀ78 ꢁC, 20 min),
affording a 7:1mixture of 19 and 20 (99% combined
yield). Rather than separating the mixture (except small
quantities for assigning the stereostructures), we pre-
ferred to proceed via an oxidative rearrangement afford-
ing the transposed a,b-unsaturated ketones 18 and 21.
The Dauben–Michno oxidative rearrangement11 (PCC,
2.2. The 7-deoxytaxane (7-nor) series
A parallel sequence of reactions was employed for the
preparation of 7-nor-B-secotaxanes. As with (10S)-2
and (10R)-2, (1 4S)-1 experienced matching with (10S)-
6 to provide 34 as a single diastereomer and mismatch-
ing with (10R)-6 to afford 37 and 38 in a nearly 1:1.3
ratio. Thus, exposure of (14S)-1 to 10-(S)-a-alkoxyor-
ganolithium, generated in situ from the tributyltinmeth-
oxymethyl carbinol (10S)-6 in the presence of nBuLi,
afforded 7-nor B-secotaxane 34 in 87% isolated yield,
with no trace of the isomer resulting from b-face attack,
nor a trace of configurational reversal at C10. The crude
reaction profile showed only one product, the one
depicted in Scheme 5, indicating that a complete facial
selectivity had occurred in that case. Full stereochemical
˚
4 A MS, CH2Cl2, 25 ꢁC, 12 h) of the mixture (16+17)
provided the transposed enone 18 (58%, 96% based on
recovered starting material) possessing the olefin at
C11-C12 position as required for the vast majority of
taxanes. This transformation allows the C10 center to

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3439
OMOM
OMOM
OtBu
OtBu
O
HO
OtBu
HO
10
MOMO
Bu3Sn
10
11
14
11
11
10
a
+
+
TBSO
(10R)-2
OTBS
(14S)-1
TBSO
O
OTBS
TBSO
O
OTBS
22
23
b
c
O
OMOM
OMOM
O
OtBu
OtBu
OtBu
OtBu
HO
10
HO
10
10
10
11
11
11
11
RO
b
OR
OR OR
OH OH
31
HO
OH
30
24
R=TBS
26 R=H
25R=TBS
27R=H
b
d
d
d
OMOM
OMOM
O
O
OtBu
OtBu
OtBu
HO
OtBu
HO
10
11
10
10
O
10
O
11
11
11
O
O
O
O
O
O
O
O
32
33
28
29
Scheme 4. Reagents and conditions: (a) nBuLi, THF, ꢀ78 ꢁC, 20 min; (b) TBAF–THF, 60 ꢁC, 2.5 h; (c) TMSOTf, collidine, ꢀ30 to 0 ꢁC, 2 h; (d)
Dess–Martin periodinane, dry CH2Cl2, py, 25 ꢁC, 1.5 h.
OMOM
OMOM
HO
Bu3Sn
HO
O
10
10
7
11
7
10
b
a
11
7
+
11
14
MOMO
TBSO
(10S)-6
HO
OH
TBSO
OTBS
OTBS
(14S)-1
35
34
c
d
OMOM
O
O
HO
O
O
10
10
10
7
11
11
7
11
7
e
O
O
TBSO
OTBS
36a
OH OH
36b
7
Scheme 5. Reagents and conditions: (a) nBuLi, THF, ꢀ78 ꢁC, 20 min; (b) TBAF–THF, 60 ꢁC, 2.5 h; (c) Dess–Martin periodinane, dry CH2Cl2, py,
25 ꢁC, 1.5 h; (d) TMSOTf, collidine, ꢀ30 to 0 ꢁC, 2 h; (e) TBAF–THF, 60 ꢁC, 2.5 h.
assignment to 34 was made possible following its con-
version to the corresponding acetals 36a (84%) and
36b (96%), prepared using exactly the same reactions
as described in Scheme 4. Also, the synthesis of enone-
aldehyde 7 was accomplished in two steps, starting with
the fluoride deprotection (TBAF–THF, 60 ꢁC, 2.5 h,
91%) followed by Dess–Martin oxidation (Dess–Martin
periodinane, dry CH2Cl2, py, 25 ꢁC, 1.5 h, 76%).
OMOM
OMOM
HO
HO
MOMO
O
10
10
11
7
11
7
7
a
10
+
11
14
+
Bu3Sn
OR OR
OR OR
TBSO
(10R)-6
OTBS
R=TBS
37
R=TBS
R=H
38
40
b
b
(14S)-1
39 R=H
c
OMOM
OMOM
HO
HO
10
10
11
7
11
7
When the fragment coupling experiment was repeated
with 10-(R)-organostannane 6, a 1:1.3 mixture of the
AC adducts 37 and 38 was formed, in 89% combined
yield, free of any C-10 inversed adduct, signifying that
the diastereoselectivity suffered only at C11 in mis-
matched cases. Following chromatographic separation,
these compounds were subjected to the same sequence
of functional group interconversions as were 22 and
23. Accordingly, fluoride mediated TBS deprotection
afforded 39 (87%) and 40 (89%) and subsequent Dess–
Martin oxidation gave 41 (86%) and 42 (89%), respec-
tively, as portrayed in Scheme 6.
O
O
O
O
42
41
Scheme 6. Reagents and conditions: (a) nBuLi, THF, ꢀ78 ꢁC, 20 min;
(b) TBAF–THF, 60 ꢁC, 2.5 h (96%); (c) Dess–Martin periodinane, dry
CH2Cl2, py, 25 ꢁC, 1.5 h.
such modest selectivity as did exist tended to favor the
b-face attack leading to a slight preference for 38 relative
to 37. It should be pointed out that in none of the cases
investigated thus far was 1,4-addition realized to a
detectable extent.
Once again, the reaction of (14S)-phorenol derivative
with (10R)-organostannane 2 was unselective, though

3440
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
2.3. Proof of stereochemistry of the resulting
B-secotaxanes
method. In common with all other such products, the
gross structure, as well as the stereochemistry, was pro-
ven in the following manner. Firstly, H–1H, H–13C
correlation spectra allowed a definite assignment of the
respective resonances due to all the protons and carbons
of the molecules. The added rigidity accompanying this
transformation allowed then for the successful measur-
ing of proximity effects using 1D NOE difference exper-
iments. The map of diagnostic NOEÕs is depicted in
Figure 2 for the most significant effects (in the left-half
of the figure, the C-ring part was omitted for clarity).
Particularly revealing was the enhancement of the sig-
nals due to protons H-21b singlet at d 4.96 ppm and
H-10 doublet at d 4.23 ppm upon irradiation of Me-15
singlet at d 1.07 ppm, and vice versa. This confirmed
that adduct 12 was the one obtained from a-face attack,
thus showing a strong matched effect between (14S)-1
and (10S)-2. On the other hand, enhancement of the sig-
nal due to proton H-21a at d 5.23 ppm upon irradiation
of Me-18 at d 1.95 ppm identified the downfield proton
singlet as H-21a and established that H-21a and Me-18
are cis.
1
1
At the outset, the steric director mode has been used to
probe the effect of conformational bias on a-alkoxy-
organolithium additions to 1. The OTBS-group at C14
plays the role of conformational director by destabiliz-
ing conformers where the sterically demanding OTBS
group occupies a quasi-axial position as portrayed in
Figure 1. Thus, in our earlier work, we observed that
the facial selectivity during the C10–C11 bonding was
conformationally controlled, while the C-10S stereocen-
ter, derived from the configurationally rigid a-alkoxyor-
ganolithium reagents (perfectly stable at below zero
temperatures between ꢀ78 and ꢀ40 ꢁC), exhibited sub-
stantial preference for one of the two enantiomers of
the racemic A-ring component. The favored sense of
attack at C-11 was from the a-face, as indicated, leading
to AC-linked 12 (stereochemistry as depicted in Scheme
2). Molecular mechanics calculations using StillÕs Mac-
romodel program, with AllingerÕs MM3 force field and
1H NMR on 1 were used to predict the face selectivity
upon nucleophilic attack at C11. J-values calculated
from MM3 for the lowest energy conformer I (Fig. 1)
correlate fairly well with the experimentally determined
values derived from the J-analysis (Jcalcd H14–H1ax =
10.9 Hz, found: 9.5 Hz; Jcalcd H14–H1eq = 5.1 Hz,
found: 5.6 Hz; Jcalcd H14–H13 = 2.7 Hz; found: 3.2 Hz).
This is not the case with the second lower energy con-
former II. Portrayed in the figure below are the two
lowest energy conformers of (14S)-1, different by
approximately 0.77 kcal/mol.
The configurational relationships for the AC adducts 22
and 23 derived from the mismatched combination of
reactants (14S)-1 with (10R)-2 have also been esta-
blished through the ensuing enone-aldehyde products
28 and 29, respectively. The map of diagnostic NOEs
is depicted in Figure 3 for the most significant effects.
The sense of attack at C11 for 28 was determined as fol-
lows: methyl-18 doublet at d 2.02 ppm showed a strong
NOE on H-10 doublet, d 3.74 ppm, and H-21a singlet at
d 4.98 ppm. NOE was also observed for H-10 doublet
upon irradiation of Me-19 singlet at d 0.81ppm and vice
versa.
Furthermore, diagnostic NOEÕs between H-14 proton
and the geminal methyl group confirms the adopted
conformation, which sets the favored sense of attack
at C-11 from the a-face. With this reasoning we investi-
gated the inherent facial selectivity of the C11 electro-
phile (14S)-1 and its match/mismatch combinations
with the C10S and C10R nucleophilic partners 2 and
6. Toward this aim, we carried out an elaborate series
of nuclear Overhauser enhancement experiments using
difference spectra, in order to establish the configuration
of the key centers (C10, C11) in the AC linked sub-
strates. In particular, we used the known AC adduct
12 and its acetal derivative 15 as a probe to test the
The stereochemical relationships of the key stereogenic
centers C10 and C11 followed from the NOE from
H10 to Me18 (and its reverse), supporting the assign-
ment of stereochemistry for 28. However, this NOE
enhancement is absent in isomer 29 resulting from a b-
face attack. Further, the stereochemistry of the latter,
shown in Figure 4, is assigned on the basis of the obser-
vation of strong enhancement of the signal due to pro-
ton H21b singlet at d 5.14 ppm upon irradiation of
18
12
13
18
14
13
11
1
14
12
13
12
18
14
1
11
1
TBSO
15
15
11
O
15
(14S)-(-)-1
I E = 0
II E = 0.77 Kcal/mol
Figure 1. Facial selectivity in the fragment coupling reaction. Arrows indicate diagnostic NOEs (gray, carbon; red, oxygen; blue, hydrogen; violet,
silicon; the tBuMe2 part of the TBS group was omitted for clarity).

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3441
21a
18
21a
12
13
14
21b
21
21b
21
1
18
A
19
15
11
10
12
13
11
14
A
9
7
10
9
1
8
15
C
3
2
4
5
20
Figure 2. Chem3D drawing of the energy minimized structure of 15 (gray, carbon; red, oxygen; blue, hydrogen). Diagnostic NOEs are shown with
blue arrows on A-ring moiety (in the left).
21a
21b
21b
21a
21
20
2
18
21
4
3
18
8
5
C
9
10
10
12
12
1
11
11
19
6
7
A
9
13
14
13
14
A
15
1
15
Figure 3. Chem3D drawing of the energy minimized structure of 28 showing key NOEs (dashed double-headed blue arrows, on the A-ring moiety;
gray, carbon; red, oxygen; blue, hydrogen, tBu group was omitted for clarity).
13
20
14
1
18
12
4
13
14
A
9
18
5
11
15
12
2
A
15
1
C
6
3
10
11
9
8
7
10
21
21b
21
19
21a
21b
21a
Figure 4. Chem3D drawing of the energy minimized structure of 29 showing key NOEs (double-headed blue arrows on the A-ring moiety; gray,
carbon; red, oxygen; blue, hydrogen, tBu group was omitted for clarity).

