Grignard 1,4-Additions to para-Substituted (2R)-N-Cinnamoylbornane-10,2-sultam Derivatives: Revised Configuration for the N,OAc-Keteneacetal Formation in the Presence of Cu(I)

Article abstract of DOI:10.1002/hlca.201500521

Using a¹⁹F-NMR analytical method, we have corrected and improved the linear correlation initially found between the diastereoselectivity observed during the EtMgBr conjugated addition to Michael acceptors of type 1, as a function of their σ

Full text of DOI:10.1002/hlca.201500521

Received Date: 10-Dec-2015
Accepted Date: 19-Jan-2016
Article Type: Full Paper
Grignard 1,4-Additions to para-Substituted (2R)-N-
Cinnamoylbornane-10,2-sultam Derivatives: Revised Configuration for
the N,OAc-Keteneacetal Formation in the Presence of CuI
by Anna Piątek*a) and Christian Chapuis*b)1)
a) Department of Chemistry, University of Warsaw, Pasteura 1, PL-02-093 Warsaw
(phone: +48-22-8220211; fax: +48-22-8225996; e-mail: apiatek@chem.uw.edu.pl)
b) Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, PL-
01-224 Warsaw (phone: +41-22-7803610; fax: +41-22-7803334; e-mail:
christian.chapuis@firmenich.com)
Dedicated to the memory of Joseph Challande (1906-1965)2).
1
)
)
Present address (and correspondence to): Firmenich SA, Corporate R&D
Division, P.O. Box 239, CH-1211 Geneva 8.
2
Active member of the French resistance (cie FTPF 93.03), arrested after
denunciation on 9th Dec. 1943 in Ambilly by the Feldgendarmes of the 9th Kp, he
was interrogated at the Hôtel Pax (#303), seat of the GeStaPo in Annemasse. In
absence of a confession, he was transferred to Fort de Montluc in Lyon (20th
Dec.), then to Compiègne, from where he was deported on 22nd Jan. 1944 by
railway convoy I.172 to Buchenwald. Assigned to the Kdo Weimar, in Block
17/56, with the official number 43062 (24th Jan.), he was liberated by the 3rd US
army forces on 11th Apr. 1945 [1]. After a convalescence period in a Red Cross
camp, he was repatriated via the hotel Lutetia in Paris, before he finally met again
with his wife and elder daughter, the late grandmother and mother of C. C.,
respectively.
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By using an 19F-NMR analytical method, we have corrected and improved the
linear correlation initially found between the diastereoselectivity observed during the
EtMgBr conjugated addition to Michael acceptors of type 1, as a function of their σpara
Hammett electronic parameters. Based on 1H-NMR analyses, we have also discovered
that the original configuration of the acetylated intermediate, obtained by either hydride,
Grignard, or cuprate conjugate additions to α-substituted N-enoyl bornane-10,2-sultams
was, from the initial report, erroneously attributed by Oppolzer et al. A new, much
simpler rationalization for these 1,4-additions is proposed.
Keywords: Grignard 1,4-addition, Conjugated, Michael additions, Cinnamoyl,
Sultam.
Introduction. - Four years ago, we presented a series of alkyl 1,4-additions to
electronically modified para-substituted (2R)-N-cinnamoylbornane-10,2-sultam
derivatives 1 [2]3). At that time, we found a clear predictable electronic influence, as
3
)
For reviews on the general use of (2R)-bornane-10,2-sultam as chiral auxiliary,
see [3]. In the last review, the authors suggest that, from both possible
stereoisomers obtainable by reduction of the camphor sulfonimine, the exo is
exclusively isolated, as a result of the steric shielding of the Me(8) substituent
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expressed by a linear correlation between the level of asymmetric induction and the
Hammett σpara parameter (log (d.r.) = –0.459σpara + 0.834, n = 13, R2 = 0.83, s.d. =
0.083) using EtMgBr in THF at -78°. Both the reactivity and selectivity were decreasing
for electron demanding para-substituents on the cinnamoyl moiety of the Michael
acceptors. We were intrigued by the fact that the two largest deviations, were both
obtained for F containing substrates, namely p-F-2a (78% de measured, calculated 71%
de) and p-CF3O-2b (73% de measured, calculated 65% de). We wondered whether this
situation originated from either the regular standard experimental error, or an eventual
analytical problem, or if any electronic factors resulting from this specific F atom could
be responsible for these deviations, and thus decided to study in more detail this class of
Michael acceptors.
Results. - We concentrated our attention on both anomalous results considered
in the introduction, in addition to their p-CF3 analog 2c (62% de measured, calculated
59% de) [2]. The initial analytical method was based on the integration of the Me(8)
exerted on the approach of the reducing agent [3e]. In fact, the endo-
stereoisomer would possess two trans-fused five member rings, which is
geometrically and thermodynamically impossible, except for some very specific
strained situations [4]. For bicyclo[2.2.1]heptane derived sultam analogs devoid
of Me(8), and consequently of disguised C2 symmetry, see [5]. For selected
reviews on asymmetric 1,4-additions, see [3f][3g].
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singlet in the 1H-NMR analysis of the crude reaction products, as earlier reported in a
similar case [6]. Although the sensitivity and precision (+/- 2%), hence experimental
error, of the high field NMR method is not fundamentally modified, we now opted for a
simple and direct 19F-NMR analysis, as earlier reported for this kind of substrates [7][8].
Indeed, with CFCl3 as reference, compound p-F-2a exhibits two distinct diastereotopic
signals at -117.39 (major) and -117.50 ppm (minor), while the p-CF3O-2b and p-CF3-2c
analogs exhibit displacements at -58.18/-58.23, and -62.68/-62.73 ppm, respectively.
The signals of the major (3R)-diastereoisomers appear systematically at higher field.
