Origin of the Base-Dependent Facial Selectivity in Annulation Reactions of Nazarov-Type Reagents with Unsaturated Indolo[2,3-a]quinolizidine Lactams

Article abstract of DOI:10.1002/ejoc.201700610

Methyl-substituted Nazarov reagent 4 reacts stereoselectively with N_ind-Boc indoloquinolizidine lactams to give the expected 3-H/15-H cis pentacyclic yohimbine-type adducts when using 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as the base. However, a dramatic change of the facial selectivity was observed when the reaction was performed in the presence of Cs₂CO₃, leading to the corresponding trans adducts. This annulation is the key step of a stereocontrolled synthesis of the 17a-carba analogue of the heteroyohimbine alkaloid akuammigine. Theoretical calculations were used to rationalize the facial selectivity of these double Michael addition reactions.

Full text of DOI:10.1002/ejoc.201700610

A Journal of
Accepted Article
Title: Origin of the Base-Dependent Facial Selectivity in Annulation
Reactions of Nazarov-Type Reagents with Unsaturated
Indolo[2,3-a]quinolizidine Lactams
Authors: Carolina Estarellas, Federica Arioli, Maria Pérez, Celeste Are,
David Hevia, Elies Molins, F. Javier Luque, Joan Bosch, and
Mercedes Amat
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700610
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700610
Supported by

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
Origin of the Base-Dependent Facial Selectivity in Annulation
Reactions of Nazarov-Type Reagents with Unsaturated Indolo[2,3-
a]quinolizidine Lactams.
Carolina Estarellas,[a] Federica Arioli,[b] Maria Pérez,[a] Celeste Are,[b] David Hevia,[b] Elies Molins,[c]
F. Javier Luque,*[a] Joan Bosch,[b] and Mercedes Amat*[b]
Abstract:
The
methyl-substituted
Nazarov
reagent
4
stereoselectively reacts with Nind-Boc indoloquinolizidine lactams to
give the expected H-3/H-15 cis pentacyclic yohimbine-type adducts
when using DBU as the base. However, a dramatic change of the
facial selectivity was observed when the reaction was performed in
the presence of Cs2CO3, leading to the corresponding trans adducts.
This annulation is the key step of a stereocontrolled synthesis of the
17a-carba-analog of the heteroyohimbine alkaloid akuammigine.
Theoretical calculations were used to rationalize the facial selectivity
of these double Michael addition reactions.
Scheme 1. Typical reactivity of the Nazarov reagent (1) and its methyl
substituted analog 2.
Introduction
Ethyl (or methyl) 3-oxo-4-pentenoate (1), known as the Nazarov
reagent,[1] is a versatile annelating agent widely used in a variety
of Robinson-type annulations, in which it sequentially acts as an
electrophilic reagent in a Michael addition and as a nucleophile
to promote the cyclization[2,3] (Scheme 1). The fact that 1 is
unstable under basic conditions and polymerizes[4] rapidly at rt
has stimulated the development of more stable analogs of 1
bearing alkyl substituents on the vinyl moiety, such as 2.[5]
These Nazarov-type reagents are able to undergo alternative
annulations involving base-catalyzed double Michael addition
reactions with α,β-unsaturated carbonyl compounds, in which
equivalent of the original Nazarov reagent 1. Derivative 3 can
participate in base-promoted double Michael annulations
(Scheme 2), avoiding the polymerization problem associated
with 1. Using unsaturated indolo[2,3-a]quinolizidine lactams A,
this reagent opened up straightforward stereodivergent routes to
yohimbine-type derivatives.[7,8] Interestingly, pentacyclic H-3/H-
15 trans adducts B were generated from Nind-unsubstituted
lactams, but the corresponding cis isomers C were formed when
the indole nitrogen bears a Boc substituent (Scheme 2).[9] This
dramatic reversal in the facial selectivity was rationalized by
the reagent successively acts as
electrophilic Michael acceptor.[6]
a nucleophile and an
In previous work[7] we have reported the preparation of the
silylated derivative 3, which behaves as a stable synthetic
[a]
[b]
[c]
Dr. C. Estarellas, Dr. M. Pérez, Prof. Dr. F. J. Luque
Department of Nutrition, Food Sciences and Gastronomy
Faculty of Pharmacy and Food Sciences, and Institute of
Biomedicine (IBUB)
University of Barcelona, 08921 Santa Coloma de Gramanet, Spain
E-mail: fjluque@ub.edu
www.ub.edu/cbdd
Dr. F. Arioli, C. Are, D. Hevia, Prof. Dr. J. Bosch, Prof. Dr. M. Amat
Laboratory of Organic Chemistry
Faculty of Pharmacy and Food Sciences, and Institute of
Biomedicine (IBUB)
University of Barcelona, 08028 Barcelona, Spain
E-mail: amat@ub.edu
www.ub.edu/sintefarma
Prof. Dr. E. Molins
Scheme 2. Stereocontrolled annulations with the silylated Nazarov reagent 3.
Institut de Ciència de Materials (CSIC)
Campus UAB, 08193 Cerdanyola, Spain
Supporting information for this article is given via a link at the end of
the document.
means of theoretical calculations, which indicated that the initial
nucleophilic attack under stereoelectronic control is hampered
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
by the presence of the bulky Boc group.[8] The reactions were
performed using either DBU (in THF)[10] or Cs2CO3 (in CH2Cl2)
as the base, although with the latter, when E = SO2C6H5, the
stereoselectivity was lower and dependent on the concentration
of Cs2CO3.
On the basis of these findings, we envisaged that the use of the
methyl-substituted Nazarov reagent 4 (Scheme 3) in double
Michael annulations with unsaturated indolo[2,3-a]quinolizidine
lactams
A
would afford pentacyclic carba-analogs of
heteroyohimbine alkaloids bearing their characteristic C-19
methyl substituent (Figure 1). Following this rationale, we report
here the enantioselective synthesis of 17a-carbaakuammigine,
taking advantage of an unexpected base-dependent
stereoselective addition in double Michael annulations with
Nazarov reagent 4. Furthermore, theoretical calculations allow
us to justify the facial selectivity of these reactions and to
disclose the key role played by cesium cations in the
stereoselective outcome.
Figure 1. Heteroyohimbine alkaloids akuammigine and tetrahydroalstonine.
Results and Discussion
Base-dependent stereoselective double Michael addition
reactions with Nazarov reagent 4
Scheme 3. Double Michael addition reactions of the methyl-substituted
Nazarov reagent 4 with unsaturated lactams 5 and 8 (compounds 8-10 are
racemic mixtures).
Reaction of enantiopure Nind-Boc lactam 5a with the Nazarov
reagent 4 using DBU as the base afforded the pentacyclic
adduct 6a, with the expected H-3/H-15 cis configuration, in
excellent yield.[11] However, to our surprise, when the reaction
was performed in the presence of Cs2CO3, which is the most
commonly used base for the generation of the enolate salt of
Nazarov reagents, the H-3/H-15 trans adduct 7a was obtained in
86% yield. A similar unexpected stereochemical result was
observed in the Cs2CO3-promoted double Michael addition of 4
to unsaturated lactam 5b: the pentacyclic H-3/H-15 trans adduct
7b was obtained in 87% yield (Scheme 3).
In agreement with a stepwise double Michael process, when the
Cs2CO3-promoted reaction from 5a was stopped after 2h, the
tetracyclic intermediate D (R = CH2OBoc) arising from the initial
Michael addition was isolated in 23% yield (Figure 2). Minor
amounts of similar open intermediates were detected by NMR in
all the annulations shown in Scheme 3, including the reactions in
presence of DBU.