3442
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
21a
21a
21b
21b
21
10
21
18
18
19
11
10
11
12
12
15
13
13
A
A
1
20
15
8
9
4
3
C
14
1
14
7
2
6
5
9
Figure 5. Chem3D drawing of the energy minimized structure of 36a showing key NOEs (double-headed blue arrows; gray, carbon; red, oxygen;
blue, hydrogen; violet, silicon, tBuMe2 group was removed for clarity).
Me-18 singlet at d 1.90 ppm. This is supported by an
NOE from the methyl-15 singlet at d 1.12 ppm to the
H10 doublet at d 4.41ppm, as well as to H21a singlet
at d 4.95 ppm and the reverse in both cases. Experimen-
tal data from NOE studies on the acetal derivatives 28
(Fig. 3) and 29 (Fig. 4) enabled unequivocal stereochem-
ical assignment and further confirmed the correctness of
previous assignments of the organostannanes (10S)-2
and (10R)-2.
the exclusive 1,2-addition (the nucleophilic addition pro-
ceeds through a stable metal-chelated intermediate)
could be used to explain the significant mismatch
between (S) and (R). Minimization of non-bonded steric
interactions on the internal chelate (five-membered ring
Li–O bridging) as well as minimization of molecular
dipole moment could explain the origin of the observed
match effect.
The stereochemical assignments of the resultant B-seco-
taxoid frameworks in 7-nor series were again based on
spatial proximity effects, measured by the 1D NOE-
DIFF technique, as for the corresponding 7-oxygenated
analogs. Full stereochemical assignment to 34 was made
possible following conversion to its corresponding acetal
36a. The downfield methyl doublet Me18 at d 1.71 ppm
gave an NOE only to the downfield singlet H21a, at d
4.80 ppm and naturally to H13 proton at 5.43 ppm.
Additional diagnostic enhancements on H10 doublet
at 4.14 ppm and highfield singlet H21b at 4.63 ppm were
observed upon irradiation of the Me15 signals appear-
ing both as a singlet at d 1.06 ppm. This confirmed that
adduct 34 was the one obtained from a-face attack,
again illustrating an outstanding matched effect between
(14S)-1 and (10S)-6 (Fig. 5).
3. Conclusion
The use of a-alkoxyorganostannanes (10S)-2 and (10S)-
6 enables various B-secotaxanes to be obtained in quan-
tity with a stereochemically defined C10/C11 coupling.
Since we were unable to obtain X-ray quality crystals
of A–C adducts 12, 22, 23, and 34 their acetal deriva-
tives 15, 28, 29, 36a (respectively) proved ideal sub-
strates for NOEDIFF experiments, and we were able
to obtain excellent support for our assignments. Com-
plete diastereocontrol was achieved when there was a
match between nucleophile (10S)-2, (1 0S)-6 and electro-
phile (14S)-1 configurations, while when there was a
mismatch, (10R)-2, (1 R0)-6 with (14S)-1 mixture of
adducts were obtained. Besides its use for stereochemical
assignments, the presence of the acetal ring is expected
to reduce the entropic cost of bringing the two reac-
ting centers (C1–C2) together, lowering the activation
energy of the reaction. An alternative intramolecular
aldol reaction in which the C10, C11 hydroxyl groups
are protected as acetals could provide additional
opportunities for stereochemical control and synthetic
efficiency.
The C10/C11 stereochemistry of A–C adducts 41 and 42
(Scheme 6) obtained from the mismatched pair of reac-
tants (14S)-1 with (10R)-6 is assigned by analogy. The
conformational difference between the two diastereo-
mers, resulting from a and b-face attack, respectively,
could provide a hint to the origin of the difference in
facial selectivity, leading to an outstanding match effect
for the (14S)-(10S) combinations. The (S)–(S) combina-
tion is a matched pair, probably because sterically
demanding groups can be oriented away from each
other and as a result there should exist few unfavorable
steric interactions. In contrast, the (S)–(R) combination
could suffer from a severe steric interaction between ste-
rically demanding groups, since chelation with the metal
during the a-alkoxyorganolithium addition could force
these substituents to orient in the same direction. It is
likely that the same argument developed to rationalize
4. Experimental
4.1. General
Solvents and reagents used in this work were purified
according to standard literature techniques and stored
under argon. Experiments, which required an inert
atmosphere were carried out under dry argon in a flame
dried glass system. Flash chromatographies were run on

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3443
silica gel (230–400 mesh) with the solvent mixture indi-
cated. Thin layer chromatography was performed on
commercial silica gel plates that were developed by
immersion in 5% phosphomolybdic acid in 95% ethanol.
ÔUsual work upÕ means washing of the organic layer with
brine, drying on anhydrous MgSO4, and evaporating in
vacuo with a rotary evaporator at aspirator pressure.
Melting points were uncorrected. IR spectra were
recorded with an FT-IR instrument through NaCl cell
windows. NMR spectra were run in CDCl3 unless other-
wise noted. Experimental evidence favoring the struc-
tures investigated came from a comprehensive range of
1H and 13C NMR data (400–300–250 and 100–75–
69.5 MHz, respectively, 1D and 2D experiments) and
corroborated by spatial proximity (NOE) studies using
mainly the 1D NOEDIFF technique.12 1H (800 MHz)
and 13C NMR (200 MHz) experiments were carried
out on a spectrometer, equipped with triple resonance
H/C/N probeheads and a three-axis pulsed field gradi-
ent modules. Gradients were used for the coherence
transfer pathway selection in HMBC and HMQC exper-
iments. In the latter, broadband decoupling was per-
formed by using adiabatic WURST-40 pulses. For all
compounds investigated, multiplicities of 13C resonances
were assigned by the SEFT technique.13 1H chemical
shifts are expressed in parts per million downfield from
TMS using the residual non-deuterated solvent as
internal standard (CDCl3 1H, 7.27 ppm; C6D6 1H,
7.15). 13C spectra were measured at 62.5 and 75 MHz
and the chemical shifts are reported relative to CDCl3
or C6D6 triplet centered, respectively, at 77.0 and
128.0 ppm. Mass spectra acquired in the positive ion
mode under electron spray ionization (ES+) using a
mobile phase of methanol, will be abbreviated as ESIMS
(MeOH).
4.2.2. General procedure for diol oxidation with Dess–
MartinÕs periodinane. To a solution of the substrate
alcohol (2.8 mmol) in dry methylene chloride (15 mL)
and pyridine (9 mL) were added 356 mg (8.4 mmol) of
periodinane and stirring continued at room temperature
for 1h 30 min. The reaction was then diluted with meth-
ylene chloride quenched with a saturated aqueous solu-
tion of sodium bicarbonate and worked up as usual.
4.2.3. General procedure for cyclic formaldehyde-acetal
formation. Cyclic diol formals were produced by a
Lewis acid catalyzed process, using TMSOTf in dry
toluene in the presence of collidine at ꢀ30 to 0 ꢁC for
approximately 2 h (TLC monitoring) as follows. A dry
flask was charged with the mono MOM-ether of the
1,2-diol (1 mmol), vacuumed, and flushed with argon
several times. Toluene (dry, 10 mL) was added and the
solution was cooled to ꢀ30 ꢁC, followed by collidine
(20 mmol) and, after 10–15 min, TMSOTf (10 mmol)
while the temperature of the bath was raised to 0 ꢁC.
After consumption of the starting material, the reaction
mixture was diluted with heptane and worked up as
usual.
4.3. A+C coupling of the matched partners (14S)-1/
(10S)-2
4.3.1. Preparation of 12 and its cyclic acetal 15. Using
the general procedure for fragment coupling on a
10 mmol scale, 12 was obtained in 92% isolated yield
(6.27 g) and as the sole diastereomer.
4.3.1.1. Compound 12. Mp: 78 ꢁC (heptane–ether).
20
½aŠ ¼ þ1 6 c( 2.0, CHCl3). IR (film): 3519, 2954, 2928,
D
2893, 2855, 1644, 1471, 1462, 1386, 1360, 1251, 1193,
1059, 1005, 912, 866, 834, 773 cmꢀ1
.
1H NMR
4.1.1. General procedure for transmetallation/A+C frag-
ment linking: the Stille method. To a magnetically stir-
red solution of Tin-MOM acetal (1mmol) in 5 mL of
anhydrous THF cooled at ꢀ78 ꢁC under argon, nBuLi
(1.05 equiv) was added and the mixture was stirred at
this temperature for 10 min before 1 (1mmol) was
added. After stirring 20 min at ꢀ78 ꢁC, the reaction mix-
ture was diluted with ether, and quenched with a satu-
rated solution of NH4Cl. Following usual work up
(ÔUsual work upÕ means washing of the organic layer
with brine, drying on anhydrous MgSO4, and evaporat-
ing in vacuo with a rotary evaporator at aspirator pres-
sure) the A+C adducts were isolated using SiO2 column
chromatography.
(500 MHz): 0.01(6H, s, Me Si), 0.05 (6H, s, Me2Si),
2
0.82 (9H, s, tBu), 0.88 (3H, s, Me-15), 0.90 (9H, s,
tBu), 1.01 (3H, s, Me-19), 1.04 (3H, s, Me-15), 1.17
(9H, s, tBu), 1.39 (1H, d, J = 15.7 Hz, H9), 1.57 (1H,
s, OH), 1.60 (2H, dd, J = 13.2, 6.9 Hz, H1), 1.72 (2H,
d, J = 9.4 Hz, H6,6), 1.74 (3H, s, Me-18), 1.80–1.82
(1H, m, H9), 2.08–2.10 (1H, m, H5), 2.30–2.32 (1H,
m, H5), 2.48–2.52 (1H, m, H3), 3.46 (3H, s, MeO),
3.77 (1H, dd, J = 8.6, 3.9 Hz, H7), 3.78 (2H, d,
J = 6.3 Hz, H2,2), 3.89 (1H, d, J = 10.7 Hz, H10),
4.21–4.23 (1H, m, H14), 4.57 (1H, s, H20), 4.69 (1H, s,
H21), 4.78 (1H, s, H21), 4.80 (1H, s, H20), 5.39 (1H,
s, H13).13C NMR (125 MHz): ꢀ5.1(2Me 2Si), ꢀ4.6
(2Me2Si), 18.2 (2Me3CSi), 19.7 (Me18), 25.2 (Me19),
25.9 (2 · 3C, tBu), 26.6 (2Me15), 29.4 (3C, tBu) 28.9
(C5), 29.7 (C6), 30.7 (C9), 39.0 (C8), 42.3 (C15), 45.2
(C1), 52.1 (C3), 56.9 (MeO), 60.6 (C2), 66.1 (C14),
72.8 (C7+CqtBu), 77.6 (C10), 84.6 (C11), 96.6 (C21),
100.7 (C20), 128.8 (C13), 136.8 (C12), 146.7 (C4).
TOFMSES+ (MEOH): 705 ([MNa]+, 100). HRESIMS
(MeOH) calcd for C38H74O6NaSi2 705.4922; found
705.4954. Anal. Calcd for C38H74O6Si2: C, 68.25; H,
10.84. Found: C, 68.47; H, 10.95.
4.2. General procedure for TBS-deprotection
4.2.1. Desilylation. Fluoride deprotection of tert-butyl-
dimethylsilyl ethers at C-14 and C-2 was carried out
with n-Bu4NF (TBAF, 1M solution in THF, 4 equiv)
in dry THF (5 mL/mmol) at 60 ꢁC for 2 h. Ethyl acetate
was then added and the mixture was washed with brine,
dried on MgSO4 and concentrated in vacuo. The residue
was purified by chromatography (SiO2, heptane–EtOAc,
1:1) to give the desired diols in high yields. It should be
pointed out that some self-deprotection on standing was
also observed.