Oppolzer et al. [9], as well as Liu and co-workers [10], earlier, judiciously
noticed that a two-fold excess of Grignard reagent was necessary for an efficient 1,4-
addition (see Table, Entries 1-3)4). When we repeated our initial conditions (2.2 mol.-
equiv. of EtMgBr, THF, -78°, 4 h), the observed diastereoisomeric excess for 2a-c
slightly decreased from 78 to 74%, and from 73 to 68% for 2a,b and remained
practically unchanged for 2c (from 62 to 60% de), in accord with the expected
calculated behavior. When these new values were incorporated into the linear
correlation, an improved equation model was found (log (d.r.) = –0.466σpara + 0.82, n =
4
)
For an example where only 1.2-1.4 mol.-equiv. of EtMgBr was used, resulting in
a chemical yield of 55-61%, see [11a][11b]. For ulterior ameliorated conditions
using 2.5 mol.-equiv., see [11c]. The stoichiometry is not indicated in [11d].
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13, R2 = 0.91, s.d. = 0.059). It is noteworthy that the usual picture in the 500 MHz 1H-
NMR shows two major singlets for the gem-dimethyl groups, accompanied by two
minor signals for the minor (S)-diastereoisomer [2]. Based on the thirteen examples
earlier studied, it appears that the worse separation between the major Me(8) and the
minor Me(9) of the (S)-diastereoisomer is observed for 2a and 2b, thus slightly
corrupting the measured ratio between major and minor Me(8) signals by integration,
although we still remain within the deviation of the standard error (ca. 4% on de) with
respect to the initial results. This point being settled and corrected, we also studied these
Michael additions under different conditions as summarized in the Table, more
specifically either in different solvents, or in the presence of both a Lewis acid and a
single equivalent of EtMgX, in analogy to the Schlenk equilibrium [2][12][13]. The
diastereoselectivity is slightly higher in toluene as compared to THF (Entries 4, 10 vs. 6,
12), while the reaction is eventually sluggish in CH2Cl2 (Entry 10 vs. 11), although the
π-facial selectivity is not drastically influenced (Entries 4, 10 vs. 5, 11). With TiCl4, the
reaction was even slower and only 31% of conversion was obtained after 24h in THF
(Entry 13). The situation was even worse with ZnBr2, although the diastereoselectivity
remained around ca. 75% de (Entry 14). When the temperature was increased, the
conversion logically increased, albeit at the expense of the diastereoselectivity (Entries
14-16). Since the situation was not optimal at 20° (Entry 17), we finally chose to
perform the reactions at 4° using an ice bath. The conversion increased by using ZnI2,
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but the π-facial selectivity dropped (Entry 18 vs. 16). When a non-chelating Lewis acid
such as BF3 · Et2O was used, the diastereoselectivity increased, but now to the expense
of the conversion (Entry 19 vs. 16), suggesting either that the SO2/C=O syn-chelated
conformation is important for the activation of the Michael acceptor, or that the
chelating bimetallic complex is formed, but reacts with modest conversion, due to the
low excess of Grignard reagent, as suggested by the sense of induction. The most
encouraging results were obtained under pseudo Schlenk conditions by using MgCl2
(Entry 20 vs. 18, or 16). It is noteworthy that MgBr2 was less efficient either in terms of
conversion or diastereoselectivity (Entry 23 vs. 20). This trend was also observed for the
analogous adducts 2b (Entry 24 vs. 21) and 2c (Entry 25 vs. 22). With MgCl2, the
decrease of diastereoselectivity follows the same electronic trend as earlier observed in
the presence of a double amount of EtMgBr (Entries 20, 21, 22 vs. 1, 2, 3). MgI2,
known to catalyze the attack and opening of THF at such a temperature, was not tested,
since we earlier also showed that the diastereoselectivity of these Grignard additions to
1d was diminishing when EtMgCl (78% de, Entry 6) was changed for EtMgBr (73% de,
Entry 7), and more spectacularly for the non-aggregating EtMgI in Et2O (31% de, Entry
8). It is worthy of note that in toluene, addition of 2.2 mol.-equiv. of EtMgI/Et2O to 1d
at -78°, failed to afford 2d (Entry 9). Similar negative results were obtained by addition
of 1.1 mol.-equiv. of either EtMgI, or Et2Mg in the presence of 1.1 mol.-equiv. of MgI2
(generated from Mg and I2) to 1d in toluene.
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Oppolzer et al. [9][14], as well as Huang et al. and Chen et al. [15], earlier also
noticed that the sense of induction could be reversed by using a cuprous salt/Grignard
reagent complex. They invoked a s-trans, rather than a s-cis conformation of the Cα=Cβ
double bond to rationalize their results. Our substrates are energetically less prone to
such a s-trans conformation, as compared to either their N-crotonoyl, or Cα-substituted
Michael acceptors [2]. Due to the lower reactivity of 1a (Entry 26), we again were
forced to work at 4° (Entry 27). At this temperature the conversion was much improved
and obviously, the sense of induction also depends on the halide used to generate the
organo-copper reagent (Entry 27 vs. 28 and 29). We thus strengthened our earlier
conviction that the alkyl Grignard 1,4-additions, with or without CuI, could be biased
due to a possible transfer of steric chiral information from the bornane skeleton to the
remote Cβ position, through a conformationally rigid multi-metallic aggregate, directing
its ‘coordinating’ ligands in thermodynamically and geometrically preferred directions,
more specifically in the case of Br– and Cl–, in contrast to the non-aggregating softer I–
[2]. In the latter case, the free nucleophile could eventually attack, as usual, the opposite
face. This could also explain the reverse selectivity observed in the presence of an
excess of either LiCl [16], or CuI non-aggregating Lewis acids [17].