To further investigate the influence of the base on the facial
selectivity of the process, we also studied the annulations of the
Nazarov reagent 4 with racemic Nind-Boc indoloquinolizidin-2-
ones 8a and 8b, which lack the protected hydroxymethyl
substituent. From a stereochemical standpoint, the results
matched those previously observed from 5. When the reaction of
8a was performed in the presence of DBU, the H-3/H-15 cis
pentacycle 9a was obtained in excellent yield.[11] In contrast,
when Cs2CO3 was used as the base, the corresponding H-3/H-
15 trans adducts 10a and 10b[12] were stereoselectively formed
in 88% and 59% yields, respectively.
Figure 2. Tetracyclic intermediate D.
The observation of positive NOE effects between H-3/H-15, C19-
Me/Hα-14, and C19-Me/Hα-18 in 6a and 9a, and between H-3/H-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
19, H-3/Hβ-18, C19-Me/H-15, and C19-Me/Hα-18 in 10a was in
agreement with the stereochemical assignments made for the
above pentacyclic derivatives. Additionally, the relative
configuration of 9a and 10a was unambiguously established by
X-ray crystallographic analysis[13] (Figure 3).
Conformational preferences of Nazarov reagents 3 and 4
Theoretical calculations were performed to understand the
unexpected reversal of the facial selectivity of Cs2CO3-catalyzed
annulation reactions of methyl-substituted Nazarov reagent 4
with unsaturated Nind-Boc indoloquinolizidine lactams 5 and 8 as
compared with similar reactions catalyzed by DBU. Calculations
were performed using the M06-2X density functional[16] and the
6-31G(d) basis set,[17] and solvent effects were accounted for by
using the SMD version[18] of the IEFPCM model (see
Experimental for details).
In a preliminary step, the conformational preference of the
anionic species generated from Nazarov reagents 3 and 4 was
determined (Figure S1 in Supporting Information). The results
pointed out that the s-cis species of 3 is favored by 1.7 kcal/mol
in CH2Cl2 relative to the s-trans conformer. It is worth noting that
the s-cis conformation has the appropriate arrangement required
for the annulation reaction that gives rise to fused pentacyclic
products (B and C in Scheme 2). In contrast, the s-cis species of
9a
4
is destabilized by 2.4 kcal/mol relative to the s-trans
conformation, which suggests that the population of the s-cis
species is less than 2% at 298 K. Accordingly, the reaction of 4
should primarily proceed through attack of the s-trans species,
which does not have the configuration required for ring closure.
Therefore, it can be expected that the double Michael addition
occurs through an intermediate step that involves the conversion
to the s-cis arrangement.
Double Michael additions with silylated Nazarov reagent 3
In order to rationalize the stereochemical outcome of the double
Michael addition reactions, we first determined the free energy
profile for the reaction of the anionic form of 3 to lactam A
(Scheme 2, with R1=Boc, R2=H, and E=CO2Me in calculations;
8c in Scheme 3) as a reference system. Calculations were
performed for the Michael additions through the Si and Re faces
of lactam 8c. Furthermore, the addition reaction was considered
to occur through the two faces of reagent 3 (denoted pro-S and
pro-R depending on the stereochemistry of the C16 stereocenter
initially formed in the first Michael addition), thus leading to four
plausible reaction channels that are schematically shown in
Scheme 4. For the specific case of the reaction between reagent
3 and lactam 8c, however, the steric hindrance arising from the
TMS group allowed us to limit calculations to only two reactive
pathways, as will be explained below.
10a
Figure 3. X-ray crystal structures of the H-3/H-15 cis and trans adducts 9a
and 10a, respectively.
Another striking aspect from the stereochemical standpoint was
the relative configuration of the C-19 stereocenter. Whereas the
expected cis relative configuration for the substituents at
positions 19 and 20 was observed in the H-3/H-15 trans adducts
7 and 10,[14] a trans C19-Me/C20-SO2C6H5 relationship was found
in the H-3/H-15 cis pentacycles 6a and 9a.[15] In all cases, the
resulting cis D/E ring junction arises from stereoelectronic
control during the Michael cyclization step.[6b,15b]
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
Scheme 4. Representation of the four plausible pathways for the initial Michael addition reactions between the Nazarov reagent (3 [R = C(TMS)=CH2] or 4 [R =
(E)-CH=CHMe]) and the lactam, and the resulting possible annulation products formed from the reaction with 4.
The stereoselective formation of the cis H-3/H-15 isomer (C in
Scheme 2) stems from the preferential attack of the silylated
reagent 3 (pro-S face) through the Re face. This is reflected in
the lower stability of the transition state (TS1) formed in the first
Michael addition through the Si face, which is destabilized by 3.1
Table 1. Comparison of the free energy differences (kcal/mol) determined
at the M062X/6-31G(d), SCS-MP2/6-31G(d), and B2PLYP-D3/def2-SVPP
levels in CH2Cl2 for the addition of the anionic form of Nazarov reagent 3
kcal/mol relative to the Re attack (Figures 4 and 5). This process
is the rate-limiting step of the annulation reaction, as the barrier
(8.2 kcal/mol) for the first Michael addition is larger than the
barrier required for ring closure (6.1 kcal/mol; TS2), which
ultimately leads to a large stabilization of the annulated product
(by nearly 24 kcal/mol relative to the pre-reactant complex). It is
worth noting that the free energy profile determined from M062X
computations is supported by the similar free energy differences
between pre-reactant, intermediate, and transition states
obtained from single-point calculations at the SCS-MP2/6-
31G(d) and B2PLYP-D3/def2-SVPP levels, as noted from the
data reported in Table 1.
(pro-S and pro-R faces for Re and Si attacks, respectively) to lactam 8c.
M062X SCS-MP2 B2PLYP-D3
Re
0.0
8.2
Si
Re
Si
Re
Si
Pre-RC
TS1
I1
2.5
0.0
3.1
0.0
2.7
11.3
-8.7
-2.5
-22.6
11.5
-9.7
-3.1
-30.6
14.9
-11.0
-4.7
-29.4
7.3
10.1
-9.5
-6.6
-26.6
-7.2
-8.0
-5.5
-29.0
TS2
P
-1.1
-24.2
Assuming that these reactions are under the Curtin-Hammett
control, the relative free energy of the transition states (TS1),
which is estimated to be around 3 kcal/mol (see Table 1), would
lead to a ratio of 160:1 for the H-3/H-15 cis and trans isomers C
and B, respectively (Scheme 2), in agreement with the
experimental data. Inspection of the rate-limiting transition state
for the Re addition (Figure 5) suggests that the steric hindrance
of the bulky N-Boc group counterbalances the stereochemical
preference for attack through the convex face of the α,β-
unsaturated lactam. Furthermore, Figure
6
shows the
asynchronicity of the double Michael addition, as the length of
the forming C···C bonds is 2.29 and 3.27 Å. Finally, Figure 6
also shows that the attack occurs with an antiperiplanar
arrangement (a, Scheme 4) of the carbon atoms involved in the
first Michael addition (H–C···C–H dihedral angle of -172.8
degrees), which locates the double bond in the appropriate
arrangement for ring closure, and avoids steric clashes between
the bulky TMS group and the lactam 8c. In contrast, the attack
through the pro-R face of reagent 3 (c, Scheme 4) is unfeasible
Figure 4. Free energy (kcal/mol) profile for the double Michael addition of the
anionic species of Nazarov reagent 3 (pro-S and pro-R faces for Re and Si
attacks, respectively) to lactam 8c derived from M062X/6-31G(d) calculations
in CH2Cl2.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
due to the steric hindrance originated by the TMS group (data
not shown).
second Michael addition is preceded by the internal rotation of
the 4 moiety, which involves a small barrier (through a rotational
transition state; Ts-rot) for the conversion of the s-trans
conformation in intermediate I1 to the s-cis arrangement in the
novel intermediate I2. This would facilitate the formation of the
second bond, as the distance between the C atoms is close to
3.1 Å. The barriers for the second Michael addition (TS2; Figure
7) through the Re and Si face are 11.1 and 12.3 kcal/mol,
respectively. The relative free energy of the transition states (1.2
kcal/mol) would lead to a ratio of 7.6:1 for the Re and Si
products, 9a and 10a, respectively. Finally, between the two
cyclized products, the Re annulation is also found to be more
stable (by 2.1 kcal/mol) than the Si addition, in agreement with
the experimental outcome (see Scheme 3).