4.3.2. Preparation of cyclic formaldehyde-acetals 13–
15. Using the general procedure for cyclic formalde-
hyde-acetal formation (646 mg, 0.98 mmol) of 12,

3444
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
afforded, after silica gel flash chromatography (hep-
H5), 2.42 (1H, d, J = 17.6 Hz, H1), 3.31 (1H, d,
J = 1.9 Hz, H3), 3.77 (1H, dd, J = 9.5, 4.1Hz, H7),
4.23 (1H, dd, J = 8.9, 4.6 Hz, H10), 4.86 (1H, s,
H20a), 4.96 (1H, s, H21b), 5.04 (1H, s, H20b), 5.23
(1H, s, H21a), 5.92 (1H, t, J = 1.2 Hz, H13), 9.68 (1H,
d, J = 2.2 Hz, H2). Diagnostic NOEs: {Me-19}: H-3,
H-10; {Me-15}: H-1, H-10, H-21b; {Me-18}: H-13, H-
21a; {H-21b}: H-10, H-21a (NOE gem); {H-10}: H-
21b. {H-3}: H-10, H-20a. 13C NMR (200 MHz): 19.2
(Me-19), 21.6 (Me-18), 24.5 (Me-15), 25.9 (Me-15),
29.0 (3C, tBu), 30.1(C6), 30.7 (C5), 37.6 (C9), 40.2
(C15), 41.7 (C8), 48.9 (C1), 64.3 (C3), 72.7 (C7), 73.3
(CqtBu), 77.0 (C10), 88.1 (C11), 95.4 (C21), 114.8
(C20), 127.6 (C13), 140.4 (C4), 163.3 (C20), 197.2
(C14), 201.3 (C2). HRESIMS (MeOH) calcd for
C25H38O5Na 441.2617; found 441.2638. Anal. Calcd
for C25H38O5: C, 71.94; H, 9.15. Found: C, 71.91; H,
9.22.
20
tane–Et2O, 99:1), 600 mg (97%) of 13: ½aŠ ¼ þ1 4 c(
D
1.1, CHCl3). IR (film): 2956, 2930, 2857, 1472, 1252,
1
1105, 1066, 835, 774 cmꢀ1. H NMR (500 MHz): 0.02
(6H, s, Me2Si), 0.06 (6H, s, Me2Si), 0.87 (9H, s, tBu),
0.91(9H, s, tBu), 1.01 (3H, s, Me15), 1.05 (3H, s,
Me19), 1.07 (3H, s, Me15), 1.17 (9H, s, tBu), 1.39 (1H,
d, J = 15.7 Hz, H9), 1.50 (1H, dd, J = 13.4, 9.2 Hz,
H1), 1.55–1.77 (3H, m, H1, H6,6), 1.72 (3H, s, Me18),
1.77 (1H, dd, J = 15.5, 11.0 Hz, H9), 2.11–2.34 (2H,
m, H5,5), 2.48 (1H, dd, J = 8.9, 3.7 Hz, H3), 3.45 (1H,
dd, J = 8.6, 3.9 Hz, H7), 3.70 (1H, dd, J = 10.3,
3.8 Hz, H2), 3.77 (1H, t, J = 9.0 Hz, H2), 4.19 (1H, m,
H10), 4.23 (1H, m, H14), 4.66 (1H, s, H20), 4.80 (1H,
s, H20), 4.89 (1H, s, H21), 5.14 (1H, s, H20), 5.40
(1H, s, H13). 13C NMR (75 MHz): ꢀ5.2 (2Me2Si),
ꢀ4.6 (2Me2Si), 18.3 (2Me3CSi), 20.5 (Me-18), 20.8
(Me19), 25.2 (Me15), 25.9 (Me15 + 2 · 3C, tBu), 29.4
(3C, tBu), 30.2 (C5), 30.6 (C6), 37.8 (C15), 39.3 (C9),
41.6 (C8), 44.9 (C1), 52.8 (C3), 60.5 (C2), 66.2 (C14),
72.1(C7+ CqtBu), 76.9 (C10), 87.8 (C11), 95.1 (C21),
110.2 (C20), 128.2 (C13), 137.5 (C12), 146.2 (C4). HRE-
SIMS (MeOH) calcd for C37H70O5NaSi2 673.4660;
found 673.4689. Anal. Calcd for C37H70O5Si2: C,
68.25; H, 10.84. Found: C, 68.47; H, 10.95.
4.4. Reactions of 1 with achiral nucleophiles; looking for
the inherent facial selectivity
4.4.1. Reactions of 1 with Tin-MOM acetal. Use of the
general procedure for transmetallation with Bu3SnCH2-
OMOM (5.0 g, 13.72 mmol) and (14S)-(ꢀ)-1 (1.84 g,
6.86 mmol) gave 1.98 g (84%) of the expected products
16+17 (in 7:1ratio), separated by flash-chromatography
(heptane–Et2O, 95:5). The taxoid A-ring precursor 1
was used both in its racemic and enantiomerically
homogeneous form (for the purpose of description of
specific rotations).
Performed according to the general procedure, TBS
deprotection of 13 (533 mg, 0.82 mmol) afforded, after
silica gel flash chromatography (heptane–AcOEt, 2:1
20
to 1:2), 332 mg (96%) of diol 14: ½aŠ ¼ þ51( c 1.3,
D
CHCl3). IR (film): 3375, 2972, 2930, 2874, 1099, 1008,
757 cmꢀ1 1H NMR (500 MHz): 1.00 (3H, s, Me15),
.
20
1.01 (3H, s, Me15), 1.05 (3H, s, Me19), 1.16 (9H, s,
tBu), 1.38 (1H, dd, J = 13.5, 9.4 Hz, H1), 1.43 (1H, d,
J = 15.3 Hz, H9), 1.62 (1H, m, H6), 1.71 (3H, t,
J = 1.6 Hz, Me18), 1.74–1.83 (3H, m, H6, H9, OH),
1.87 (1H, ddd, J = 13.5, 6.9, 1.5 Hz, H1), 2.15 (1H, m,
H5), 2.32 (1H, m, H5), 2.45 (1H, m, H3), 3.46 (1H, m,
H7), 3.64–3.82 (2H, m, H2,2), 4.19 (3H, m, H14, H10,
OH), 4.78 (1H, s, H20), 4.91 (1H, s, H20), 4.97 (1H, s,
H21), 5.08 (1H, s, H21), 5.56 (1H, s, H13). 13C NMR
(125 MHz): 20.5 (Me18, Me19), 24.0 (Me15), 25.2
(Me15), 29.1 (3C, tBu), 30.0 (C5), 30.1(C6), 36.7 (C2),
39.8 (C15), 41.8 (C8), 43.9 (C1), 52.0 (C3), 59.2 (C2),
65.4 (C14), 72.2 (C7), 73.0 (CqtBu), 76.5 (C10), 88.0
(C11), 94.8 (C21), 110.6 (C20), 127.7 (C13), 138.8
(C12), 146.6 (C4). HRESIMS (MeOH) calcd for
C25H42O5Na 445.2930; found 445.2952. Anal. Calcd
for C25H42O5, 1 H2O: C, 68.15; H, 10.07. Found: C,
68.02; H, 9.73.
4.4.1.1. Compound 16. ½aŠ ¼ ꢀ5 (c 1.1, CHCl3). IR
D
(film): 3565, 2955, 2929, 2857, 1472, 1255, 1068, 1040,
1
835 cmꢀ1. H NMR (300 MHz): 0.06 (3H, s, Me2Si),
0.07 (3H, s, Me2Si), 0.88 (9H, s, tBu), 0.97 (6H, s,
Me15), 1.62 (1H, d, J = 8.7 Hz, H1), 1.64 (1H, dd,
J = 7.2, 1.2 Hz, H1), 1.76 (3H, t, J = 1.7 Hz, Me18),
2.78 (1H, s, OH), 3.37 (3H, s, CH3O), 3.47 (1H, d,
J = 10.1 Hz, H10), 3.77 (1H, d, J = 10.1 Hz, H10),
4.23 (1H, dddd, J = 8.7, 7.2, 1.7, 1.3 Hz, H14), 4.62
(1H, d, J = 6.4 Hz), 4.65 (1H, d, J = 6.4 Hz), 5.42 (1H,
q, J = 1.3 Hz, H13). 13C NMR (75 MHz): ꢀ4.5 (Me2Si),
18.3 (Me3CSi), 18.6 (Me18), 23.1 (Me15), 25.1 (Me15),
26.0 (3C, tBu), 39.4 (Cq-15), 44.8 (C1), 55.7 (CH3O),
66.4 (C14), 70.9 (C10), 75.8 (C11), 97.2, 129.0 (C13),
138.2 (C12). HRESIMS (MeOH) calcd for C18H36O4N-
aSi 367.2281; found 367.2269. Anal. Calcd for
C18H36O4Si+0.25 C7H16: C, 64.18; H, 10.91. Found:
C, 64.11; H, 10.93.
20
D
Periodinane oxidation of 14 (307 mg, 0.78 mmol),
achieved according to the general procedure, afforded
after silica gel flash chromatography (heptane–AcOEt,
4.4.1.2. Compound 17. ½aŠ ¼ ꢀ40 (c 0.8, CHCl3).
IR (film): 3501, 2955, 2927, 2857, 1463, 1255, 1044,
835 cmꢀ1. H NMR (400 MHz): 0.05 (3H, s, Me2Si),
1
9:1to 3):1, 260 mg (85%) of enone-aldehyde
15:
0.06 (3H, s, Me2Si), 0.83 (9H, s, tBu), 0.94 (3H, s,
Me15), 1.08 (3H, s, Me15), 1.65 (1H, d, J = 6.3 Hz,
H1), 1.68 (1H, d, J = 10.2 Hz, H1), 1.79 (3H, t,
J = 1.5 Hz, Me18), 3.37 (3H, s, CH3O), 3.53 (1H, d,
J = 10.0 Hz, H10), 3.61 (1H, d, J = 10.0 Hz, H10),
4.16 (2H, m, OH), 4.63 (2H, s), 5.45 (1H, br s, H13).
13C NMR (100 MHz): ꢀ4.6 (Me2Si), 18.3 (Me3CSi),
19.3 (Me18), 23.8 (Me15), 25.1 (Me15), 25.9 (3C, tBu),
40.0 (Cq-15), 43.6 (C1), 55.8 (CH3O), 65.3 (C14), 70.6
20
½aŠ ¼ ꢀ84 (c 1.2, CHCl3). IR (film): 2975, 1718, 1666,
D
1
1365, 1266, 1097, 739 cmꢀ1. H NMR (800 MHz): 1.03
(3H, s, Me19), 1.07 (3H, s, Me15), 1.12 (9H, s, tBu),
1.13 (3H, s, Me15), 1.61 (1H, dddd, J = 13.5, 11.5, 9.5,
4.7 Hz, H6), 1.69 (2H, m, H9,9), 1.77 (1H, dq,
J = 13.5, 4.5 Hz, H6), 1.95 (3H, d, J = 1.4 Hz, Me18),
2.02 (1H, dt, J = 14.1, 5.2 Hz, H5), 2.18 (1H, dd,
J = 17.6, 1.2 Hz, H1), 2.33 (1H, dt, J = 14.1, 4.8 Hz,

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3445
(C10), 74.7 (C11), 97.2, 129.2 (C13), 138.3 (C12). HRE-
SIMS (MeOH) calcd for C18H36O4NaSi 367.2281; found
367.2258.
(MeOH) calcd for C19H38O2SiNa 349.2539, found
349.2522. Anal. Calcd for C19H38O2Si+0.1C H16: C,
7
70.29; H, 11.86. Found: C, 70.37; H, 11.77.
4.4.2. The Dauben–Michno rearrangement on allylic
alcohols 16+17. To a stirring solution of the allylic ter-
tiary alcohol 16+17 (370 mg, 1.07 mmol) as a mixture, in
Performed as above, the Dauben–Michno rearrange-
ment on allylic alcohols 19+20 (111 mg, 0.35 mmol,
from (14S)-(ꢀ)-1) afforded after silica gel flash chroma-
tography (hexane–EtOAc, 98:2) the corresponding a,b-
unsaturated ketone 21 (92 mg, 83%) as a colorless oil,
along with unreacted starting material (9 mg, 9%).
˚
dry CH2Cl2 (5 mL), were added 400 mg of MS 4 A and
PCC (463 mg, 2.14 mmol). The reaction mixture was
stirred at room temperature overnight, Et2O was added,
the suspension was applied to fluorisil column, and
eluted with Et2O. The eluate was concentrated and the
residue was purified by silica gel flash chromatography
(hexane–EtOAc, 1:9) affording the corresponding a,b-
unsaturated ketone 18 (211 mg, 58%) as a colorless oil
along with recovered starting material 16+17 (110 mg,
38%).