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Discussion. – We initially decided to study the 1,4-additions because the remote
reactive β-center was believed to be poorly sterically influenced by the prosthetic group,
and thus we hoped to put in evidence the stereoelectronic effect of the pyramidalized N
lone pair (lp) [2]5). Indeed, in 1986 Oppolzer and Poli rationalized the hydride
conjugated addition to N-2-methyl-pent-2-enoyl sultam 4c by a bottom Cβ-re face attack
on the SO2/C=O anti and C=O/C=C s-cis conformation, followed, after rotation and
chelation of the resulting (Z)-5b to the pseudo equatorial S=O, by addition of the
electrophile on the bottom Cα-re face [22], sterically directed by the masked C2
chirophor6) (Scheme 2). Two years later, in the light of the transoid form exhibited by
5
)
For a 1,4-vinyl cuprate additions systematically opposite to the N lp, whatever
the adopted SO2/C=O syn or anti, C=O/C=C s-cis disposition, see [17]. For
similar 1,4-additions of alkenylzirconocene chloride, see [18]. For X-ray
analyses of SO2/C=O syn conformers of type 3, see [19] and references cited
therein. For thiol 1,4-conjugated additions on N-methacryloyl sultam 4a with
Cα-re protonation, see [20]. For radical conjugated additions with similar π-
facial H. insertion, see [21]. For specific references related to 1,4-additions using
this prosthetic group, see [2].
6
)
In the anti-s-cis orientation, the Cβ is slightly closer to C(2), as compared to SO2.
In fact the Cα electrophilic addition, due to the pseudo C2 symmetry of the
chirophor, may equally be performed in the anti-s-cis conformation. At that time
this rotation seemed necessary since the pseudo equatorial Li-chelated S=O/C=O
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this kind of α-substituted Michael acceptors in the crystalline state [23]7), Oppolzer et
al., succeeding in trapping the corresponding (E)-ketene N,OAc acetal, consequently
modified their initial rationalization in the specific case of α-substituted Michael
acceptors, now suggesting that they should react in a s-trans conformation to afford 6
[23] (Scheme 2). These authors did not mention the fact that (E)-5b should be
protonated in a contra-steric fashion in order to respect the final configuration at the Cα
center. In fact this problem was already discussed and resolved in the meantime, by
proposing chelation of the intermediate (E)-5b with the bottom pseudo axial S=O
syn s-cis conformer, as initial reactive conformation, would not be as selective as
for the sterically C(2) influenced proximate Cα, as wisely later recognized by
Kim and Curran [3d]. Indeed, in this conformation the Cβ is practically
equidistant to both the SO2 and C(2) centers. For 1,4-additions, we have in the
past rather privileged a stereoelectronic control of the N lp, although we could
not prove it up to now, and it would only apply to the anti-s-cis conformer in the
present case [2]. This reactive conformation was nevertheless correctly
recognized by Oppolzer and Poli in their initial study [22].
7
)
For ulterior examples, see [24]. In the crystalline state the SO2/C=O anti-
conformations exhibit the following O=C-Cα=Cβ transoid dihedral angles: 4b
134° [23]; 4a 137° [24a]; 131° [24b]; 141° [24c].
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moiety, thus offering the apparently less hindered front face to the electrophile trajectory
[3b][3c][9]8).
We earlier demonstrated that the non-chelated minor SO2/C=O syn-conformer
may, in some instances, be more reactive than its thermodynamically more stable anti-
conformer [7], thus following the Acree-Curtin-Hammett principle [28]. Furthermore,
the sense of induction may strongly depend on the chelating properties of the reagent
and additives, as well as on the conformationally rigidifying low temperature of the
reaction9). The necessity, for an efficient Grignard addition, to use at least two
equivalents of EtMgBr, suggests, as proposed by Oppolzer et al., a chelated
8
)
When a dienophile possessing a modified chiral sulfonamide auxiliary lacking
the pseudo-equatorial S=O was used for a Diels-Alder cycloaddition, TiCl4
chelation with the pseudo axial S=O resulted in total inversion of the π-facial
selectivity [25]. It is noteworthy that RMgX/CuI and Gilman reagents
(R2CuLi.PBu3) both induce the same π-facial selectivities in both Cβ and
concomitant electrophilic Cα additions for very similar Michael acceptors
[14][26][27]. For a stereochemical error in [6b], see footnote 4 in [2].
Although we are working with pure (E)-stereoisomers, Feringa et al. earlier
showed that the sense of induction may depend not only on the configuration of
the Michael acceptor, but also on the kinetics of both its conjugated addition and
(Z) to (E) isomerization [13].
9
)
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intermediate aggregated with a second equivalent of metallic nucleophile10). This
chelation usually involves the pseudo-equatorial S=O substituent, as seen by an X-ray
structure analysis [30]. It is noteworthy that amongst the multiple diastereoselective
chemical reactions using bornane-10,2-sultam as chiral auxiliary, the conjugate
additions would belong to the very rare examples necessitating involvement of the
pseudo axial S=O for chelation [3c]. We already expressed our doubts for this specific
chelation [2], especially in the case of α-substituted substrates, since the R3 substituent
should exhibit severe steric repulsion with both the C(3) and Me(8) backbone (Scheme
3), as compared to the pseudo equatorial S=O/C=O syn-conformation11).
The rationalization proposed by Oppolzer et al. seems sound for the simple
Grignard additions through a chelating bi-metallic complex as presented in Scheme 3
[3c][9], where the O=C-C=C dihedral angle is obviously deflected from 0° by the steric
influence of the C(3) sultam backbone, and the proximity of the Mg-R2, thus offering its
bottom Cβ face to the Grignard reagent. On the other hand, we have strong doubts
10
)
)
Such an aggregate was also invoked to explain the absence of 1,6-addition in
case of a N-(2,4-dienoyl)camphorsultam [9]; furthermore, >3.0 mol.-equiv. were
necessary for bis-chelated N-fumaroyl derivatives [29].