Figure 5. Representation of the transition state (TS1) formed in the Re attack
of reagent 3 (pro-S face) to lactam 8c. For the sake of clarity, only selected
hydrogen atoms are shown. Complete geometrical data of pre-reactants,
transition states, and intermediates is available in Supporting Information.
Double Michael additions with methyl-substituted Nazarov
reagent 4
Next, we examined the annulation reaction between lactam 8a
and Nazarov reagent 4. It is worth noting that the stereochemical
outcome obtained for H-3/H-15 and C-19/C-20 centers is
different depending on the base, DBU or Cs2CO3, used to
catalyze the reaction (see Scheme 3). As noted above (see
Figure 4), the addition reaction was performed considering the
attack of the s-trans species of 4, which was found to be the
predominant form in solution. The annulation reaction was
studied through the Re and Si faces of lactam 8a. In contrast to
the Nazarov reagent 3, the absence of the bulky TMS group
permits the attack of 4 through both pro-R and pro-S faces (see
Scheme 4).
Compared to the reaction of the silylated reagent 3, the free
energy profile for the DBU-promoted attack of reagent 4 to
lactam 8a shows distinctive trends (see Figure 6). First, in the
most favored approach of the reactants the Nazarov reagent is
oriented with the carbonyl oxygens opposite to the sulfonyl
group in the lactam, leading to a gauche arrangement for the C-
H groups that participate in the first Michael addition (H–C···C–H
dihedral angle of 58.1 and 61.6 degrees in the TSs formed for
the Re and Si attacks; note that this approach was sterically
impeded by the bulky TMS unit in the reaction of 3 with lactam
8c). This arrangement avoids the repulsion between the lone
pairs of the oxygen atoms in the Nazarov reagent and the
sulfonyl group, while it permits the formation of C-H···O
interactions between the reactants. Indeed, this approach leads
to pre-reactant complexes that are more favored (by 3-4
kcal/mol) than those obtained for an antiperiplanar approach.
The stability of the transition state for the first Michael addition
(TS1; Figure 7) is similar for the Re and Si attacks, leading to
intermediates (I1) with geometrical features unfeasible for the
second addition, as the distance between the reactive C atoms
involved in the second Michael addition is close to 3.7 Å due to
the s-trans arrangement of the Nazarov reagent. In fact, the
Figure 6. Free energy (kcal/mol) profile for the DBU-catalyzed double Michael
addition of the anionic species of Nazarov reagent 4 to lactam 8a derived from
M062X/6-31G(d) calculations in CH2Cl2.
This reactive pathway leads to the experimental stereochemical
outcome (see Scheme 3), as noted in the transition state for the
second Michael addition (TS2) through the Re face of lactam 8a,
which shows the proper orientation of the reactants for the cis H-
3/H-15 and trans C19-Me/C20-E(SO2Ph) arrangements of the final
product 9a (Figure 7). The barrier for the cyclization can be
ascribed to the formation of a boat-like structure in the forming
six-membered ring, which is assisted by
a
significant
pyramidalization (20.6 and 30.5 degrees) of the carbon atoms
involved in ring closure. On the other hand, the transition state is
stabilized by the formation of several C–H···O hydrogen bonds
between the sulfonyl oxygens of the lactam and hydrogen atoms
of the Nazarov reagent.
As a final remark, the transition state corresponding to the Re
attack of reagent 4 in the less stable s-cis conformation (Figure
S1 in Supporting Information) to lactam 8a was also identified.
Compared to the transition state formed upon attack of the s-
trans conformation (TS1 in Figure 7) through the Re face, it was
found to be destabilized by 0.6 kcal/mol. This finding, in
conjunction with the low population of the s-cis conformer (< 2%;
see above), supports the mechanistic pathway shown in Figure
6.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
atoms are shown. Complete geometrical data of pre-reactants, transition
states, and intermediates is available in Supporting Information.
The effect of the cesium cation
Why does the replacement of DBU by Cs2CO3 revert the
stereochemical outcome of the reaction with Nazarov reagent 4?
We hypothesize that the cesium cation plays a dual role in this
reaction. First, through coordination to the carbonyl oxygen
atoms of 4, the Cs+ cation affords the electrostatic stabilization
for generation of the anionic form of the Nazarov reagent
(Scheme S1 in Supporting Information). Second, such
electrostatic stabilization suggests that the ionic pair Cs+-4- can
be the reactive species for the addition to lactams 8. This
assumption is supported by the relatively low permittivity of
dichloromethane (ε = 8.9 at rt), and by the excess of Cs2CO3
relative to the Nazarov reagent 4, which were in a 2:1 ratio
under the reaction conditions (see Experimental). On the other
hand, although the presence of ionic pairs when DBU is used
cannot be ruled out, delocalization of the positive charge in the
amidinium unit and the much larger size of DBU compared to the
localized unit charge and smaller size of the Cs+ cation (and
hence the stronger electrostatic potential) suggests that the
presence of ionic pairs should be more relevant for the Cs+
cation. Further support comes from both experimental and
theoretical evidence about the formation of cesium-coordinated
aggregates of diketones and carboxylic acids. [19-21]
Under these circumstances, coordination of the Cs+ cation to the
oxygen atoms of the ester or sulfonyl groups of lactams 8 may
affect the relative stability of the annulation reaction through the
two diastereotopic faces of the lactam. To this end, the attack of
the Nazarov reagent 4 should proceed via an antiperiplanar
approach between the carbon atoms that will form the first C--C
bond, as this approach would place the oxygen atoms of both 4
and the activating E group close for coordination to the Cs+
cation. To check the feasibility of this mechanistic hypothesis,
we determined the free energy profile for the addition of the
Cs+···4 complex to lactam 8c (see Scheme 3; note that the
benzyl group of 8b was replaced by methyl in present
calculations).
The transition states (TS1) for the first Michael addition between
reagent 4 and lactam 8c (Figure 8) have similar stabilities, the
Re approach being slightly more favorable (by 0.6 kcal/mol). As
noted in Figure 9, the Cs+ cation is coordinated to the carbonyl
oxygens of 4 and to the carbonyl oxygen of the ester group in
lactam 8b, with distances close to 2.9 Å, thus assisting the
proper arrangement of the reactants in the annulation reaction.
As noted above, this requires the Nazarov reagent 4 to be
oriented with the carbonyl oxygens pointing toward the
molecular edge that contains the ester group in the lactam, so
that the attack occurs with a slightly distorted antiperiplanar
arrangement of the carbon atoms involved in the first Michael
addition (H–C···C–H dihedral angle of -160.7 and 133.5 degrees
for the Re and Si additions, respectively). Figure 9 also shows
the asynchronicity of the double Michael addition, as the length
of the forming C--C bonds is 2.11 (2.16) and 3.43 (3.49) Å for
the Si (Re) addition, thus making necessary the internal rotation
to the 4 s-cis conformation required for cyclization, as noted
before for the DBU-catalyzed process.
Figure 8. Free energy (kcal/mol) profile for the first Michael addition of the
Cs+···4 complex to lactam 8c derived from M062X/6-31G(d) calculations in
CH2Cl2.