4.4.3.2.
3-Butyl-6-(tert-butyl-dimethyl-silanyloxy)-
20
2,4,4-trimethyl-cyclohex-2-enone 21. ½aŠ ¼ꢀ125 (c
D
1.4, CHCl3). IR (film): 2957, 2930, 2858, 1685, 1472,
1248, 1152, 1039, 836, 779 cmꢀ1. H NMR (300 MHz):
1
0.08 (3H, s, Me2Si), 0.16 (3H, s, Me2Si), 0.87–0.89
(3H, m, Me10), 0.89 (9H, s tBu), 1.16 (3H, s, Me4),
1.20 (3H, s, Me4), 1.35–1.43 (4H, m, H8,8, H9,9), 1.76
(3H, s, Me2), 1.91 (1H, d, J = 8.0 Hz, H5), 1.91
(1H, d, J = 10.5 Hz, H5), 2.14 (2H, m, H7,7), 4.27 (1H,
dd, J = 10.5, 8.0 Hz, H6). 13C NMR (75 MHz): ꢀ5.4
(MeSi), ꢀ4.4 (MeSi), 11.8 (Me2), 13.8 (Me10), 18.6
(Me3CSi), 23.6 (C9), 25.9 (3C, tBu+Me4), 29.4 (Me4),
30.5 (C7), 31.0 (C8), 37.6 (C4), 47.0 (C5), 71.1 (C6),
129.0 (C2), 163.8 (C3), 198.7 (C1). HRESIMS (MeOH)
calcd for C19H36O2NaSi 347.2382; found 347.2387.
Anal. Calcd for C19H36O2: C, 70.31; H, 11.18. Found:
C, 70.51; H, 11.31.
20
4.4.2.1. Compound 18. ½aŠ ¼ ꢀ122 (c 1.5, CHCl3).
D
IR (film): 2953, 2929, 2886, 2858, 1692, 1471, 1363,
1
1249, 1152, 1103, 939, 920, 857, 837 cmꢀ1. H NMR
(500 MHz): ꢀ0.09 (3H, s, Me2Si), ꢀ0.03 (3H, s, Me2Si),
0.75 (9H, s, tBu), 1.03 (3H, s, Me15), 1.09 (3H, s, Me15),
1.70 (3H, s, Me18), 1.72–1.83 (2H, m, H1,1), 3.25 (3H, s,
MeO), 3.98 (2H, d, J = 1.8 Hz, H10,10), 4.17 (1H, dd,
J = 12.4, 6.2 Hz, H14), 4.50 (2H, s). 13C NMR
(125 MHz): ꢀ5.3 (MeSi), ꢀ4.4 (MeSi), 11.8 (Me18),
18.6 (Cq tBu), 25.5 (Me15), 25.8 (3C, tBu), 29.1
(Me15), 36.8, 46.8 (C1), 55.8 (MeO), 64.1 (C10), 71.1
(C14), 96.7, 133.1 (C12), 155.8 (C11), 199.1 (C13).
ESIMS (MeOH): 365.2 ([MH]+, 100). HRESIMS
(MeOH) calcd for C18H34O4NaSi 365.2124; found
365.2112. Anal. Calcd for C18H34O4Si: C, 63.11; H,
10.00. Found: C, 63.65; H, 10.16.
4.5. Coupling of the mismatched partners (14S)-1/(10R)-2
Starting from (10R)-2 (1.38 g, 1.96 mmol) and (14S)-1
(406 mg, 1.96 mmol) the Stille method was repeated to
afford, after SiO2 column chromatography (eluent hep-
tane–ether, 30:1), a mixture of two A+C adducts 22
and 23 (1.12 g, 84% combined) yield as a 1:1.3 mixture.
4.4.3. Reaction of [ ]-1 and (14S)-(ꢀ)-1 with nBuli. To
a stirring solution of (14S)-(ꢀ)-1 (1.00 g, 3.7 mmol) in
20
THF (7 mL) were added, at ꢀ78 ꢁC under argon, nBuLi
1.6 M in hexane (3.5 mL, 5.6 mmol). The reaction mix-
ture was stirred 25 min at ꢀ78 ꢁC (TLC monitoring),
then diluted with ether, quenched with a saturated solu-
tion of NH4Cl extracted with Et2O, and worked up as
usual. After purification by flash chromatography (hep-
tane–Et2O, 99:1 to 9:1), were obtained 1.20 g (99%) of
19 and 20 as a 7:1mixture. Only 19 was obtained pure
and characterized, 20 could not be efficiently separated
and thus not characterized.
4.5.1. Slower eluting adduct 22. ½aŠ ¼ þ286 (c 1.35,
CHCl3). IR (film): 3472, 2955, 2920,D2853, 1470, 1462,
1385, 1359, 1256, 1192, 1068, 1054, 1024, 866, 835,
1
773, 667, 626 cmꢀ1. H NMR (500 MHz): 0.03 (3H, s,
MeSi), 0.04 (3H, s, MeSi), 0.05 (3H, s, MeSi), 0.07
(3H, s, MeSi), 0.86 (3H, s, Me15), 0.86 (9H, s, tBu),
0.87 (9H, s, tBu), 0.94 (3H, s, Me15), 1.11 (3H, s,
Me19), 1.13 (9H, s, tBu), 1.46–1.55 (3H, m), 1.70 (3H,
s, Me18), 1.76–1.80 (1H, m), 1.86 (1H, dd, J = 12.8,
10.0 Hz, H1), 1.98 (1H, d, J = 14.7 Hz), 2.12–2.15 (2H,
m), 2.25–2.32 (1H, m), 3.50 (3H, s, CH3O), 3.58 (1H,
dd, J = 9.4, 3.9 Hz), 3.82 (1H, d, J = 11.5 Hz), 3.88
4.4.3.1.
2,6,6-trimethyl-cyclohex-2-enol 19. IR (film): 3498,
2957, 2930, 2858, 1068, 835, 773 cmꢀ1 1H NMR
1-Butyl-4-(tert-butyl-dimethyl-silanyloxy)-
(1H, dd, J = 9.7, 3.5 Hz), 3.91(H1 , q,
J = 9.7 Hz,
.
OH), 4.20–4.24 (2H, m), 4.52 (1H, s), 4.60 (1H, d,
J = 6.4 Hz, H20), 4.68 (1H, s), 4.78 (1H, d, J = 6.4 Hz,
H20), 5.50 (1H, s, H13). 13C NMR (125 MHz): ꢀ5.4
(MeSi), ꢀ5.3 (MeSi), ꢀ4.7 (MeSi), ꢀ4.5 (MeSi), 18.1
(Me18), 18.3 (Me3CSi), 18.4 (Me3CSi), 25.6 (2 · 3C,
tBu), 27.2 (Me15), 27.7 (Me15), 29.4 (Me19), 29.6 (3C,
tBu), 30.5 (C5), 31.0 (C6), 36.1 (C15), 40.2 (C9), 42.1
(C8), 45.6 (C1), 54.2 (C3), 56.9 (CH3O), 62.8 (C2),
66.5 (C14), 72.2 (C10), 73.8 (CqtBu), 78.7 (C11), 89.8
(C7), 101.2 (OCH2), 109.8 (C20), 131.6 (C13), 136.7
(C12), 147.9 (C4). TOFMSES+ (MEOH): 705
([MNa]+, 100). HRESIMS (MeOH) calcd for
C38H74O6NaSi2 705.4922; found 705.4913. Anal. Calcd
(300 MHz): 0.06 (6H, 2s, Me2Si), 0.89 (9H, s, tBu),
0.92 (3H, m, Me10), 0.95 (3H, s, Me6), 0.97 (3H, s,
Me6), 1.20–1.43 (5H, m, H8,8, H9,9, OH), 1.58 (1H,
dd, J = 15.5, 13.8 Hz, H7), 1.60 (1H, ddd, J = 13.5,
6.9, 1.5 Hz, H5), 1.70 (1H, dd, J = 13.1, 9.3 Hz, H5),
1.73 (1H, ddd, J = 15.5, 8.4, 7.2 Hz, H7), 1.73 (3H, t,
J = 1.7 Hz, Me2), 4.22 (1H, dddd, J = 9.3, 6.9, 1.7,
1.3 Hz, H4), 5.38 (1H, q, J = 1.3 Hz, H3). 13C NMR
(75 MHz): ꢀ4.4 (Me2Si), 14.0 (Me10), 18.3 (Me3CSi)
18.8 (Me2), 23.8 (Me6), 23.9 (C9), 24.8 (Me6), 26.0
(3C, tBu), 28.1(C8), 37.8 (C7), 40.0 (C6), 45.0 (C5),
66.5 (C4), 77.8 (C1), 127.9 (C3), 139.1 (C2). HRESIMS

3446
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
for C38H74O6Si2: C, 66.81; H, 10.92. Found: C, 65.73;
H, 10.91.
([MNa]+, 100). HRESIMS (MeOH) calcd for
C37H70O5NaSi2 673.4660; found 673.4701. Anal. Calcd
for C37H70O5Si2: C, 68.25; H, 10.84. Found: C, 68.73;
H, 11.41.
20
4.5.2. Faster eluting adduct 23. ½aŠ ¼ ꢀ53 (c 1.90,
D
CHCl3). IR (film): 3519, 2952, 2930, 2884, 2853, 1470,
1460, 1385, 1359, 1254, 1189, 1145, 1098, 1063, 935,
Starting from 22 the general procedure for cyclic form-
aldehyde-acetal formation was repeated on a 0.24 mmol
scale to afford 126 mg of 24 (81%).
1
884, 835, 773 cmꢀ1. H NMR (500 MHz): 0.005 (3H,
s, MeSi), 0.01(3H, s, MeSi), 0.02 (3H, s, MeSi), 0.03
(3H, s, MeSi), 0.87 (9H, s, tBu), 0.88 (9H, s, tBu), 0.90
(3H, s, Me15), 0.96 (3H, s, Me15), 1.14 (9H, s, tBu),
1.15 (3H, s, Me19), 1.37 (1H, dd, J = 15.7, 10.7 Hz,
H1), 145–1.51 (2H, m), 1.58–1.62 (1H, m), 1.77–1.80
(2H, m), 1.82 (3H, t, J = 1.3 Hz, Me18), 1.95 (1H, dd,
J = 15.1, 6.3 Hz, H1), 2.08–2.10 (1H, m, H5), 2.14–
2.18 (1H, m, H5), 2.30–2.38 (1H, m, H3), 3.42 (3H, s,
CH3O), 3.50 (1H, dd, J = 10.7, 4.4 Hz), 3.82 (1H, t,
J = 10.1 Hz), 3.90 (1H, dd, J = 9.5, 3.1Hz), 3.98 (1H,
br s, OH), 4.15–4.18 (1H, m), 4.56 (1H, s), 4.64 (1H,
d, J = 6.3 Hz, H20), 4.70 (1H, s), 4.88 (1H, d,
J = 6.3 Hz, H20), 5.42–5.45 (1H, m, H13). 13C NMR
(125 MHz): ꢀ 5.5 (MeSi), ꢀ5.4 (MeSi), ꢀ4.8 (MeSi),
ꢀ4.7 (MeSi), 18.1 (Me3CSi), 18.2 (Me3CSi), 20.2
(Me18), 24.9 (Me15), 25.8 (Me15), 25.9 (2 · 3C, tBu),
27.8 (Me19), 29.2 (3C, tBu), 30.1(C5), 30.9 (C6), 35.9
(C15), 37.9 (C9), 41.9 (C8), 43.9 (C1), 54.4 (C3), 56.9
(CH3O), 62.1 (C2), 64.4 (C14), 72.2 (C10), 73.0 (CqtBu),
77.2 (C11), 85.9 (C7), 101.1 (OCH2), 110.6 (C20), 127.3
(C13), 137.8 (C12), 147.3 (C4). TOFMSES+ (MEOH):
705 ([MNa]+, 100). HRESIMS (MeOH) calcd for
C38H74O6NaSi2 705.4922; found 705.4925. Anal. Calcd
for C38H74O6Si2: C, 66.81; H, 10.92. Found: C, 66.71;
H, 10.94.