11
Based on B3LYP/6-31G-d,p calculations, we estimated this pseudo axial
complexation to be ca. 5 kcal/mol higher in energy, as compared to the pseudo
equatorial S=O….Li+O–-C=Cα coordination.
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concerning the transition state of the corresponding cuprous catalyzed, or cuprate
additions as represented in references [3b][14][26a]. Indeed, in their drawings, Oppolzer
et al. do not specify which of the S=O bonds is involved for chelation, furthermore
coordination with the pseudo axial S=O would reduce the reactivity of the chelate, since
the N lp would be in the nodal plane and thus unavailable for the activating
delocalization of the π-system. Additionally to the fact that the s-trans conformation is
thermodynamically higher in energy as compared to the s-cis disposition for the Cα-
unsubstituted substrates, we also think that the distance between the Cβ position and the
Mg atom is inappropriate to allow this bimetallic complex to operate as depicted in [14].
Indeed, the distance decreases by ca. 20% in the s-cis conformation and thus would
minimize the steric interaction of either the Me(8), or the C(3) with the CuI π-complex,
and then Cu-Cβ σ-bond [31]. Furthermore, they omitted to take into account the fact that
they used an excess of alkyl-Grignard (2.5 mol.-equiv.). Their rationalization perfectly
accounts for the observed final configuration. However in our laboratory, for more than
a decade, we use another simpler rule of thumb, which avoids this conformational
complication, by considering only the syn-s-cis conformation. We rather suggest, in the
light of Feringa’s observations and rationalization, as expressed in a catalytic context,
that we could eventually have a tri-metallic complex, where one equivalent of Mg
would be responsible for chelation, while the second Mg atom would complex with both
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the first Mg atom and the cuprous salt in an apical mode [13]. In such an arrangement
we need to explain why either the Cu…C=C π-complex, or the Cu-Cβ σ-bond, prior to
alkyl transfer, occurs on the top face rather than on the usual sterically more accessible
bottom face. We suggest either that the bottom CuI aggregation is destabilized by a
steric interaction with the pseudo axial S=O moiety, or that the CuI top coordination is
additionally stabilized by the N lp. The first proposal is very certainly geometrically
more appropriate. In this case, the O=C-C=C dihedral angle is maintained close to 0°
and leads to a (Z)-enolate (R3 < CHR1R2), while under non-aggregating condition this
angle is greater and the opposite enolate is obtained by nucleophilic approach on the
opposite face. Our hypothesis also accounts perfectly for both the Cβ conjugated
additions, as well as for the Cα electrophilic trapping of the intermediate enolate, whose
stereochemical final outcomes were earlier reported [3a][3b][9][11][14][15][26a][32].
Although this monolithic explanation is tempting by its logic and simplicity, our
rationalization was never published, because we were faced by several contradictions
concerning the acetylating trapping of the transient (E)- and (Z)-enolates, as published
by Oppolzer et al. [3b]12)[23][26a]. During the preparation of the present manuscript,
hindered by the reported low chemical yield of an isolated ketene N,OAc acetal (<20%,
12
)
It is noteworthy that on page 42, Scheme 10, structure 14 should have an Et
instead of a Me substituent in β-position.
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based on 4a [26a]), as well as the fact that, for instance, toluene instead of THF was
used to stereoselectively generate another ketene N,OAc acetal from 4c [23], with
sometimes, as we shall see, the addition of HMPA (hexamethylphosphoric triamide)
[32], we decided to have a much closer look at their experimental data. Although
announced as imminent in their preliminary communications13), these primordial
experimental results were never confirmed in a full paper, and we had to read and check
several Ph. D. theses to find them, and to have access to their NMR analyses [32]. We
attributed their 13C-NMR signals to each C atoms of both (E)- and (Z)-ketene N,OAc
acetals 7a and 7b, but this exercise was inconclusive since the respective displacements
are very similar. To our upmost surprise, their stereochemical attributions were in
contrast to our own expectations based on 1H-NMR analyses of the vinyl-Me
displacements14). We confirmed our own attributions after synthesis of 7b (4a, 2.3 mol.-
equiv. EtMgCl, THF, -78°, then AcCl, -78° to 20°, 90% yield). Indeed, although the
NOESY was non-instructive for the vinyl-Me, a full analysis allowed to determine that
the bornane C(2)-H was correlating with the CH2-Et, thus allowing us to attribute the
13
)
)
See reference 7 in [14], and reference 23 in [26a].
14
For 1H-NMR comparison with (E)- and (Z)-O-silyl ketene N,O-acetals attributed
on the basis of NOE experiments, with expected shifts, see [33]. We attributed
the signals at 1.79/1.56, and 1.80/1.54 ppm to the (E)-/(Z)-7a, -7b stereomers,
respectively.
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(E) configuration to 7b issued from this experiment (Scheme 4). We finally consolidated
our work by preparing (Z)-7a (4b, L-Selectride®, THF, -78° to -42°, then AcCl, -78° to -
42°, 90% yield), whose configuration was confirmed by the full NOESY analysis:
correlations between the C(2)-H and the CH3-vinyl, as well as between the OAc and
both signals of the vinyl-CH2CH3 were evident. The analytical data and corrected
stereochemical assignments, partially extracted from the original Ph. D. thesis are now
presented as addendum in the present Exp. Part for the sake of completeness and
comparison, corrected with our own attributions. Bedazzled by a single crystal X-ray
structure analysis as origin of their stereochemical determination, supplementary NMR
experiments were initially obviously either neglected, or ignored15). We concluded that,
working in parallel in both (E)- and (Z)-series, the analytical samples were eventually
inadvertently inverted at some point, either in one of the synthetic, NMR, or X-ray
laboratories16)! Alternatively, the probability that the crystallographer picked up a single
crystal of the minor stereomer for his X-ray analysis is negligible, but cannot be totally
excluded17).
15
)
This solid piece of experimental evidence also hindered and confused our own
analytical and critical mind for years!