Figure 7. Representation of the transition states (TS1 and TS2) formed in the
DBU-catalyzed double Michael additions of the anionic form of Nazarov
reagent 4 to lactam 8a. The approach occurs through the pro-R face of 4 and
the Re face of the lactam. For the sake of clarity, only selected hydrogen
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
Whether the Cs+ cation remains coordinated along the rest of
the cyclization reaction is more questionable, because the
formation of the first C–C bond in intermediate I1 is concomitant
to a charge transfer from the Nazarov reagent to carbon atom
C20 in the lactam. Thus, the Mulliken charge of this latter atom
changes from -0.05 e in the pre-reactant (Pre-RC) complex to -
0.18 e in I1, whereas the net charge of the oxygen atoms in the
Nazarov reagent varies from -0.63 e in Pre-RC to -0.52 e in I1.
The charge transfer from 4 to 8c should weaken the electrostatic
stabilization between the Nazarov reagent and the Cs+ cation,
which presumably might be released to the solvent environment.
The theoretical computation of the absolute free energy of Cs+
originated via the Re and Si addition of Cs+···4 to lactam 8c
indicate that the cation release from the intermediate is favored
by 4.6 kcal/mol in the two cases, as expected from the charge
transfer from 4 to 8c.
Based on the preceding discussion, the free energy profile
leading from the intermediate I1 to the ring closure was
determined with and without the presence of the coordinated Cs+
cation (Figure 10). The results indicate that the transition state
(TS2) for the second Michael addition via the Si face is favored
in the two cases: the Re TS2 is destabilized by 1.1 kcal/mol in
the presence of Cs+, increasing up to 2.6 kcal/mol in the
absence of Cs+ coordination, which would lead to
a
stereochemical ratio of 81:1 for the Si and Re cyclized products.
Compared to the reaction with the coordinated Cs+ cation, this
represents a 13-fold increase in the stereoselectivity of the
annulation reaction.
Scheme 5. Calculation of the relative free energy of Cs+ release between the
pre-reactant complex and the intermediate formed after the first Michael
addition between the anionic species of 4 and lactam 8c.
Figure 9. Representation of the transition state (TS1) formed in the first
Michael addition of the Cs+···4 complex to lactam 8c. The approach occurs
through the Si (top; pro-R face of 4), and Re (bottom; pro-S face of 4) faces of
the lactam. For the sake of clarity, only selected hydrogen atoms are shown.
The Cs+ cation is shown as a violet sphere. Complete geometrical data of pre-
reactants, transition states, and intermediates is available in Supporting
Information.
coordination is challenging, especially due to the difficulty in
estimating the solvation contribution in the complex environment
of the reaction. However, this term cancels out when the relative
free energy of Cs+ release from the pre-reactant complex (Pre-
RC) and the intermediate (I1) is determined, as noted in Scheme
5. Calculations performed for the corresponding species
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
Figure 10. Free energy (kcal/mol) profile for the second Michael addition of
the anionic species of Nazarov reagent 4 to lactam 8c in the absence (top)
and presence (bottom) of coordinated Cs+ cation derived from M062X/6-
31G(d) calculations in CH2Cl2.
Michael addition to adopt an antiperiplanar orientation, which in
turn determines the final stereochemical outcome of the cyclized
product.
To further explore the crucial role of cesium in the mechanism of
the double Michael addition, the reaction between lactam 8a and
Nazarov reagent 4 was performed using Li2CO3 instead of
Cs2CO3. In this case, the tetracyclic intermediate D (Figure 2; R
= H), resulting from the initial Michael addition, was isolated as a
C15 mixture of stereoisomers. An additional treatment (CH2Cl2,
20h) with Li2CO3 did not lead to any pentacyclic cyclized product.
The different outcome obtained in the presence of Li2CO3 can be
explained by the structural constraints imposed by the lower
ionic radius of Li+, which would perturb the structural and
energetic features of the Cs+-coordinated reactive complex.
Thus, theoretical calculations revealed that the intrinsic stability
of the TS (TS1) for the first Michael addition is penalized by
around 4 and 7 kcal/mol upon replacement of the Cs+ cation by
K+ and Li+, respectively. A significant destabilization was also
found for the intermediate I1 (data not shown). Overall, these
findings point out the relevance of the cation in dictating the final
outcome of the annulation process.
Inspection of the transition state for the second Michael addition
(Figure 11) reveals that the formation of the second C–C bond is
more advanced in the absence of coordinated Cs+, as noted in
the shorter length of the forming bond (2.08 Å versus 2.18 Å in
the absence and presence of Cs+ cation, respectively; see
Figure 11), as well as in the larger pyramidalization of the
respective carbon atoms (close to 19 degrees in the absence of
Cs+ cation versus 15 degrees with coordinated Cs+ cation). Let
us note that the addition through the Si face yields the
experimental stereochemistry characterized by trans H-3/H-15
and cis C19-Me/C20-CO2Me relationships (Figure 11).
Enantioselective synthesis of 17a-carbaakuammigine
To illustrate the synthetic potential of the methodology and the
versatility of pentacyclic Nazarov-derived adducts in the
synthesis of yohimbine-type targets, we examined the
conversion of the enantiopure epiallo derivative 7a into 17a-
carbaakuammigine (15). Reductive removal of the activating
phenylsulfonyl group of 7a using Na/Hg at −78 °C was
completely stereoselective, with retention of configuration,[22]
leading to the D/E cis-fused pentacycle 11 in excellent yield
(Scheme 6). After chemoselective deprotection of the hydroxy
group, the removal of the C-6 hydroxymethyl substituent of 12
was accomplished in 62% overall yield by oxidation to a
carboxylic acid, followed by tin-mediated radical decarbonylation
of the corresponding acyl selenide.[23] Then, the resulting
enolizable β-ketoester 13 was converted to α,β-unsaturated
ester 14 by palladium-catalyzed reductive coupling[24] of the
corresponding vinyl triflate. Finally, after deprotection of the
indole nitrogen, chemoselective alane reduction of the lactam
carbonyl completed the enantioselective synthesis of 17a-
carbaakuammigine (15).
Figure 11. Representation of the transition state (TS2) formed in the second
Michael addition of the anionic species of Nazarov reagent 4 to lactam 8c in
the absence (top) and presence (bottom) of coordinated Cs+ cation. The
approach occurs through the pro-R face of 4 and the Si face of the lactam. For
the sake of clarity, only selected hydrogen atoms are shown. The Cs+ cation is
shown as
a violet sphere. Complete geometrical data of pre-reactants,
transition states, and intermediates is available in Supporting Information.
Overall, the present results suggest that coordination of the Cs+
cation to the carbonyl oxygens of both the Nazarov reagent and
the activating E group of the lactam is a key factor in promoting
the proper arrangement of 4 relative to the lactam. The
coordination forces the carbon atoms that participate in the first
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
withdrawing group in the lactam, as this determines the
preferred orientation of the reactants, and eventually the final
stereochemical outcome of the cyclized products. Support to the
specific role of Cs+ cation in determining the products of the
double Michael addition comes from the very different outcome
obtained upon replacement of Cs2CO3 by Li2CO3, since no
pentacyclic cyclized product was isolated in this latter case.
Overall, this study points out that the base can be an effective
player for the control of the stereoselective addition, and hence
choice of the base may be a crucial factor in dictating the most
efficient way to attain the derised cyclized product. These
findings open new avenues for the fine regulation of the targeted
product obtained in these chemical reactions.