20
D
4.6.2. Compound 24. ½aŠ ¼ þ5 (c 1.1, CHCl3). IR
(film): 2952, 2927, 2853, 1469, 1460, 1387, 1360, 1254,
1190, 1098, 1067, 1020, 1005, 953, 918, 873, 834 cmꢀ1
.
1H NMR (500 MHz): 0.04 (3H, s, MeSi), 0.06 (3H, s,
MeSi), 0.07 (3H, s, MeSi), 0.09 (3H, s, MeSi), 0.89
(3H, s, Me15), 0.90 (18H, s, 2tBu), 0.96 (3H, s, Me15),
1.07 (3H, s, Me19), 1.19 (9H, s, tBu), 1.53–1.66 (2H,
m), 1.76 (3H, s, Me18), 1.81 (1H, dd, J = 8.6, 4.4 Hz),
1.89–1.99 (2H, m), 2.14–2.26 (2H, m), 2.35 (1H, dd,
J = 13.0, 5.6 Hz, H1), 2.42 (1H, dd, J = 7.5, 3.4 Hz,
H3), 3.69 (1H, dd, J = 9.7, 4.4 Hz, H7), 3.88 (1H, dd,
J = 13.4, 1.4 Hz, H10), 3.90 (1H, dd, J = 10.0, 3.6 Hz,
H2), 4.02 (1H, dd, J = 9.9, 7.5 Hz, H2), 4.26–4.30 (1H,
m, H14), 4.61 (1H, s, H20), 4.74 (1H, s, H20), 4.88
(1H, s, H21), 5.17 (1H, s, H21), 5.55 (1H, s, H13). 13C
NMR (125 MHz): ꢀ5.4 (MeSi), ꢀ5.3 (MeSi), ꢀ4.7
(MeSi), ꢀ4.6 (MeSi), 18.2 (Me18), 18.3 (Me3CSi), 18.8
(Me3CSi), 25.9 (2Me15), 25.9 (2 · 3C, tBu) 29.4
(Me19), 29.5 (3C, tBu), 30.7 (C6), 31.1 (C5), 32.5
(C15), 39.7 (C9), 42.1 (C8), 43.8 (C1), 53.6 (C3), 63.2
(C2), 66.4 (C14), 72.2 (C7), 73.2 (CqtBu), 79.2 (C10),
86.4 (C11), 94.5 (C21), 109.8 (C20), 131.7 (C13), 135.5
(C12), 148.3 (C4). TOFMSES+ (MEOH): 673
([MNa]+, 100). HRESIMS (MeOH) calcd for
C37H70O5NaSi2 673.4660; found 673.4694. Anal. Calcd
for C37H70O5Si2, 0.38 CH2Cl2: C, 67.02; H, 10.65.
Found: C, 66.99; H, 10.95.
4.6. Preparation of cyclic formaldehyde-acetals 24–29
Starting from 23 the general procedure for cyclic form-
aldehyde-acetal formation was repeated on a 1mmol
scale to afford 533 mg of 25 (82%).
4.7. Fluoride deprotection of 24 and 25
20
D
4.6.1. Compound 25. ½aŠ ¼ ꢀ79 (c 2.1, CHCl3). IR
Use of the general procedure for TBS-deprotection on
24 (500 mg, 0.77 mmol) gave 295 mg (91%) of 26.
(film): 2950, 2927, 2852, 1470, 1460, 1385, 1359, 1254,
1191, 1096, 1072, 1018, 1018, 979, 917, 884, 833, 773,
20
661cm ꢀ1
.
1H NMR (500 MHz): 0.03 (3H, s, MeSi),
4.7.1. Compound 26. ½aŠ ¼ þ24 (c 0.5, CHCl3). IR
D
0.04 (3H, s, MeSi), 0.06 (3H, s, MeSi), 0.09 (3H, s,
MeSi), 0.90 (18H, s, 2tBu), 0.94 (3H, s, Me15), 1.00
(3H, s, Me15), 1.15 (9H, s, tBu), 1.18 (3H, s, Me19),
1.48 (1H, dd, J = 11.2, 4.5 Hz), 1.55 (1H, d,
J = 14.7 Hz), 1.58–1.70 (2H, m), 1.75 (3H, s, Me18),
1.86–1.90 (2H, m), 2.16–2.20 (1H, m), 2.34 (1H, dd,
J = 7.2, 3.4 Hz, H1), 2.43 (1H, dt, J = 13.6, 5.6 Hz,
H3), 3.70 (1H, dd, J = 10.5, 4.9 Hz, H7), 3.90 (1H, dd,
J = 9.8, 3.7 Hz, H2), 4.02 (1H, dd, J = 9.8, 7.5 Hz,
H2), 4.16–4.20 (2H, m, H10, H14), 4.61 (1H, s, H20),
4.74 (1H, s, H20), 4.90 (1H, s, H21), 5.15 (1H, s,
H21), 5.46–5.48 (1H, m, H13). 13C NMR (125 MHz):
ꢀ5.4 (MeSi), ꢀ5.3 (MeSi), ꢀ4.7 (MeSi), ꢀ4.5 (MeSi),
18.1 (Me3CSi), 18.2 (Me3CSi), 20.5 (Me19), 25.3
(Me18), 25.8 (3C, tBu), 25.9 (3C, tBu), 26.7 (Me15),
29.1(3C, tBu), 29.7 (Me15), 30.6 (C6), 31.1 (C5), 35.5
(Cq15), 36.8 (C9), 41.6 (C8), 43.2 (C1), 54.5 (C3), 63.0
(C2), 64.3 (C14), 72.1 (C7), 73.0 (Cq, tBu), 77.2 (C10),
87.3 (C11), 94.9 (C21), 110.2 (C20), 126.7 (C13), 138.2
(C12), 148.1 (C4). TOFMSES+ (MEOH): 673
(film): 3430, 2965, 2926, 2855, 1095, 1006 cmꢀ1
.
1H
NMR (800 MHz): 0.87 (3H, s, Me19), 0.95 (3H, s,
Me15), 1.05 (3H, s, Me15), 1.19 (9H, s, tBu), 1.54 (1H,
OH), 1.60 (1H, m, H6), 1.77 (3H, t, J = 1.4 Hz,
Me18), 1.78 (1H, dd, J = 13.4, 5.9 Hz, H1), 1.80 (2H,
m, H5,5), 1.84 (1H, dd, J = 14.6, 9.5 Hz, H9), 1.88
(1H, dd, J = 13.4, 9.3 Hz, H1), 2.18 (1H, m, H6), 2.27
(1H, d, J = 14.6 Hz, H9), 2.46 (1H, dd, J = 9.4,
4.5 Hz, H3), 3.49 (1H, dd, J = 10.2, 4.5 Hz, H7), 3.62
(1H, t, J = 9.8 Hz, H2), 3.83 (1H, d, J = 9.5 Hz, H10),
4.07 (1H, dd, J = 9.8, 4.2 Hz, H2), 4.27 (1H, m, H14),
4.77 (1H, br s, H20a), 4.90 (1H, br s, H20b), 4.91 (1H,
s, H21a), 5.20 (1H, s, H21b), 5.65 (1H, m, H13). Diag-
nostic NOEs: {Me-19}: H-3, H-10, H-9, H-6; {Me-
18}: H-10, H-13, H-21a; {H-3}: H-20a; {H-10}: Me-
18, H-21a; {H-21a}: H-10, H-21b (NOE gem). 13C
NMR (200 MHz): 18.2 (Me18), 18.9 (Me19), 25.9 (2C,
Me15), 29.3 (3C, tBu), 29.4 (C6), 30.7 (C5), 33.4 (C9),
40.0 (Cq15), 41.6 (Cq8), 43.6 (C1), 54.9 (C3), 60.0
(C2), 65.7 (C14), 72.1 (C7), 73.5 (Cq, tBu), 78.7 (C10),

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3447
86.4 (Cq 11), 94.7 (C21), 112.2 (C20), 130.2 (C13), 137.4
(C12), 146.4 (C4). HRESIMS (MeOH) calcd for
C25H42O5Na 445.2930; found 445.2930. Anal. Calcd
for C25H42O5+0.3 C7H16: C, 71.91; H, 10.42. Found:
C, 72.09; H, 10.55.
The general procedure was repeated as above on 27
(176g, 0.42 mmol) to afford after chromatography (hep-
tane–EtOAc, 2:1) 29 (152 mg, 87%).
20
4.8.2. Enone-aldehyde 29. ½aŠ ¼ ꢀ248 (c 1.2, CHCl3).
IR (film): 2971, 2933, 2874, D1720, 1668, 1364, 1190,
Use of the general procedure for TBS-deprotection on
1096, 1067 cmꢀ1 1H NMR (800 MHz): 0.91(3H, s,
.
25 (500 mg, 0.77 mmol) gave 306 mg (94%) of 27.
Me19), 1.09 (9H, s, tBu), 1.10 (3H, s, Me15), 1.12 (3H,
s, Me15), 1.54 (1H, tdd, J = 13.7, 11.5, 4.6 Hz, H6),
1.67 (1H, d, J = 14.9 Hz, H9), 1.78 (1H, m, H6), 1.81
(1H, d, J = 15.0 Hz, H9), 1.90 (3H, s, Me18), 2.06
(1H, br t, J = 14.4 Hz, H5), 2.20 (1H, bd, J = 14.1 Hz,
H5), 2.22 (1H, d, J = 17.5 Hz, H1), 2.29 (1H, d,
J = 17.5 Hz, H1), 3.42 (1H, s, H3), 4.00 (1H, dd,
J = 11.0, 4.6 Hz, H7), 4.41 (1H, d, J = 10.5 Hz, H10),
4.92 (1H, s, H20a), 4.95 (1H, s, H21a), 5.01 (1H, s,
H20b), 5.14 (1H, s, H21b), 5.93 (1H, s, H13), 9.418
(1H, s, H2). Diagnostic NOEs: {Me-19}: H-6, H-9,
H-10; {Me-15}: H-10; {Me-18}: H-13, H-21b; {H-10}:
H-21a, Me-19; {H-3}: H-20a, Me-19H; {H-20a}: H-3,
H-20b (NOE gem); {H-21a}: H-10, H-21b (NOE gem).
13C NMR (200 MHz): 17.0 (Me19), 21.7 (Me18), 24.7
(Me-15), 25.8 (Me15), 29.0 (3C, tBu), 30.0 (C5), 30.5
(C6), 37.0 (C9), 40.4 (C8), 40.6 (C15), 49.4 (C1), 65.9
(C3), 71.8 (C7), 73.4 (Cq, tBu), 77.3 (C10), 87.7 (C11),
95.5 (C21), 115.9 (C20), 127.7 (C13), 139.5 (C4), 163.9
(C12), 196.8 (C14), 199.0 (C2). HRESIMS (MeOH)
calcd for C25H38O5Na 441.2617; found 441.2601.
20
4.7.2. Compound 27. ½aŠ ¼ ꢀ70 (c 0.8, CHCl3). IR
D
(film): 3400, 2959, 2926, 2855, 1094, 1008 cmꢀ1
.