16
17
)
)
For another example of E/Z inversion, see footnote 41 in [34].
For an example where we corrected a conformational equilibrium initially biased
on the basis of a single crystal X-ray structure analysis, see [35]. We are
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Conclusions. – By using an alternative 19F-NMR analytical method, we
cosmetically corrected and improved the linear correlation between the
diastereoselectivity observed during the EtMgBr conjugated addition to Michael
acceptors of type 1, as a function of their σpara Hammett electronic parameters. We also
discovered that the initial configuration of the trapped intermediate enolates derived
from α-substituted N-enoyl bornane-10,2-sultams was erroneously attributed by
Oppolzer et al.. Consequently, the rationalizations for these kinds of substrates, as
reported during the last thirty years, should be revised at the light of the following
proposals referring to Scheme 3: In these cases the (2R)-N-enoyl-bornane-10,2-sultam
reacts in a O=C-Cα=Cβ s-cisoid conformation. The SO2/C=O orientation is
thermodynamically more stable in the anti-disposition under non chelating conditions,
but may react in the syn conformation either under chelating control, or when the
substitutions render this minor conformer more reactive, thus following the Acree-
Curtin-Hammett principle. For Grignard, or non-aggregating Grignard/CuI conditions,
the nucleophile attacks from the bottom face, opposite to the N lp, whatever is the small
or larger O=C-Cα=Cβ torsion angle. In case of unsubstituted Cα, this angle, close to 0°,
leads to a transient (Z)-enolate, while the larger angle resulting from α-substitution
particularly indebted to both Prof. H.-R. Hagemann and Dr. D. Jeannerat
(University of Geneva) for their help in the stereochemical analysis of (E)-7b.
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leads to either a (E)-enolate (for R3 < CHR1R2), or (Z)-enolate (for R3 > CHR1R2)18).
Consequently, the α-electrophilic addition depends on the transient enolate, and results
from the classical steric control exerted by the masked C2 symmetry of the bornane-
10,2-sultam [3d]. For aggregating CuI/Grignard conditions, we suggest a trimetallic
complex, were the CuI is connected, via one of its substituents, to the apical position of
the non-chelated Mg atom, opposite to the pseudo axial S=O, thus adding the R2
nucleophile on the top of the s-cis conformer19). This situation enforces the O=C-Cα=Cβ
18
)
The configuration of the resulting Cα-substituted enolate is inverted for a small
nucleophile like H–. In the anti-s-cis complex with L-Selectride®, the O=C-C=C
dihedral angle is obviously closer to 0° than in the Grignard syn-s-cisoid
bimetallic chelate, eventually due to the size of the nucleophile, and/or the
geometry of the complex in the TS.
19
)
It is noteworthy that in the case of Gilman reagents a large excess is always used
(2.6 to 10.0 mol.-equiv.), so that a multi-metallic square planar π-complex
would also approach from the top face [36], for the reasons exposed here above,
or alternatively from the bottom face in the anti-s-cis conformation for either
steric or stereoelectronic reasons. For Gilman reagents exhibiting the same π-
facial selectivity as RMgX/CuI, see footnote 8, for Gilman reagents reacting
similarly to simple RMgX, see [6a][16a][16c][37]. In the case of [38] a
thermodynamically more stable s-trans reactive conformation cannot be
excluded; furthermore, similar addition to a β-tAm analog would help in
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torsion angle to be smaller, and thus leads to either a transient (Z)-enolate (for R3 <
CHR1R2), or (E)-enolate (R3 > CHR1R2). The consecutive Cα electrophilic attack being
similarly mainly sterically directed by the bornane-10,2-sultam skeleton. The chiral
auxiliary overrides the influence of the newly formed Cβ-stereocenter, which only
modulates the final result. As the stereoelectronic influence of the N lp remains to be
clarified20), and in view of the multiple conformational and chelating freedoms
envisaged, further theoretical TS# calculations are obviously necessary to support a firm
conclusion concerning our aggregated tri-metallic hypothesis21). In this case, copper
salts, such as CuCN, CuSCN, Cu(OTf)n=1,2, as well as the more complex Gilman
understanding the influence of the terminal unsaturation on the CuI π-facial
complex formation.
20
)
Based on electrostatic and dipolar interactions, we anticipated that the X-ray
analysis of (2R)-N-2'-carbonylpyrimidine 3a would exhibit a rare SO2/C=O syn
conformation, in analogy to (2R)-N-picolinoylbornane-10,2-sultam 3b [19], but
in the solid state, we rather observed an usual anti conformation (S-N-C=O =
153.38(13)°), very similar to (2R)-N-benzoylbornane-10,2-sultam 3c [19]. The
syntheses and structural analyses of N-carbonyl-2-pyrazine, -4-pyrimidine, and -
3-piridazine are under investigations.
21
)
According to the model suggested by Feringa et al. [13], aggregation of the
cuprous salt on the chelating Mg atom may also be envisaged, although we
privilege our option, due to the steric influence of either the Me(8), or C(3), or
pseudo axial S=O, depending on the considered chelation [14].
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reagents, will also be included in this experimental study, with trapping of the
intermediate ketene N,OAc acetals22). These results, with supplementary hydride 1,4-
additions in the presence of chelating Lewis acids, shall be presented in due course.
Experimental Part
General, see [40]. Crystallographic data of 3a were deposited as supplementary
material with the Cambridge Crystallographic Data Centre and allocated the deposition
number CCDC-1428062. These data can be obtained free of charge via
www.ccdc.ac.uk/data_request/cif.
The preparation of 1a, 1b, 1c, 1d, and 1e are described in the Exper. Part
reported in [2], as well as in the literature cited therein. The conjugate additions of
EtMgX, as well as analytical data of 2a, 2b, 2c, 2d, and 2e are also described in [2].