Experimental Section
Reaction of unsaturated lactams 5a and 8a with Nazarov reagent 4
using DBU. A solution of unsaturated lactam 5a[7] o 8a[8] (1 equiv.) in
anhydrous THF was added at 0 °C under an inert atmosphere to a
solution of the Nazarov reagent 4 (2 equiv.) and DBU (1 equiv.) in
anhydrous THF (0.02 M), and the mixture was allowed to warm slowly to
room temperature. After 20h of stirring at room temperature, the mixture
was quenched with H2O and extracted with EtOAc. The combined
organic extracts were washed with brine, dried over anhydrous MgSO4,
Scheme 6. Enantioselective synthesis of 17a-carbaakuammigine.
The cis ring junction of the above pentacyclic derivatives 11-15
was initially deduced by 1H NMR, from the observation of
positive NOE effects between H-15/H-20, H-15/C19-Me, and H-
20/C19-Me in 11 and the triflate derived from 13. Additionally, the
H-3/H-15 trans stereochemistry in this series was
unambiguously confirmed when the spectroscopic NMR data of
enantiopure compound 13 proved to be identical to those of
racemic 13 prepared by dephenylsulfonylation of 10a, of known
relative configuration (Scheme 7).
filtered,
and
concentrated
under
reduced
pressure.
Flash
chromatography of the resulting residue (9:1 hexane-EtOAc) afforded
compounds 6a (83%) or 9a (76%), respectively, as pale yellow foams.
22
Compound 6a: [α]D +75.4 (c=0.86 in CHCl3); 1H NMR (400 MHz,
CDCl3, COSY, g-HSQC, enol form, 25°C, TMS): δ=0.97 (d, J = 6.8 Hz,
3H, CH3), 1.43 [s, 9H, (CH3)3C], 1.44 (masked, 1H, H-14), 1.73 [s, 9H,
(CH3)3C], 2.17 (dd, J = 18.4, 0.8 Hz, 1H, H-18), 2.77 (ddd, J = 16.8, 6.0,
2.4 Hz, 1H, H-6), 2.87 (dt, J = 16.8, 1.6 Hz, 1H, H-6), 3.05 (m, 1H, H-19),
3.14-3.21 (m, 2H, H-18, H-14), 3.67 (dd, J = 10.8, 5.2 Hz, 1H, CH2O),
3.85 (dd, J = 10.8, 8.8 Hz, 1H, CH2O), 3.92 (s, 3H, CH3O), 3.96 (m, 1H,
H-15), 5.14 (dd, J = 10.4, 2.0 Hz, 1H, H-3), 5.49 (m, 1H, H-5), 7.23 (td, J
= 7.6, 1.2 Hz, 1H, HAR), 7.29 (td, J = 6.8, 1.2 Hz, 1H, HAR), 7.40 (dd, J =
6.8, 1.2 Hz, 1H, HAR), 7.57 (tt, J = 7.6, 0.8 Hz, 2H, H-m C6H5), 7.67 (tt, J
= 7.6, 1.2 Hz, 1H, H-p C6H5), 7.94 (d, J = 7.6 Hz, 1H, HAR), 8.01 (dd, J =
7.6, 0.8 Hz, 2H, H-o C6H5), 12.40 (s, 1H, OH); 13C NMR (100.6 MHz,
CDCl3, 25°C, TMS): δ=20.8 (CH3), 22.2 (C-6), 27.7 [(CH3)3C], 28.3
[(CH3)3C], 30.5 (C-19), 31.5 (C-15), 33.1 (C-18), 35.0 (C-14), 45.7 (C-5),
52.1 (CH3O), 52.7 (C-3), 64.8 (CH2O), 76.0 (C-20), 82.4 [(CH3)3C], 84.4
[(CH3)3C], 97.3 (C-16), 114.4 (CAR), 116.1 (CHAR), 118.3 (CHAR), 123.1
(CHAR), 124.8 (CHAR), 128.4 (2C-m C6H5), 128.8 (CAR), 131.1 (2C-o
C6H5), 133.4 (CAR), 134.1 (C-p C6H5), 136.6 (CAR), 136.7 (CAR), 150.1
(CO), 153.0 (CO), 165.7 (CO), 170.9, 172.1 (C-17, CO); IR (ATR Pike) ν:
1645, 1739 cm-1 (C=O); HRMS (ESI) calcd for [C39H46N2O11S + Na]+:
773.2715, found 773.2717. Compound 9a: 1H NMR (400 MHz, CDCl3,
COSY, g-HSQC, enol form, 25°C, TMS): δ=0.97 (d, J = 6.8 Hz, 3H, CH3),
1.42 (masked, 1H, H-14), 1.72 [s, 9H, (CH3)3C], 2.17 (dd, J = 17.6 Hz, 1H,
H-18eq), 2.55-2.68 (m, 3H, 2H-6, H-5), 3.02-3.17 (m, 3H, H-18, H-14, H-
19), 3.88 (m, 1H, H-15), 3.92 (s, 3H, CH3O), 4,84 (m, 1H, H-5), 5.12 (dd,
J = 10.0, 2.4 Hz, 1H, H-3), 7.23 (td, J = 7.6, 1.2 Hz, 1H, HAR), 7.28 (td, J
= 6.8, 1.2 Hz, 1H, HAR), 7.39 (dd, J = 6.8, 1.2 Hz, 1H, HAR), 7.56 (tt, J =
7.6, 0.8 Hz, 2H, H-m C6H5), 7.65 (tt, J = 7.6, 1.2 Hz, 1H, H-p C6H5), 7.91
(d, J = 7.6 Hz, 1H, HAR), 7.99 (dd, J = 7.6, 0.8 Hz, 2H, H-o C6H5), 12.45
(s, 1H, OH); 13C NMR (100.6 MHz, CDCl3, 25°C, TMS): δ=20.9 (CH3),
21.6 (C-6), 28.3 [(CH3)3C], 30.1 (C-19), 31.5 (C-15), 33.1 (C-18), 34.6 (C-
14), 40.3 (C-5), 52.1 (CH3O), 55.3 (C-3), 75.8 (C-20), 84.3 [(CH3)3C],
97.3 (C-16), 115.9 (CHAR), 118.3 (CHAR), 118.4 (CAR), 123.1 (CHAR),
124.7 (CHAR), 128.4 (2C-m C6H5), 128.6 (CAR), 130.9 (2C-o C6H5), 134.0
Scheme 7. Confirmation of the relative strereochemistry of 13.
Conclusions
The potential of the annulation reactions performed with different
Nazarov-like
reagents
to
accomplish
the
controlled
stereoselective synthesis of complex heterocyclic compounds is
well known, as illustrated here in the synthesis of yohimbine-
type adducts. However, the present results highlight the
dramatic change of the facial selectivity triggered by the
apparently minor change originated upon replacement of DBU
by Cs2CO3 as the base. We propose that this unexpected effect
can be related to the coordination of the Cs+ cation to the
carbonyl oxygens of both the Nazarov reagent and the electron-
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
(C-p C6H5), 134.9 (CAR), 136.3 (CAR), 136.7 (CAR), 150.2 (CO), 165.2
(CO), 170.9, 172.0 (C-17, CO); IR (ATR Pike) ν: 1648, 1731 cm-1 (C=O);
HRMS (ESI) calcd for [C33H36N2O8S + H]+: 621.2265, found 621.2272.