1H
NMR (300 MHz): 0.87 (3H, s, Me19), 0.94 (3H, s,
Me15), 1.05 (9H, s, tBu), 1.13 (3H, s, Me15), 1.37
(1H, dd, J = 16.0, 11.0, H9), 1.55–1.73 (3H, m, H6,
H1, H9), 1.70 (3H, s, Me12), 1.78–1.86 (3H, m, H6,
H1, OH), 2.13 (3H, m, H5,5, OH), 2.36 (1H, dd,
J = 11.5, 6.4 Hz, H3), 3.31 (1H, dd, J = 10.7, 4.8 Hz,
H7), 3.46 (1H, t, J = 9.7 Hz, H2), 4.01(H1, dd,
J = 9.8, 4.5 Hz, H2), 4.08 (1H, br s, H14), 4.14 (1H,
d, J = 9.9 Hz, H10), 4.72 (1H, s, H20), 4.82 (1H, s,
H20), 4.84 (1H, s, H21), 5.13 (1H, s, H21), 5.55 (1H,
s, H13). 13C NMR (75 MHz): 18.5 (Me19), 20.7
(Me18), 25.3 (Me15), 26.6 (Me15), 29.1 (3C, tBu),
39.7 (C5), 30.7 (C6), 35.5 (C15), 37.1 (C9), 41.2
(C8), 42.8 (C1), 55.9 (C3), 59.8 (C2), 64.4 (C14), 71.8
(C7), 73.4 (Cq, tBu), 77.1 (C10), 87.2 (C11), 95.1
(C21), 112.7 (C20), 126.0 (C13), 140.2 (C12), 146.0
(C4). HRESIMS (MeOH) calcd for C25H42O5Na
445.2930; found 445.2953. Anal. Calcd for C25H42-
O5+0.5 C7H16: C, 72.42; H, 10.66. Found: C, 72.44;
H, 10.88.
4.9. Preparation of enone-aldehydes 32 and 33
The deprotection of tert-butyldimethylsilyl ethers at
C-14 and C-2 on A+C adducts 22 and 23 is done
according to the general procedure on a 0.5 mmol scale
affording after the usual work up and SiO2 flash chro-
matography (heptane–EtOAc, 2:1to :13) the corre-
sponding triols 30 (182 mg, 80%) and 31 (188 mg,
83%), respectively.
4.8. Periodinane oxidation of 26 and 27
The general procedure was repeated as above on 26
(228 mg, 0.54 mmol) to afford after chromatography
(heptane–EtOAc, 2:1) 28 (197 mg, 87%).
20
4.8.1. Enone-aldehyde 28. ½aŠ ¼ ꢀ165 (c 1.2, CHCl3).
D
20
IR (film): 2971, 1719, 1660, 1097, 1068 cmꢀ1. H NMR
(800 MHz): 0.81 (3H, s, Me19), 1.04 (3H, s, Me15), 1.06
(3H, s, Me15), 1.15 (9H, s, tBu), 1.54 (1H, ddd, J = 13.3,
4.6, 2.5 Hz, H6), 1.84 (1H, dtd, J = 13.1, 4.8, 2.9 Hz,
H6), 1.93 (1H, m, H9), 2.02 (3H, d, J = 1.4 Hz,
Me18), 2.10 (1H, m, H5), 2.20 (1H, dd, J = 18.6,
1.1 Hz, H1), 2.24 (1H, m, H5), 2.41 (1H, dd, J = 14.1,
11.7 Hz, H9), 2.71 (1H, d, J = 18.6 Hz, H1), 3.43 (1H,
s, H3), 3.74 (1H, dd, J = 11.7, 1.3 Hz, H10), 4.08 (1H,
dd, J = 10.9, 4.6 Hz, H7), 4.92 (1H, t, J = 1.8 Hz,
H20a), 4.98 (1H, s, H21a), 5.03 (1H, t, J = 1.9 Hz,
H20b), 5.26 (1H, s, H21b), 5.98 (1H, t, J = 1.3 Hz,
H13), 9.47 (1H, d, J = 1.6 Hz, H2). Diagnostic NOEs:
{Me-19}: H-3, H-10; {Me-15}: H-1, H-1, H-9; {Me-
18}: H-10, H-13, H-21a; {H-3}: H-20a; {H-10}: Me-
18, H-21a, Me-19; {H-21a}: H-10, H-21b (NOE gem).
13C NMR (200 MHz): 16.9 (M-19), 19.5 (Me18), 24.7
(Me15), 27.3 (Me-15), 29.3 (3C, tBu), 30.1(C5), 30.5
(C6), 32.7 (C9), 40.2 (C15), 41.1 (C8), 49.0 (C1), 65.8
(C3), 72.1(C7), 73.3 ( Cq, tBu), 80.6 (C10), 86.7
(C11), 95.5 (C21), 115.8 (C20), 128.4 (C13), 139.6
(C4), 161.9 (C12), 197.3 (C14), 199.5 (C2). HRESIMS
(MeOH) calcd for C25H38O5Na 441.2617; found
441.2609.
4.9.1. Triol 30. ½aŠ ¼ þ71( c 1.0, CHCl3). IR (film):
1
D
3435, 2971, 1650, 1461, 1388, 1362, 1190, 1083, 1053,
1
1025, 949, 887, 754 cmꢀ1. H NMR (500 MHz): 0.92
(3H, s, Me15), 0.95 (3H, s, Me15), 1.09 (3H, s, Me19),
1.17 (9H, s, tBu), 1.28–1.32 (2H, m, OH, H9), 1.36
(1H, br s, OH), 1.55–1.62 (2H, m, H6,6), 1.70 (1H, br
s, OH), 1.75 (3H, s, Me18), 1.81 (2H, d, J = 7.9 Hz,
H1,1), 2.02 (1H, d, J = 14.6 Hz, H9), 2.16–2.21 (1H,
m, H5), 2.28–2.34 (2H, m, H3, H5), 3.41(H1 , dd,
J = 7.8, 3.8 Hz, H7), 3.46 (3H, s, MeO), 3.63 (1H, t,
J = 10.2 Hz, H2), 3.76 (1H, d, J = 10.6 Hz, H2), 3.99
(1H, dd, J = 10.2, 3.9 Hz, H10), 4.15–4.26 (1H, m,
H14), 4.62 (1H, d, J = 6.5 Hz, H20), 4.69 (1H, s,
H21), 4.82 (1H, d, J = 6.5 Hz, H20), 4.87 (1H, s,
H21), 5.59 (1H, s, H13). 13C NMR (75 MHz): 18.5
(Me18), 20.3 (Me15), 26.6 (Me15), 26.9 (Me19), 29.2
(3C, tBu), 29.8 (C5), 30.2 (C6), 37.2 (C15), 40.6 (C9),
41.8 (C8), 44.8 (C1), 54.0 (C3), 57.0 (CH3O), 59.8
(C2), 65.6 (C14), 71.7 (C10), 73.3 (CqtBu), 78.9 (C11),
88.2 (C7), 101.0 (OCH2), 110.1 (C20), 130.0 (C13),
138.4 (12), 147.6 (C4). CIMS: 455 ([MH]+, 30), 437
(86), 419 (35), 405 (31), 163 (100). Analysis: calcd for
C26H46O6 C, 68.69; H, 10.20, found: C, 68.51; H, 9.99.
TOFMSES+ (MEOH): 477 ([MNa]+, 100). HRESIMS

3448
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
(MeOH) calcd for C26H46O6Na 477.3192; found
477.3195.
17.4, 21.0, 24.1, 27.6, 29.0 (3C), 30.0, 30.2, 38.0, 40.0,
40.9, 50.4, 57.2, 65.6, 71.8, 73.5, 78.1, 85.9, 100.6,
115.4, 128.3, 139.9, 162.9, 197.6, 198.4. ESIMS
(MeOH): 489 ([MK]+, 8), 473 ([MNa]+, 100). HRE-
SIMS (MeOH) calcd for C26H42O6Na 473.2879; found
473.2872.
20
4.9.2. Triol 31. ½aŠ ¼ ꢀ62 (c 1.1, CHCl3). IR (film):
D
3401, 2972, 1649, 1460, 1388, 1378, 1362, 1190, 1050,
1
1025, 933, 887, 753 cmꢀ1. H NMR (500 MHz): 0.94
(3H, s, Me18), 1.00 (3H, s, Me15), 1.12 (9H, s, tBu),
1.16 (3H, s, Me15), 1.22–1.38 (4H, m, H9, OH, H6,6),
1.60–1.66 (2H, m, OH, H1), 1.84 (1H, d, J = 15.7 Hz,
H1), 1.86 (3H, s, Me18), 2.02 (1H, dd, J = 15.3,
6.7 Hz, H9), 2.20–2.26 (3H, m, H3, H5,5), 3.35 (1H,
dd, J = 10.5, 4.3 Hz, H7), 3.51 (3H, s, OMe), 3.53–
3.57 (1H, m, H2), 3.93–3.99 (2H, m, H10, H2), 4.12
(1H, dd, J = 10.4, 4.3 Hz, H14), 4.16 (1H, br s, OH),
4.70 (1H, d, J = 6.1 Hz, H20), 4.75 (1H, s, H21), 4.89
(1H, d, J = 6.1 Hz, H20), 4.92 (1H, br s, H21), 5.64
(1H, br s, H13). 13C NMR (75 MHz): 18.6 (Me18),
20.0 (Me15), 24.8 (Me15), 27.8 (Me19), 28.9 (C5), 29.0
(3C, tBu), 30.6 (C6), 36.0 (C15), 37.9 (C9), 41.5 (C8),
43.4 (C1), 55.7 (C3), 56.9 (CH3O), 59.3 (C2), 64.3
(C14), 71.7 (C10), 73.2 (CqtBu), 77.1(C11), 84.5 (C7),
100.7 (OCH2), 112.5 (C20), 126.8 (C13), 139.1 (C12),
145.9 (C4). TOFMSES+ (MEOH): 477 ([MNa]+, 100).
HRESIMS (MeOH) calcd for C26H46O6Na 477.3192;
found 477.3202.
4.10. Preparation of the matched 7-nor B-secotaxoids
7 and 36
The procedure of Still was repeated as above on (10S)-6
(177 mg, 0.28 mmol) and (14S)-1 (75.3 mg, 0.28 mmol)
to afford after SiO2 column chromatography (eluent
heptane–ether, 25:1) gave 150 mg (87%) of 34.
20
4.10.1. Compound 34. ½aŠ ¼ ꢀ20 (c 1.6, CHCl3). IR
D
(film): 3513, 2954, 2929, 2856, 1652, 1471, 1462, 1360,
1255, 1144, 1060, 884, 835, 773 cmꢀ1
.
1H NMR
(300 MHz): 0.01(3H, s), 0.02 (3H, s), 0.04 (3H, s),
0.06 (3H, s), 0.86 (9H, s), 0.88 (9H, s), 1.00 (6H, s),
1.04 (3H, s), 1.16–2.41 (12H, m), 1.76 (3H, s), 3.46
(3H, s), 3.68 (1H, dd, J = 10.2, 3.7 Hz), 3.80–3.94 (2H,
m), 4.19–4.29 (1H, m), 4.55 (1H, br s), 4.64 (1H, d,
J = 6.2 Hz), 4.76 (1H, br s), 4.78 (1H, d, J = 6.2 Hz),
5.41(1H, br s). 13C NMR (75 MHz): ꢀ5.4 (2C), ꢀ4.6
(2C), 18.1, 19.9, 23.0, 25.0, 25.8, 25.9 (6C), 26.7, 33.6,
35.1, 37.1, 39.2, 42.5, 45.3, 56.9 (2C), 62.6, 65.8, 76.6,
85.0, 100.7, 107.1, 109.3, 128.2, 137.2, 148.9. ESIMS
(MeOH): 649 ([MK]+, 14), 633 ([MNa]+, 100). HRE-
SIMS (MeOH) calcd for C34H66O5NaSi2 633.4347;
found 633.4340.
Dess–Martin periodinane oxidation of triols 30 and 31 is
achieved according to the general procedure on a
0.2 mmol scale leading, after silica gel column chroma-
tography using heptane–EtOAc, 3:1as eluent, to 32
(76 mg, 84%) and 33 (78 mg, 86%), respectively.