(Pyrimidin-2-yl)[(3aS,6R,7aR)-(tetrahydro-8,8-dimethyl-2,2-dioxido-3a,6-
methano-2,1-benzothiazol-1(3H,4H)-yl)]methanone (3a). A soln. of (+)-(1R)-
bornane-10,2-sultam (190 mg, 0.89 mmol,) in dry toluene (5 ml) was slowly added to
the suspension of NaH (60% in mineral oil, 38 mg, 0.97 mmol) in dry toluene (5 ml) at
0° under Ar. After 30 min at 20°, the mixture was cooled to 0° and a freshly prepared
soln. of pyrimidine-2-carbonyl chloride (0.81 mmol, [41]) in toluene (5 ml) was slowly
22
)
The role of the solvent, as well as of coordinating or disaggregating additives,
such as TMSCl and LiCl, shall also be explored [39].
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added. The mixture was stirred overnight at 20°. H2O (5 ml) was added and the aq.
phase was extracted with CH2Cl2. The org. phase was dried (MgSO4), filtered, and
concentrated under vacuum. The residue was purified on CC (SiO2, hexane/AcOEt 8:2)
to afford 3 in 79% yield. M.p. 68 – 72° (EtOH). [α]D20 = –137.2 (c = 1.0, CHCl3). 1H-
NMR (CDCl3, 200 MHz): 0.93 (s, 3 H); 1.21 (s, 3 H); 1.24 – 1.44 (m, 2 H); 1.73 – 2.10
(m, 3 H); 3.48 (q, J = 13.6, 20.4, 2 H); 4.22 – 4.26 (m, 1 H); 7.46 (t, J = 4.9, 1 H); 8.89
(d, J = 4.9, 2 H). 13C-NMR (CDCl3, 200MHz): 20.1 (q), 21.8 (q), 26.4 (t), 33.5 (t), 38.6
(t), 45.5 (d), 48.0 (s), 49.1 (s), 53.3 (t), 66.2 (d), 122.7 (d), 157.6 (2d), 159.6 (s), 164.3
(s) HR-MS: 344.1044 ([M + Na]+, C15H19N3NaO3S+; calc. 344.1045).
(1Z)-1-[(3aS,6R,7aR)-Tetrahydro-8,8-dimethyl-2,2-dioxido-3a,6-methano-
2,1-benzothiazol-1(3H,4H)-yl]-2-methylbut-1-en-1-yl Acetate ((Z)-7a). L-Selectride®
(1.0M/THF, 0.34 mmol, 0.34 ml) was added dropwise at -78° to a soln. of N-tigloyl
sultam 4b (83 mg, 0.28 mmol) in THF (5 ml). After stirring for 2 h at -42°
(MeCN/CO2), the mixture was treated with AcCl (0.105 ml, 1.47 mmol) at -78°. After 1
h at -42°, the reaction was quenched with an aq. sat. NH4Cl soln. Workup and CC (SiO2,
cyclohexane/AcOEt 9:1) to afforded pure (Z)-7a (90% yield) Z/E ratio 96:4 by 1H-
NMR. Rf (cyclohexane/AcOEt 9:1) = 0.10. [α]D20 = –53.5 (c = 3.4, CHCl3). For
analyses: vide infra.
(1E)-1-[(3aS,6R,7aR)-Tetrahydro-8,8-Dimethyl-2,2-dioxido-3a,6-methano-
2,1-benzothiazol-1(3H,4H)-yl]-2-methylpent-1-en-1-yl Acetate ((E)-7b). EtMgCl
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(2M/THF, 0.25 ml, 0.5 mmol) was added dropwise at -78° to a soln. of N-
methacryloylsultam 4a (63 mg, 0.22 mmol) in THF (2 ml) and the mixture was allowed
to warm to 20° in 15 min. After cooling to -78°, AcCl (0.035 ml, 0.5 mmol) was added
in one portion and the mixture was slowly warmed to 20°. After 4 h, the reaction was
quenched with an aq. sat. NH4Cl soln. Workup, then purification by CC (SiO2,
cyclohexane/AcOEt 9:1) afforded pure (E)-7b (90% yield). Rf (cyclohexane/AcOEt 9:1)
= 0.11. [α]D20 = +44.1 (c = 0.9, CHCl3). For analyses: vide infra. After four weeks in
CDCl3, the E/Z ratio was 94:6 by 13C-NMR analysis, since the E/Z-stereoisomers were
not resolved on our apolar HP-1 GC capillary column (6.5 psi H2; 30 m/0.32 mm/0.25
μm; 220° iso, 4.65 min, 99% pure).
Addendum
The following section corresponds to the experimental data reported in [32]23),
corrected for some details with the help of the original hand-written reports, as well as
with our own stereochemical inverted (E)- and (Z)-attributions24).
23
)
)
It is noteworthy that on Page 31 of this thesis, in Table 10, Entries 6 and 7, the
E/Z ratios of ketene N,OAc acetals should be inverted! (irrespectively of the
error of attribution).
24
We are indebted to Prof. G. Poli (University Pierre et Marie Curie, Paris) for
providing us with his hand-written archives, as well as for his comments on this
manuscript. We thank Drs. J.-M. Gaudin and C. Starkenmann (Firmenich SA)
This article is protected by copyright. All rights reserved.

(1Z)-1-[(3aS,6R,7aR)-Tetrahydro-8,8-dimethyl-2,2-dioxido-3a,6-methano-
2,1-benzothiazol-1(3H,4H)-yl]-2-methylbut-1-en-1-yl Acetate (Z)-7a: MeLi (0.85 ml,
1.37 mmol) was added dropwise at -40° to a soln. of CuI.PBu3 (268 mg, 0.68 mmol) in
THF (4 ml). Then, the suspension was cooled to -80° and the methacryloylsultam 4a (97
mg, 0.34 mmol) in THF (2 ml) was added. After 1 h stirring at -80°, AcCl (0.242 ml, 3.4
mmol) was added and the mixture was warmed slowly to 20°. After 1 h, the reaction
was quenched with an aq. sat. NH4Cl soln. Workup and FC (SiO2, hexane/AcOEt 3:1)
without altering the stereoisomer ratio furnished the title compound (Z)-7a (81 mg, 73%
yield. Z/E ratio 88:12 by 1H-NMR. GC (10 psi H2, OV-1, 12m, 0.2 mm; 150°, 10 min,
then 10°/min to 250°: 15.61 min, not separated, 96% pure).