170.9 (C-17), 171.9 (CO). Compound 10b: 1H NMR (400 MHz, CDCl3,
COSY, g-HSQC, enol form, 25°C, TMS): δ=1.18 (br s, 3H, CH3), 1.67 [s,
10H, (CH3)3C, H-14], 2.00-2.40 (m, 2H, H-14, H-19), 2.45-2.90 (m, 5H,
2H-6, H-5, 2H-18), 3.38 (br s, 1H, H-15), 3.82 (s, 3H, CH3O), 4.97-6.05
(m, 2H, H-5, H-3), 5.07 (d, J = 12.8 Hz, 1H, CH2C6H5), 5.13 (d, J = 12.8
Hz, 1H, CH2C6H5), 7.12-7.31 (3m, 7H, HAR), 7.40 (d, J = 7.6 Hz, 1H, HAR),
7.95 (d, J = 7.6 Hz, 1H, HAR); 13C NMR (100.6 MHz, CDCl3, 25°C, TMS):
δ=15.1 (CH3), 21.6 (C-6), 28.2 [(CH3)3C], 30.3 (C-19), 31.5 (C-15), 34.2,
34.9 (C-14, C-18), 42.5 (C-5), 51.9 (CH3O), 53.6 (C-3), 57.4 (C-20), 66.8
(CH2C6H5), 84.0 [(CH3)3C], 97.2 (C-16), 115.6 (CHAR), 116.0 (CAR), 118.2
(CHAR), 122.9 (CHAR), 124.4 (CHAR), 127.6-128.3 (CAR, C-o, m, p C6H5),
135.6 (CAR, C-i C6H5), 136.6 (CAR), 150.2 (CO), 168.1-172.1 (C-17, 3CO);
IR (ATR Pike) ν: 1652, 1728 cm-1 (C=O); HRMS (ESI) calcd for
[C35H38N2O8 + H]+: 615.2701, found: 615.2701.
Reaction of unsaturated lactams 5 and 8 with Nazarov reagent 4
using Cs2CO3. A solution of unsaturated lactam 5a[7], 5b[7], 8a[8] or 8b[7]
(1 equiv.) in anhydrous CH2Cl2 (0.02-0.005 M) was added at 0 °C under
an inert atmosphere to a solution of the Nazarov reagent 4 (3 equiv.) and
Cs2CO3 (6 equiv.) in anhydrous CH2Cl2, and the mixture was allowed to
warm slowly to room temperature. After 20 h of stirring at room
temperature, the mixture was concentrated under reduced pressure.
Flash chromatography (9:1 hexane-EtOAc) of the resulting oil afforded
compounds 7a (86%), 7b (87%), 10a (88%) or 10b (59%), respectively,
as pale yellow foams. Compound 7a (enol-keto ratio, 9:1): m.p. 98-
100 °C; [α]D22 +20.5 (c=0.7 in CHCl3); 1H NMR (400 MHz, CDCl3, COSY,
g-HSQC, enol form, 25°C, TMS): δ=1.20 (d, J = 6.4 Hz, 3H, CH3), 1.41 [s,
9H, (CH3)3C], 1.69 [s, 9H, (CH3)3C], 1.95 (dd, J = 18.0, 1.6 Hz, 1H, H-18),
2.25 (ddd, J = 14.0, 12.0, 3.2 Hz, 1H, H-14), 2.56 (d, J = 16.4 Hz, 1H, H-
6), 2.69 (ddd, J = 16.4, 4.4, 2.4 Hz, 1H, H-6), 2.81 (m, 2H, H-18, H-19),
3.16 (dt, J = 14.0, 3.2, 3.2 Hz, 1H, H-14), 3.80 (m, 1H, CH2O), 3.81 (s,
3H, CH3O), 4.08 (m, 2H, H-15, CH2O), 4.94 (d, J = 11.2 Hz, 1H, H-3),
5.63-5.71 (m, 1H, H-5), 7.20-7.60 (m, 6H, HAR), 7.87 (dd, J = 8.0, 1.2 Hz,
1H, HAR), 8.00 (dd, J = 8.0, 1.2 Hz, 2H, HAR), 12.2 (s, 1H, OH); 13C NMR
(100.6 MHz, CDCl3, 25°C, TMS): δ=14.1 (CH3), 21.8 (C-6), 27.6
[(CH3)3C], 28.3 [(CH3)3C], 28.7 (C-15), 29.3 (C-14), 31.6 (C-19), 35.2 (C-
18), 45.6 (C-5), 49.3 (C-3), 52.0 (CH3O), 64.3 (CH2O), 70.0 (C-20), 82.3
[(CH3)3C], 84.3 [(CH3)3C], 96.7 (C-16), 114.9 (CAR), 116.0 (CHAR), 118.1
(CHAR), 123.0 (CHAR), 124.6 (CHAR), 128.2, 131.2 (C-o, m C6H5), 128.8
(CAR), 133.6, 133.7 (CAR, C-p C6H5), 136.5 (CAR), 138.7 (C-i C6H5), 150.1
(CO), 153.1 (CO), 166.4 (CO), 171.6 (C-17, CO); IR (film) ν: 1728, 1640
cm-1 (C=O); HRMS (ESI) calcd for [C39H46N2O11S + H]+: 751.2895, found:
751.2892; Anal. Cald for C39H46N2O11S: C, 62.38; H, 6.17; N, 3.73.
Found: C, 62.15; H, 6.34; N, 3.36. Compound 7b (enol-keto ratio, >9:1):
1H NMR (400 MHz, CDCl3, COSY, g-HSQC, enol form, 25°C, TMS):
δ=1.26 (d, J = 11.2 Hz, 3H, CH3), 1.45 [s, 9H, (CH3)3C], 1.68 [s, 9H,
(CH3)3C], 2.01 (m, 1H, H-14), 2.10 (masked, 1H, H-14), 2.40 (m, 1H, H-
19), 2.65 (d, J = 16.4 Hz, 1H, H-6), 2.68-2.79 (m, 2H, H-18), 2.76-2.90
(ddd, J = 16.4, 6.4, 2.4 Hz, 1H, H-6), 3.49 (m, 1H, H-15), 3.83 (s, 3H,
CH3O), 3.96 (t, J = 10.4 Hz, 1H, CH2O), 4.11 (dd, J = 10.4, 7.2 Hz, 1H,
CH2O), 4.94 (dm, J = 8.4 Hz, 1H, H-3), 5.11 (d, J = 12.4 Hz, 1H,
CH2C6H5), 5.17 (d, J = 12.4 Hz, 1H, CH2C6H5), 5.74 (m, 1H, H-5), 7.19-
7.36 (m, 7H, HAR), 7.39 (d, J = 7,6, 1,2 Hz, 1H, HAR), 7.94 (d, J = 7,6, 1,2
Hz, 1H, HAR), 12.2 (s, 1H, OH); 13C NMR (100.6 MHz, CDCl3, 25°C,
TMS): δ=14.1 (CH3), 22.0 (C-6), 27.6 [(CH3)3C], 28.2 [(CH3)3C], 30.4 (C-
19), 31.8 (C-15), 34.0 (C-14, C-18), 45.6 (C-5), 49.0 (C-3), 51.8 (CH3O),
57.8 (C-20), 64.4 (CH2O), 67.0 (CH2C6H5), 82.2 [(CH3)3C], 84.0 [(CH3)3C],
97.0 (C-16), 114.9 (CAR), 115.8 (CHAR), 118.1 (CHAR), 122.9 (CHAR),
124.5 (CHAR), 127.7-128.8 (CAR, C-o, m, p C6H5), 134.4 (CAR), 135.6 (C-i
C6H5), 136.6 (CAR), 149.9 (CO), 153.1 (CO), 168.3-172.1 (C-17, 3CO); IR
When reaction from 5a was carried out for 2 h at 0 °C, the intermediate D
was isolated (23%) by flash chromatography (9:1 hexane-EtOAc). Major
isomer: 1H NMR (400 MHz, CDCl3, COSY, g-HSQC, 25°C, TMS): δ=1.42
[s, 9H, (CH3)3], 1.73 [s, 9H, (CH3)3], 1.74 (m, 1H, H-1), 1.94 (ddd, J =
11.6, 7.2, 1.6 Hz, 3H, CH3), 2.54 (m, 1H, H-1), 2.91 (m, 2H, H-7), 3.61 (m,
1H, H-2), 3.72 (s, 3H, CH3O), 3.94 (tt, J = 10.8, 3.6 Hz, 1H, CH2O), 4.17