20
D
4.9.3. Enone-aldehyde 32. ½aŠ ¼ ꢀ111 (c 1.6, CHCl3).
The deprotection of tert-butyldimethylsilyl ethers at
C-14 and C-2 of 34 (73 mg, 0.12 mmol) using the general
procedure afforded, after the usual work up and SiO2
IR (film): 3435, 2971, 2933, 1719, 1666, 1471, 1455,
1416, 1389, 1364, 1309, 1270, 1249, 1214, 1190, 1147,
1085, 1054, 1018, 905 cmꢀ1. H NMR (300 MHz): 0.79
flash chromatography (heptane–EtOAc, 1:1), 41 mg
1
20
(3H, s), 1.03 (3H, s), 1.09 (9H, s), 1.14 (3H, s), 1.16–
2.28 (6H, m), 1.98 (3H, s), 2.18 (1H, d, J = 17.9 Hz),
2.73 (1H, d, J = 17.9 Hz), 3.02 (1H, s), 3.52 (3H, s),
3.79 (1H, d, J = 10.0 Hz), 3.94 (1H, dd, J = 10.4,
4.3 Hz), 4.68 (1H, s), 4.71 (1H, d, J = 6.5 Hz), 4.80
(1H, d, J = 6.5 Hz), 4.82 (1H, br s), 4.98 (1H, br s),
5.98 (1H, s), 9.56 (1H, t, J = 1.7 Hz). 13C NMR
(75 MHz): 17.4, 19.7, 26.2, 27.8, 29.2 (3C), 30.0, 30.4,
36.2, 40.9, 41.8, 50.6, 57.3, 65.3, 71.9, 73.3, 79.8, 89.0,
101.0, 115.1, 129.3, 140.0, 162.5, 198.2, 198.7. ESIMS
(MeOH): 489 ([MK]+, 22), 473 ([MNa]+, 100). HRE-
SIMS (MeOH) calcd for C26H42O6Na 473.2879; found
473.2872.
(91%) of triol 35: ½aŠ ¼ þ2 (c1.8, CHCl3). IR
D
(film): 3401, 2931, 1646, 1455, 1379, 1358, 1248, 1209,
1142, 1083, 1055, 1022, 984, 911, 890, 754 cmꢀ1 1H
.
NMR (300 MHz): 1.02 (9H, s), 1.21–2.16 (11H, m),
1.25 (1H, t, J = 7.2 Hz), 1.79 (3H, s), 2.63 (2H, br s),
3.46 (3H, s), 3.62 (1H, dd, J = 10.7, 7.7 Hz), 3.84 (1H,
dd, J = 10.7, 5.2 Hz), 3.88 (1H, d, J = 10.0 Hz), 4.16–
4.27 (1H, m), 4.64 (1H, d, J = 6.1Hz), 4.73 (1H, br s),
4.78 (1H, d, J = 6.1 Hz), 4.87 (1H, s), 5.56 (1H, br s).
13C NMR (75 MHz): 19.7, 22.7, 24.8, 25.0, 26.4, 32.6,
34.5, 37.0, 39.3, 43.0, 44.7, 56.9, 58.0, 60.6, 65.0, 77.5,
84.5, 100.4, 110.6, 127.9, 138.4, 147.9. ESIMS (MeOH):
421([MK] +, 16), 405 ([MNa]+, 100). HRESIMS
(MeOH) calcd for C22H38O5Na 405.2617; found
405.2619.
20
4.9.4. Enone-aldehyde 33. ½aŠ ¼ ꢀ242 (c 2.3, CHCl3).
IR (film): 3470, 2972, 2877, D1722, 1716, 1661, 1622,
1469, 1455, 1440, 1389, 1372, 1315, 1281, 1248, 1189,
The oxidation of triol 35 (37 mg, 0.10 mmol) was carried
out by addition of Dess–Martin periodinane (266 mg,
0.63 mmol) according to the general procedure. The
usual work up allowed, after filtration through a short
silica gel column using heptane–EtOAc, 3:1as eluent,
1082, 1068, 1050, 1027, 1011, 909 cmꢀ1 1H NMR
.
(300 MHz): 0.94 (3H, s), 1.08 (9H, s), 1.12 (3H, s),
1.13 (3H, s), 1.46–2.08 (3H, m), 1.67 (1H, dd,
J = 15.2, 10.5 Hz), 1.87 (1H, d, J = 15.2 Hz), 2.00 (3H,
s), 2.21H(1, d,
J = 17.9 Hz), 2.55 (1H, d,
28 mg (76%) of the desired enone-aldehyde 7:
20
J = 17.9 Hz), 3.08 (1H, s), 3.51 (3H, s), 3.95 (1H, dd,
J = 11.0, 4.5 Hz), 4.10 (1H, d, J = 10.3 Hz), 4.52 (1H,
s), 4.78 (1H, d, J = 6.6 Hz), 4.81 (1H, br s), 4.82 (1H,
d, J = 6.6 Hz), 4.86 (1H, br s), 5.00 (1H, br s), 5.96
(1H, s), 9.56 (1H, d, J = 1.8 Hz). 13C NMR (75 MHz):
½aŠ ¼ ꢀ64 (c 1.3, CHCl3). IR (film): 3467, 2935, 1718,
D
1661, 1442, 1373, 1335, 1276, 1146, 1087, 1062, 1024,
1
906, 755 cmꢀ1. H NMR (300 MHz): 1.04 (3H, s), 1.12
(6H, s), 1.15–2.27 (8H, m), 2.04 (3H, d, J = 1.2 Hz),
2.63 (1H, d, J = 18.5 Hz), 2.78 (1H, d, J = 2.5 Hz),

I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
3449
3.50 (3H, s), 3.99 (1H, dd, J = 8.8, 3.0 Hz), 4.39 (1H, br
s), 4.68 (1H, d, J = 6.5 Hz), 4.69 (1H, s), 4.80 (1H, s),
4.82 (1H, d, J = 6.5 Hz), 4.99 (1H, s), 5.98 (1H, s),
65.6 (C14), 77.2 (C10), 87.8 (C11), 94.9 (C21), 111.7
(C20), 127.5 (C13), 139.1 (C12), 147.1 (C4). HRESIMS
(MeOH) calcd for C21H34O4Na 373.2355; found
373.2360. Anal. Calcd for C21H34O4: C, 71.96; H, 9.78.
Found: C, 71.97; H, 9.97.
9.71(H1 , d,
J = 2.7 Hz). 13C NMR (75 MHz): 21.2,
22.3, 24.1, 24.6, 27.7, 33.2, 35.4, 37.7, 40.0, 40.6, 50.2,
57.0, 67.0, 78.5, 85.6, 100.4, 113.6, 128.2, 141.8, 163.3,
198.0, 201.3. ESIMS (MeOH): 417 ([MK]+, 8), 401
([MNa]+, 100). HRESIMS (MeOH) calcd for
C22H34O5Na 401.2304; found 401.2301.
4.12. Coupling of the mismatched partners (14S)-1/(10R)-
6; preparation of B-secotaxoids 37–42
Use of the general procedure for fragment coupling
(10R)-6 (316 mg, 0.50 mmol) and (14S)-1 (134 mg,
0.50 mmol) afforded, after SiO2 column chromatogra-
phy (eluent heptane–ether, 25:1), a mixture of two
A+C adducts 37 and 38 as a 1:1.3 mixture in a 89%
combined yield.
4.11. Preparation of cyclic formaldehyde-acetals 36a and
36b
Using the general procedure for cyclic formaldehyde-
acetal formation (27 mg, 0.044 mmol) of 34, afforded,
after silica gel flash chromatography (heptane–Et2O,
25:1), 25 mg (84%) of 36a.
20
D
4.12.1. Compound 37 (faster eluting isomer). ½aŠ
¼
þ1 4 c( 1.3, CHCl3). IR (film): 3487, 2954, 2929, 2856,
20
4.11.1. Compound 36a. ½aŠ ¼ þ1 0 c( 1.1, CHCl3). IR
D
1648, 1472, 1462, 1395, 1361, 1255, 1088, 1063, 1041,
(film): 2951, 2925, 2853, 1470, 1460, 1362, 1256, 1099,
1
1026, 1005, 870, 835, 774 cmꢀ1. H NMR (500 MHz):
1
1062, 1026, 1005, 974, 866, 835, 773 cmꢀ1. H NMR
0.02 (3H, s), 0.03 (3H, s), 0.05 (3H, s), 0.06 (3H, s),
0.87 (9H, s), 0.89 (9H, s), 0.97 (6H, s), 0.99–1.06 (2H,
m), 1.10 (3H, m), 1.13–1.16 (1H, m), 1.42–1.48 (1H,
m), 1.55 (2H, dd, J = 9.7, 4.2), 1.60–1.64 (2H, m), 1.72
(3H, s), 1.91–1.98 (2H, m), 2.05–2.10 (1H, m), 2.16–
2.23 (1H, m), 3.49 (3H, s), 3.74 (1H, t, J = 9.7 Hz),
4.00 (1H, dd, J = 9.7, 3.8 Hz), 4.27 (1H, m), 4.33 (1H,
s), 4.61 (1H, br s), 4.64 (1H, d, J = 6.6 Hz), 4.78 (1H,
s), 4.85 (1H, d, J = 6.6 Hz), 5.47 (1H, br s). 13C NMR
(125 MHz): ꢀ5.3 (2C), ꢀ4.5 (2C), 18.1, 18.2, 18.4,
22.9, 24.9, 25.9 (6C), 27.1, 27.3, 32.4, 35.8, 36.9, 40.7,
40.8, 45.2, 55.5, 56.9, 61.0, 66.0, 78.6, 88.8, 101.4,
110.2, 130.8, 137.0, 147.2. ESIMS (MeOH): 649
([MK]+, 32), 633 ([MNa]+, 100). HRESIMS (MeOH)
calcd for C34H66O5NaSi2 633.4347; found 633.4346.
(800 MHz): 0.03 (3H, s, MeSi), 0.06 (3H, s, MeSi),
0.08 (3H, s, MeSi), 0.09 (3H, s, MeSi), 0.88 (9H, s,
tBu), 0.91(9H, s, tBu), 1.01 (3H, s, Me19), 1.06 (6H,
s, 2Me15), 1.42–1.68 (8H, m), 1.71 (3H, t, J = 1.6 Hz,
Me18), 1.94 (1H, t, J = 5.9 Hz, H3), 2.04 (1H, td,
J = 13.5, 5.1 Hz, H1), 2.11 (1H, m, H1), 3.72 (2H, d,
J = 6.0 Hz, H2,2), 4.14 (1H, d, J = 9.9 Hz, H10), 4.16–
4.18 (1H, m, H14), 4.63 (1H, d, J = 2.2 Hz, H21b),
4.80 (1H, s, H21a), 4.90 (1H, s, H20a), 5.14 (1H, s,
H20b), 5.43 (1H, s, H13). Diagnostic NOEs: {Me-18}:
H-13, H-21a; {Me-15}: H-10, H-21b; {H-21b}: H-10,
H-21a (NOE gem). 13C NMR (125 MHz): ꢀ5.0 (MeSi),
ꢀ4.9 (MeSi), ꢀ3.9 (MeSi), ꢀ3.8 (MeSi), 18.2 (Cq, tBu),
18.5 (Cq, tBu), 20.9 (Me18), 23.5 (C6), 25.4 (Me19), 25.5
(Me15), 25.6 (Me15), 26.3 (3C, tBu), 26.5 (3C, tBu), 33.7
(C5), 35.5 (C9), 37.8 (C15), 39.6 (C8), 40.4 (C7), 45.0
(C1), 56.8 (C3), 62.2 (C2), 66.3 (C14), 77.6 (C10), 88.4
(C11), 95.4 (C21), 110.1 (C21), 128.1 (C13), 138.3 (12),
148.6 (C4). HRESIMS (MeOH) calcd for C33H62O4Na-
Si2 601.4084; found 601.4099. Anal. Calcd for
C33H62O4Si2 · 0.22 CH2Cl2: C, 66.68; H, 10.52. Found:
C, 66.69; H, 10.66
20
D
4.12.2. Compound 38 (slower eluting isomer). ½aŠ
¼
ꢀ55 (c 1.1, CHCl3). IR (film): 3514, 2953, 2929, 2856,
1648, 1472, 1462, 1386, 1360, 1255, 1146, 1088, 1062,
1037, 939, 835, 773 cmꢀ1. H NMR (250 MHz): 0.02
1
(6H, s), 0.05 (6H, s), 0.83 (9H, s), 0.87 (9H, s), 0.96
(3H, s), 0.98 (3H, s), 1.14 (3H, s), 0.82–2.21 (12H, m),
1.83 (3H, s), 3.48 (3H, s), 3.58–4.34 (4H, m), 4.59 (1H,
br s), 4.64 (1H, d, J = 6.3 Hz), 4.79 (1H, br s), 4.83
(1H, d, J = 6.3 Hz), 5.46 (1H, br s). 13C NMR
(62.5 MHz): ꢀ5.4 (2C), ꢀ4.7, ꢀ4.6, 18.1, 18.2, 20.2,
23.2, 24.9, 25.5, 25.9 (6C), 27.9, 32.7, 35.7, 35.8, 37.0,
41.6, 44.5, 56.1, 56.9, 61.4, 64.2, 77.2, 85.4, 101.0,
110.1, 127.4, 137.4, 147.9. ESIMS (MeOH): 649
([MK]+, 12), 633 ([MNa]+, 100). HRESIMS (MeOH)
calcd for C34H66O5NaSi2 633.4347; found 633.4349.