Alternatively, L-Selectride® (1.0M/THF, 0.46 mmol, 0.46 ml) was added
dropwise at -80° to a soln. of tigloylsultam 4b (114 mg, 0.38 mmol) in toluene (7 ml).
After stirring for 1 h at -60°, the mixture was treated with AcCl (0.143 ml, 2 mmol) at -
80°. After a slow warming to -60° during 1 h, the reaction was quenched with an aq. sat.
NH4Cl soln. Workup and FC (SiO2, hexane/AcOEt 3:1) then crystallization (hexane)
afforded pure (Z)-7a (101 mg, 81% yield) Z/E ratio 99:1 by 1H-NMR. M.p.: 104 – 105°.
for providing us with the e-mail address, and the Ph. D. thesis of Dr. A. J.
Kingma (BASF GmbH, Ludwigshafen), respectively. Finally, we are particularly
indebted to this latter for allowing us to incorporate the corrigendum of his Ph.
D. thesis in the present report [32].
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GC (10 psi H2, OV-1, 12 m, 0.2 mm; 150°, 10 min, then 10°/min to 250°: 15.60 min,
99% pure). IR: 2970, 2920, 1760, 1680, 1460, 1360, 1330, 1250. 1H-NMR: 0.84 (s, 3
H); 0.99 (t, J = 7.5, 3 H); 1.13 (s, 3 H); 1.23 – 1.29 (m, 1 H); 1.40 – 1.46 (m, 1 H); 1.53
– 1.61 (m, 1 H); 1.56 (s, 3 H); 1.80 – 2.00 (m, 4 H); 2.13 – 2.24 (m, 1 H); 2.16 (s, 3 H);
2.32 – 2.43 (m, 1 H); 3.18 (s, 2 H); 3.34 (dd, J = 8, 4.5, 1 H). 13C-NMR: 167.9 (s); 133.7
(s); 127.9 (s); 63.9 (d); 49.6 (t); 49.5 (s); 47.5 (s); 44.4 (d); 35.6 (t); 32.5 (t); 26.9 (t);
25.1 (t); 20.3 (q); 20.1 (2q); 15.5 (q); 12.9 (q). MS: 341 (1, M+), 299 (17), 152 (6), 135
(100), 107 (30), 93 (28), 84 (35), 69 (43), 55 (32). HR-MS: 341.1670 (M+,
C17H27NO4S+; calc. 341.1661).
(1E)-1-[(3aS,6R,7aR)-Tetrahydro-8,8-dimethyl-2,2-dioxido-3a,6-methano-
2,1-benzothiazol-1(3H,4H)-yl]-2-methylbut-1-en-1-yl Acetate ((E)-7a). MeMgCl
(0.35 ml, 1.04 mmol) was added at -80° dropwise to a soln. of N-methacryloylsultam 4a
(118 mg, 0.42 mmol) in THF (5 ml) and the mixture was allowed to reach 20° in 15
min. After cooling to -80°, HMPA (0.5 ml) and AcCl (0.30 ml, 4.16 mmol) were added
in one portion and the reaction was slowly warmed to 20°. After 2 h stirring, the
reaction was quenched with an aq. sat. NH4Cl soln. Workup and FC (SiO2,
hexane/AcOEt 3:1) without altering the stereoisomer ratio furnished the title compound
(E)-7a (26 mg, 20% yield) E/Z ratio 87:13 by 1H-NMR. GC (10 psi H2, OV-1, 12 m, 0.2
mm; 150°, 10 min, then 10°/min to 250°: 15.61 min, 82% pure). IR: 2970, 2920, 1760,
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1680, 1460, 1360, 1330, 1250. 1H-NMR: 0.84 (s, 3 H); 0.90 (t, J = 7.5, 3 H); 1.121 (s, 3
H); 1.17 – 1.23 (m, 1 H); 1.37 (t, J = 9, 1 H); 1.46 – 1.52 (m, 2 H); 1.74 – 1.86 (m, 2 H);
1.79 (s, 3 H); 1.88 – 1.98 (m, 3 H); 2.13 (s, 3 H); 3.12 (d, J = 13.5, 1 H); 3.18 (d, J =
13.5, 1 H); 3.29 (dd, J = 8, 4.5, 1 H); 13C-NMR: 168.5 (s); 133.4 (s); 127.9 (s); 63.9 (d);
49.6 (t); 49.5 (s); 47.5 (s); 44.3 (d); 35.6 (t); 32.5 (t); 26.9 (t); 25.3 (t); 20.5 (q); 20.3 (q);
20.1 (q); 16.2 (q); 11.3 (q). MS: 341 (2, M+), 299 (38), 152 (10), 135 (100), 107 (30), 93
(30), 84 (30), 69 (28), 57 (28). HR-MS: 341.1661 (M+, C17H27NO4S+, calc. 341.1661).