(ddd, J = 10.8, 6.4, 5.6 Hz, 1H, CH2O), 4.27 (d, J = 4.0 Hz, 1H, H-3), 4.32
(d, J = 6.0 Hz, 1H, CHCOO), 5.34-5.44 (m, 2H, H-6, H-12b), 6.20-6.28 (m,
1H, CH=), 7.07-7.14 (dq, J = 15.8, 6.8 Hz, 1H, CH=), 7.23-7.33 (2m, 2H,
HAR), 7.41 (dm, J = 8.0 Hz, 1H, HAR), 7.57 (m, 2H, HAR), 7.68 (m, 1H,
HAR), 7.99 (m, 2H, HAR), 8.11 (d, J = 8.0 Hz, 1H, HAR); 13C NMR (100.6
MHz, CDCl3, 25°C, TMS): δ=18.6 (CH3), 21.7 (C-7), 27.7 [(CH3)3C], 28.2
[(CH3)3C], 31.6 (C-2), 34.2 (C-1), 45.6, 51.0 (C-6, C-12b), 52.6 (CH3O),
58.4 (C-3), 65.6 (CH2O), 70.1 (CHCOO), 82.3 [(CH3)3C], 84.9 [(CH3)3C],
113.6 (CAR), 115.9 (CAR), 118.1 (CHAR), 122.9 (CHAR), 124.8 (CHAR),
128.4-131.7 (CHAR), 134.1 (CH=), 136.8 (CAR), 137.8 (CAR), 146.1 (CH=),
1
153.2 (CO), 162.1 (CO), 168.9 (CO), 192.5 (CO). Minor isomer: H NMR
(400 MHz, CDCl3, COSY, g-HSQC, 25°C, TMS): δ=1.44 [s, 9H, (CH3)3],
1.52 (m, 1H, H-1), 1.77 [s, 9H, (CH3)3], 1.97 (ddd, J = 11.6, 7.2, 1.6 Hz,
3H, CH3), 2.72 (m, 1H, H-1), 2.91 (m, 2H, H-7), 3.70 (m, 1H, H-2), 3.72 (s,
3H, CH3O), 4.00 (m, 1H, CH2O), 4.02 (d, J = 6.0 Hz, 1H, H-3), 4.17 (m,
1H, CH2O), 4.45 (d, J = 6.0 Hz, 1H, CHCOO), 5.34-5.44 (m, 2H, H-6, H-
12b), 6.20-6.28 (m, 1H, CH=), 6.92-7.05 (dq, J = 15.8, 6.8 Hz, 1H, CH=),
7.23-7.33 (2m, 2H, HAR), 7.41 (dm, J = 8.0 Hz, 1H, HAR), 7.57 (m, 2H,
HAR), 7.68 (m, 1H, HAR), 7.99 (m, 2H, HAR), 8.15 (d, J = 8.0 Hz, 1H, HAR);
13C NMR (100.6 MHz, CDCl3, 25°C, TMS): δ=18.5 (CH3), 21.5 (C-7),
27.7 [(CH3)3C], 28.3 [(CH3)3C], 31.2 (C-2), 36.0 (C-1), 45.6, 50.9 (C-6, C-
12b), 52.7 (CH3O), 58.4 (C-3), 65.5 (CH2O), 68.9 (CHCOO), 82.3
[(CH3)3C], 85.1 [(CH3)3C], 113.6 (CAR), 116.0 (CAR), 118.0 (CHAR), 123.0
(CHAR), 124.8 (CHAR), 128.4-131.7 (CHAR), 133.9 (CH=), 136.9 (CAR),
138.1 (CAR), 145.4 (CH=), 149.8 (CO), 162.3 (CO), 168.5 (CO), 192.6
(CO).
Computational methods. Full geometry optimizations were performed
with the M06-2X[16] density functional method by using the 6-31G(d)[17]
basis set. The nature of the stationary points was verified by inspection of
the vibrational frequencies within the harmonic oscillator-rigid rotor
approximation. In specific cases the free energy profile of the annulation
reactions was determined from single-point calculations performed at the
spin-component scaled MP2 (SCS-MP2)[25] level with the 6-31G(d) basis,
and from B2PLYPD3[26] calculations with the def2-SVPP[27] basis. These
methods have proved valuable for the study of reactive processes.[28]
The relative free energies were estimated by combining the energy
differences with the thermal/entropy corrections derived from frequency
analysis. To this end, the free energy corrections were calculated using
Truhlar's quasiharmonic approximation,[29,30] where real harmonic
vibrational frequencies lower than 100 cm-1 were raised to 100 cm-1, as
has been utilized in other chemical reactivity studies.[31-33] Finally, the
effect of solvation in dichloromethane was taken into account using the
(film) ν: 1728, 1646 cm-1 (C=O); HRMS (ESI) calcd for [C41H48N2O11
+
H]+: 745.3331, found 745.3322. Compound 10a: 1H NMR (400 MHz,
CDCl3, COSY, g-HSQC, enol form, 25°C, TMS): δ=1.18 (d, J = 6.8 Hz,
3H, CH3), 1.69 [s, 9H, (CH3)3C], 2.00 (dd, J = 18.4, 2.0 Hz, 1H, H-18),
2.27 (ddd, J = 14.4, 11.6, 2.6 Hz, 1H, H-14), 2.48-2.61 (m, 3H, 2H-6, H-
18), 2.74 (m, 2H, H-19, H-5), 3.25 (dt, J = 14.4, 4.0 Hz, 1H, H-14), 3.93 (s,
3H, CH3O), 3.99 (br. s, 1H, H-15), 4.99 (m, 2H, H-3, H-5), 7.21-7.29 (m,
2H, HAR), 7.37-7.42 (m, 3H, HAR), 7.53 (tt, J = 8.0, 1.2 Hz, 1H, HAR), 7.89
(dd, J = 8.0, 1.2 Hz, 1H, HAR), 8.00 (dd, J = 8.0, 1.2 Hz, 2H, HAR), 12.40
(s, 1H, OH); 13C NMR (100.6 MHz, CDCl3, 25°C, TMS): δ=14.1 (CH3),
21.4 (C-6), 28.3 [(CH3)3C], 28.5, 28.6 (C-15, C-14), 31.1 (C-19), 35.3 (C-
18), 40.6 (C-5), 52.1 (CH3O), 53.1 (C-3), 76.2 (C-20), 84.4 [(CH3)3C],
97.0 (C-16), 115.8 (CAR), 118.2 (CHAR), 118.9 (CHAR), 122.9 (CHAR),
124.4 (CHAR), 128.2, 131.1 (C-o, m C6H5), 128.9 (CAR), 133.7 (C-p C6H5),
135.1 (CAR), 136.3 (CAR), 138.6 (C-i C6H5), 150.3 (CO), 165.1 (CO),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
SMD version[18] of the IEF-PCM[31] continuum solvation method. SMD
calculations were performed at the B3LYP/6-31G(d)[35] level, which was
one of the six electronic structure methods used in the optimization of the
SMD method. All DFT computations were carried out using the keyword
Integral(Grid=Ultrafine) as implemented in Gaussian09,[36] which was
used to carry out these calculations.
[7]
[8]
[9]
M. Amat, F. Arioli, M. Pérez, E. Molins, J. Bosch, Org. Lett. 2013, 15,
2470−2473.
F. Arioli, M. Pérez, C. Are, C. Estarellas, J. L. Luque, J. Bosch, M. Amat,
Chem. Eur. J. 2015, 21, 13382−13389.