Use of the general procedure for TBS-deprotection on
36a (25 mg, 0.043 mmol) gave 15 mg (96%) of 36b.
20
4.11.2. Compound 36b. ½aŠ ¼ þ38 (c 1.1, CHCl3). IR
D
(film): 3354, 2930, 2869, 1454, 1376, 1216, 1100, 1007,
1
971, 891, 755 cmꢀ1. H NMR (800 MHz): 1.02 (3H, s,
Me15), 1.04 (3H, s, Me15), 1.08 (3H, s, Me19), 1.42
(1H, dd, J = 9.4 Hz, H1), 1.44–1.65 (8H, m), 1.72 (3H,
s, Me18), 1.88 (1H, ddd, J = 13.4, 6.9, 1.4 Hz, H1),
2.12 (1H, dd, J = 9.9, 4.3 Hz, H3), 2.13–2.16 (2H, m),
3.66 (1H, t, J = 10.3 Hz, H2), 3.78 (1H, dd, J = 10.4,
4.3 Hz), 4.24 (1H, t, J = 5.7 Hz, H10), 4.26–4.30 (1H,
m, H14), 4.78 (1H, s, H21), 4.95 (1H, s, H20), 4.86
(1H, s, H21), 5.12 (1H, s, H20), 5.58 (1H, s, H13). Diag-
nostic NOEs: {Me-18}: H-13, H-21a; {Me-15}: H-10,
H-21b; {H-21b}: H-10, H-21a (NOE gem). 13C NMR
(200 MHz): 20.5 (Me19), 22.6 (C6), 24.4 (Me18), 24.9
(Me15), 25.5 (Me15), 32.0 (C5), 34.7 (C9), 37.0 (C15),
39.6 (C8), 40.5 (C7), 44.0 (C1), 56.2 (C3), 59.4 (C2),
The deprotection of tert-butyldimethylsilyl ethers at
C-14 and C-2 of 37 and 38 on a 0.3 mmol scale using
the general procedure afforded, after the usual work
up and SiO2 flash chromatography (heptane–EtOAc,
2:1to 1:3), 96 mg (87%) of triol 39 and 98 mg (89%)
of triol 40, respectively.
20
4.12.3. Compound 39. ½aŠ ¼ þ54 (c 1.1, CHCl3). IR
D
(film): 3400, 2930, 1648, 1472, 1443, 1380, 1215, 1145,
1088, 1065, 1026, 945, 892, 849 cmꢀ1
.
1H NMR

3450
I.Safir et al./ Tetrahedron: Asymmetry 16 (2005) 3436–3450
(300 MHz): 0.92 (3H, s), 0.96 (3H, s), 1.10 (3H, s), 1.21–
2.17 (11H, m), 1.75 (3H, s), 2.48 (2H, br s), 3.50 (3H, s),
36.6, 39.8, 42.1, 50.4, 57.2, 65.4, 78.1, 85.7, 100.6,
114.7, 128.3, 141.7, 163.2, 197.7, 200.0. ESIMS
(MeOH): 417 ([MK]+, 58), 401([MNa] +, 100). HRE-
SIMS (MeOH) calcd for C22H34O5Na 401.2304; found
401.2307.
3.61H(1, dd,
J = 10.9, 7.0 Hz), 3.73 (1H, d,
J = 10.1 Hz), 3.86–3.97 (1H, m), 4.19–4.31 (1H, m),
4.34 (1H, s), 4.63 (1H, d, J = 6.6 Hz), 4.72 (1H, s),
4.82 (1H, d, J = 6.6 Hz), 4.86 (1H, s), 5.62 (1H, br s).
13C NMR (75 MHz): 18.4, 22.5, 24.3, 26.9, 27.1, 32.2,
33.6, 36.7, 41.1, 42.5, 44.5, 57.0, 57.3, 61.3, 65.5, 78.9,
88.2, 101.1, 110.6, 129.7, 138.8, 148.4. ESIMS (MeOH):
421([MK] +, 18), 405 ([MNa]+, 100).
Acknowledgments
The authors thank the European Commission for a
Research Training Grant to Dr. J. I. Candela Lena
and Professor Jean-Yves Lallemand for his kind interest
20
4.12.4. Compound 40. ½aŠ ¼ ꢀ70 (c 1.3, CHCl3). IR
(film): 3584, 3401, 2931, 1D645, 1454, 1380, 1147, 1060,
´
and constant encouragements. Dr. J. I. Martın Her-
1
1024, 929, 891 cmꢀ1. H NMR (300 MHz): 0.98 (3H,
´
nando, Dr. J. Quılez del Moral and Dr. M. Rico Ferre-
s), 0.99 (3H, s), 1.15 (3H, s), 1.18–2.18 (13H, m), 1.85
(3H, s), 3.49 (3H, s), 3.54 (1H, d, J = 10.2 Hz), 3.83–
3.92 (2H, m), 4.02 (1H, s), 4.04–4.11 (1H, m), 4.66
(1H, d, J = 6.3 Hz), 4.74 (1H, br s), 4.85 (1H, d,
J = 6.3 Hz), 4.94 (1H, br s), 5.62 (1H, br s). 13C NMR
(75 MHz): 20.1, 22.7, 24.7, 24.8, 28.1, 31.1, 35.2, 35.7,
36.7, 42.2, 44.0, 56.2, 57.0, 59.5, 64.2, 77.2, 84.7, 100.8,
112.3, 126.6, 139.2, 147.1. ESIMS (MeOH): 421
([MK]+, 22), 405 ([MNa]+, 100).
ira are gratefully acknowledged for their participation in
the initial steps of this study and the Hoffmann-La-
Roche company (Basel) for a generous gift of phorenol.
References
´
´
1. Martın Hernando, J. I.; Quılez del Moral, J.; Rico
Ferreira, M.; Candela Lena, J. I.; Arseniyadis, S. Tetra-
hedron: Asymmetry 1999, 10, 783–797; Rico Ferreira, M.;
Dess–Martin periodinane oxidation of triols 39 (63 mg,
0.16 mmol) and 40 (37 mg, 0.10 mmol) is achieved
according to the general procedure leading, after silica
gel column chromatography using heptane–EtOAc, 3:1
as eluent, to 41 (48 mg, 86%) and 42 (32 mg, 89%),
respectively.
´
Martın Hernando, J. I.; Candela-Lena, J. I.; Birlirakis, N.;
´
Arseniyadis, S. Synlett 2000, 113–115; Martın Hernando,
J. I.; Rico Ferreira, M.; Candela Lena, J. I.; Birlirakis, N.;
Arseniyadis, S. Tetrahedron Lett. 2000, 41, 863–866.
2. Still, W. C. J.Am.Chem.Soc. 1978, 100, 1481–1486.
´
3. Martın Hernando, J. I.; Rico Ferreira, M.; Candela Lena,
J. I.; Birlirakis, N.; Arseniyadis, S. Tetrahedron: Asymme-
try 2000, 11, 951–973.
4. Shigemori, H.; Sakurai, C. A.; Hosoyama, H.; Kobayashi,
A.; Kajiyama, S.; Kobayashi, J. Tetrahedron 1999, 55,
2553–2558.
20
4.12.5. Enone-aldehyde 41. ½aŠ ¼ ꢀ68 (c 1.9, CHCl3).
D
IR (film): 3584, 3435, 2931, 1716, 1667, 1443, 1414,
1371, 1309, 1214, 1149, 1087, 1063, 1018, 904 cmꢀ1
.
1H NMR (300 MHz): 0.86 (3H, s), 1.04 (3H, s), 1.15
(3H, s), 0.87–2.26 (9H, m), 1.99 (3H, d, J = 0.8 Hz),
2.71(1H, d, J = 18.3 Hz), 2.77 (1H, s), 3.52 (3H, s),
3.78 (1H, d, J = 10.4 Hz), 4.68 (1H, d, J = 6.6 Hz),
4.75 (1H, s), 4.78 (1H, s), 4.81 (1H, d, J = 6.6 Hz),
4.97 (1H, s), 5.99 (1H, br s), 9.68 (1H, d, J = 2.6 Hz).
13C NMR (75 MHz): 19.8, 22.1, 23.4, 25.9, 27.9, 32.1,
35.3, 36.5, 40.4, 41.7, 50.3, 57.3, 65.1, 79.4, 88.3, 100.8,
114.3, 129.4, 141.6, 162.8, 198.4, 199.9. ESIMS
(MeOH): 417 ([MK]+, 32), 401([MNa] +, 100).
5. Zhang, H.; Takeda, Y.; Minami, Y.; Yoshida, K.;
Matsumoto, T.; Xiang, W.; Mu, O.; Sun, H. Chem.Lett.
1994, 957–960.
6. Broger, E. A.; Crameri, Y.; Schmid, R.; Siegfried, T.
Hoffmann-La-Roche, Eur. Pat. 691325, 1995.
´
7. Candela Lena, J. I.; Rico Ferreira, M.; Martın Hernando,
J. I.; Arseniyadis, S. Tetrahedron: Asymmetry 2001, 12,
3281–3291, and references cited therein.
8. Except for compounds 19, 20, and 21, which are of no use
for taxoid construction, the taxoid numbering has been
used throughout the manuscript.
9. Organometallic carbon nucleophiles generally react with
carbon electrophiles with retention of configuration: Still,
W. C.; Sreekumar, C. J.Am.Chem.Soc. 1980, 102, 1201–
1202; Sawyer, J. S.; Macdonald, T. L.; McGarvey, G. J. J.
Am.Chem.Soc. 1984, 106, 3376–3377.
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F.; Johnson, C. R.; Medich, J. R. Org.Synth. 1992, 71,
133–139.
20
D
4.12.6. Enone-aldehyde 42. ½aŠ ¼ ꢀ221(
c
1.1,
CHCl3). IR (film): 3459, 2938, 1719, 1662, 1442, 1376,
1334, 1308, 1273, 1149, 1085, 1063, 1016, 907,
755 cmꢀ1 1H NMR (250 MHz): 0.98 (3H, s), 1.11
.
(3H, s), 1.13 (3H, s), 1.19–2.06 (6H, m), 1.43 (1H, d,
J = 15.2 Hz), 1.74 (1H, d, J = 10.6 Hz), 2.01 (3H,
d, J = 1.0 Hz), 2.21 (1H, d, J = 18.3 Hz), 2.50 (1H, d,
J = 18.3 Hz), 2.87 (1H, s), 3.50 (3H, s), 4.08 (1H, d,
J = 10.4 Hz), 4.58 (1H, s), 4.70 (1H, d, J = 6.4 Hz),
4.81 (1H, s), 4.83 (1H, d, J = 6.4 Hz), 4.99 (1H, s),
5.98 (1H, s), 9.63 (1H, d, J = 2.6 Hz). 13C NMR
(62.5 MHz): 21.3, 22.2, 23.9, 24.1, 27.7, 31.8, 35.4,
11. Dauben, W. G.; Michno, D. M. J.Org.Chem. 1977, 42,
682–685.
12. Hall, L. D.; Sanders, J. K. M. J.Am.Chem.Soc.
102, 5703–5711.
1980,
13. LeCocq, C.; Lallemand, J.-Y. J.Chem.Soc,. Chem.
Commun. 1981, 150–152.