(1Z)-1-[(3aS,6R,7aR)-Tetrahydro-8,8-Dimethyl-2,2-dioxido-3a,6-methano-
2,1-benzothiazol-1(3H,4H)-yl]-2-methylpent-1-en-1-yl Acetate ((Z)-7b). L-
Selectride® (1.0M/THF, 0.8 ml, 0.8 mmol) was added at -80° dropwise to a soln. of N-
[(E)-2-methylpent-2-enoyl]bornane-10,2-sultam 4c (200 mg, 0.643 mmol) in THF
(6ml). Then after 5 min, the mixture was warmed to -30° over 30 min and stirring was
continued for further 2 h. The mixture was cooled to -80° and AcCl (0.1 ml, 1.415
mmol) was added. The mixture was slowly warmed up to -60° in 1 h. Addition of
NH4Cl, then workup and FC (hexane/AcOEt 3:1) afforded pure (Z)-7b (191 mg, 84%
yield) which was crystallized (MeOH) (134 mg, 59% yield)25).
25
)
This experiment conducted to the controversial single crystal X-ray structure
determination showing the (E)-configuration [3b][23].
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Alternatively, EtMgCl (0,59 ml, 1.2 mmol) was added dropwise at -80° to a
slurry of CuCl (9.3 mg, 0.09 mmol) in THF (3 ml). Then, a soln. of methacryloylsultam
4a (134 mg, 0.47 mmol) in THF (2 ml) was slowly added. The mixture was stirred for
15 min, then AcCl (0.167 ml, 2.35 mmol) was added in one portion, and the mixtue was
warmed to 20° over 2 h. Workup then FC (hexane/AcOEt 4:1) afforded (Z)-7b (155 mg,
93% yield), further crystallized (hexane) to afford pure (Z)-7b (137 mg, 82% yield).
M.p.: 125°. GC (10 psi H2, OV-1, 12 m, 0.2 mm; 150°, 10 min, then 7.5°/min to 250°:
16.73 min, 100% pure). IR: 2960, 2880, 1760, 1690, 1330. 1H-NMR: 0.82 (t, J = 7.0, 3
H); 0.87 (s, 3 H); 1.12 (s, 3 H); 1.18 – 1.60 (m, 5 H); 1.54 (s, 3 H); 1.76 – 1.98 (m, 4 H);
2.03 – 2.09 (m, 1 H); 2.15 (s, 3 H); 2.36 – 2.40 (m, 1 H); 3.14 (d, J = 13.5, 1 H); 3.18 (d,
J = 13.5, 1 H); 3.33 (dd, J = 7.5, 4.5, 1 H). 13C-NMR: 168.0 (s); 132.4 (s); 128.5 (s);
64.0 (d), 49.7 (t); 49.6 (s); 47.6 (s); 44.5 (d); 35.7 (t); 34.3 (t); 32.6 (t); 26.9 (t); 21.5 (t);
20.4 (q); 20.3 (q); 20.1 (q); 15.9 (q); 13.8 (q). MS: 355 (0.9, M+), 313 (40), 284 (34),
220 (13), 152 (19), 135 (100), 107 (89), 98 (64), 93 (84), 69 (80). HR-MS: 313.1716
+
(M+, C18H29NSO4 -C2H2O, calc. 313.1711).
(1E)-1-[(3aS,6R,7aR)-Tetrahydro-8,8-Dimethyl-2,2-dioxido-3a,6-methano-
2,1-benzothiazol-1(3H,4H)-yl]-2-methylpent-1-en-1-yl Acetate ((E)-7b). Starting
from N-[2-methylidene-pentanoyl]bornane-10,2-sultam 4d [22] (61 mg, 0.196 mmol)
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the same procedure described for the preparation of (Z)-7b, by using L-Selectride® was
followed. FC (SiO2, hexane/AcOEt 3:1) afforded pure (E)-7b (58 mg, 84% yield).
Alternatively26), EtMgCl (2M/THF, 83 μl, 0.17 mmol) was added at -80°
dropwise to a soln. of methacryloylsultam 4a (31.4 mg, 0.11 mmol) in THF (1 ml), and
the mixture was allowed to warm to 20° over 15 min. After cooling to -80°, AcCl (17.4
μl, 0.25 mmol) was added in one portion and the mixture was slowly warmed to 20°.
After 2 h stirring, the reaction was quenched with an aq. sat. NH4Cl soln. Workup, FC
(SiO2, hexane/AcOEt 7:1) afforded (30 mg, 77% yield) pure (E)-7b (24 mg, 61% yield)
after crystallization. M.p.: 100 – 101°. GC (10 psi H2, OV-1, 12 m, 0.2 mm; 150°, 10
min, then 10°/min to 250°: 15.65 min, 100% pure). IR: 2960, 2880, 1765, 1685, 1460,
1370, 1330, 1H-NMR: 0.81 (t, J = 7.5, 3 H); 0.86 (s, 3 H); 1.13 (s, 3 H); 1.20 – 1.24 (m,
1 H); 1.32 – 1.46 (m, 3 H); 1.52 (dd, J = 13.5, 8.0, 1 H); 1.80 (s, 3 H); 1.80 – 2.00 (m, 6
H); 2.15 (s, 3 H); 3.14 (d, J = 13.5, 1 H); 3.18 (d, J = 13.5, 1 H); 3.31 (dd, J = 8.0, 4.5, 1
H). 13C-NMR: 168.6 (s); 132.2 (s); 128.5 (s); 64.0 (d); 49.7 (s); 49.7 (t); 47.6 (s); 44.4
(d); 35.7 (t); 34.3 (t); 32.6 (t); 26.9 (t); 20.6 (q); 20.4 (q); 20.2 (q); 20.1 (t); 16.8 (q);
26
)
It is noteworthy that for this example, only 1.5 equiv. of Grignard reagent,
instead of the recommended 2.0 – 2.5 fold excess was used! This may eventually
account for the lower chemical yield. It may also indicate that this experiment
was eventually performed at the beginning of the project, although references
[11a][11b] refer to later examples.
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13.9 (q). MS 355 (0.7, M+), 313 (30), 284 (25), 135 (100), 107 (61), 98 (42), 93 (61), 69
+
(80). HR-MS: 313.1697 (M+, C18H29NSO4 -C2H2O; calc. 313.1711).
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