Similar differences in the facial selectivity have been observed in
conjugate addition reactions to Nind-unsubstituted and Nind-Boc
indoloquinolizidine lactams. a) S. M. Allin, J. S. Khera, C. I. Thomas, J.
Witherington, K. Doyle, M. R. J. Elsegood, M. Edgar, Tetrahedron Lett.
2006, 47, 1961−1964; b) S. M. Allin, J. S. Khera, J. Witherington, M. R.
J. Elsegood, Tetrahedron Lett. 2006, 47, 5737−5739. c) A. Deiters, M.
Pettersson, S. F. Martin, J. Org. Chem. 2006, 71, 6547−6561.
Acknowledgements
Financial support from the MINECO/FEDER, Spain (Projects
SAF2014-57094-R, CTQ2015-65384-R, ENE2015-63969, and
SEV2015-0496) and the Generalitat de Catalunya (Grants
2014SGR-0155 and 2014SGR-1189) is gratefully acknowledged.
Thanks are also due to the MINECO (Spain) for fellowships to F.
A. (AP2010-1663) and C. E. (FPDI-2013-15572), Icrea
Academia for financial support to F. J. L., and the Leonardo da
Vinci programme (Unipharma-Graduates 9) for a mobility grant
to C. A. We also acknowledge the Consorci de Serveis
Universitaris de Catalunya (CSUC) for their computational
facilities, as well as the networking contribution from the COST
Action CM1407.
[10] For DBU-promoted stereoselective annulation reactions with the
original Nazarov reagent, see reference [4d].
[11] Minor amounts (≈5%) of the corresponding H-3/H-15 trans isomer were
also isolated.
[12] Another stereoisomer, with
isolated in 19% yield.
a H-3/H-15 cis stereochemistry, was
[13] The absolute configurations of compounds 9a and 10a were
unambiguously determined by X-ray crystallographic analysis. CCDC-
1528357 (9a) and CCDC-1528358 (10a) contain the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[14] This stereochemical outcome is the same as that found in related
annulations of the methyl-substituted Nazarov reagent
(methoxycarbonyl)-2-cyclohexenones: see references [6a,b].
2 with 2-
[15] a) For the stereoselective generation of cis-trans decaline adducts in
the base-catalyzed double Michael addition of the β-keto phenylsulfinyl
(or sulfonyl) analogs of 4 to 2-methoxycarbonyl)-2-cyclohexenone, see:
C. Spino, P. Deslongchamps, Tetrahedron Lett. 1990, 31, 3969−3972.
See also b) G. Berthiaume, J.-F. Lavallée, P. Deslongchamps,
Tetrahedron Lett. 1986, 27, 5451−5454.
Keywords: Density functional calculations • Michael addition •
Nazarov reagent • quantum chemical calculations •
stereoselectivity
[1]
a) First reported by: I. N. Nazarov, S. I. Zavyalov, Zh. Obshch. Khim.
1953, 23, 1703; Engl. Transl. 1953, 23, 1793; Chem. Abstr., 1954,
48:13667h; For improved preparations, see: b) R. Zibuck, J. M. Streiber,
J. Org. Chem. 1989, 54, 4717−4719; c) R. Zibuck, J. M. Streiber, Org.
Synth. 1993, 71, 236−241 and references cited therein.
[16] Y. Zhao, D.G. Truhlar, Theor. Chem. Acc. 2008, 120, 215−241.
[17] P.C. Hariharan, J. A. Pople, Theor. Chim. Acta 1973, 28, 213−218.
[18] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009,
113, 6378−6396.
[2]
[3]
For reviews, see: a) R. Zibuck in Encyclopedia of Reagents for Organic
Synthesis Vol. 5 (Ed.: L. A. Paquette), Wiley, Chichester, 1995; pp.
3558−3559; b) G. Audran, P. Brémond, M. Feuerstein, S. R. A. Marque,
M. Santelli, Tetrahedron 2013, 69, 8325−8348.
[19] C. Mayeux, L. Massi, J.-F. Gal, L. Charles, P. Burk, Chem. Eur. J. 2014,
20, 815−823.
[20] E. S. Vikulova, K. V. Zherikova, N. V. Kuratieva, N. B. Morozova, I. K.
Igumenov, J. Coord. Chem. 2013, 66, 2235−2249.
Molecules that contain both a nucleophilic and an electrophilic site have
been referred to as amphoteric: a) T. B. Samarakoon, M. Y. Hur, R. D.
Kurtz, P. R. Hanson Org. Lett. 2010, 12, 2182−2185; b) For a review,
see: Z. He, A. Zajdlik, A. K. Yudin, Acc. Chem. Res. 2014, 47,
1029−1040.
[21] A. Facchetti, A. Streitwieser, J. Org. Chem. 2004, 69, 8345−8355.
[22] For the stereoselective removal of a phenylsulfonyl group placed at the
α-position of a lactam carbonyl, see: Y. C. Jung, C. H. Yoon, E. Turos,
K. S. Yoo, K. W. Jung, J. Org. Chem. 2007, 72, 10114−10122.
[23] a) S. M. Allin, C. I. Thomas, J. E. Allard, K. Doyle, M. R. J. Elsegood,
Tetrahedron Lett. 2004, 45, 7103−7105; b) S. M. Allin, C. I. Thomas, K.
Doyle, M. R. J. Elsegood, J. Org. Chem. 2005, 70, 357−359; c) M.
Amat, C. Ramos, M. Pérez, E. Molins, P. Florindo, J. Bosch, Chem.
Commun. 2013, 49, 1954−1956.
[4]
a) J. E. Ellis, J. S. Dutcher, C. H. Heathcock, Synth. Commun. 1974, 4,
71−77; b) Y. Hoashi, T. Yabuta, P. Yuan, H. Miyabe, Y. Takemoto,
Tetrahedron 2006, 62, 365−374; c) S. Benetti, S. Carli, C. De Risi, G. P.
Pollini, A. C. Veronese, V. Zanirato, Synlett 2008, 2609−2612; d) C.-H.
Tu, Y.-K. Wu, K.-S. Shia, S.-C. Kuo, H.-J. Liu, M.-T. Hsieh, Synlett
2014, 25, 543−546. See also reference [2a].
[24] W. J. Scott, J. K. Stille, J. Am. Chem. Soc. 1986, 108, 3033−3044.
[25] S. Grimme, J. Chem. Phys. 2003, 118, 9095−9102.
[26] a) S. Grimme, J. Chem. Phys. 2006, 124, 034108, b) S. Grimme, S.
Ehrlich, L. Goerigk, J. Comp. Chem. 2011, 32, 1456−1465.
[27] F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys. 2005, 7,
3297−3305.
[5]
[6]
a) P. Pollet; S. Gelin, Synthesis 1978, 142–143; b) R. Zibuck in
Encyclopedia of Reagents for Organic Synthesis Vol. 2, (Ed.: L. A.
Paquette), Wiley, Chichester, 1995; pp. 936−937.
a) J.-F. Lavallée, P. Deslongchamps, Tetrahedron Lett. 1988, 29,
5117−5118; b) J.-F. Lavallée, C. Spino, R. Ruel, K. T. Hogan, P.
Deslongchamps, Can. J. Chem. 1992, 70, 1406−1426. For examples
on the use of alkyl-substituted Nazarov reagents in the synthesis of
complex polycyclic systems, see: c) R. Ruel, P. Deslongchamps, Can.
J. Chem. 1992, 70, 1939−1949; d) M. S. Reddy, H. Zhang, S. Phoenix,
P. Deslongchamps, Chem. Asian J. 2009, 4, 726−741. For recent
applications, including organocatalytic Robinson annulations, see: e) B.
Berkes, K. Ozsváth, L. Molnár, T. Gáti, T. Holczbauer, G. Kardos, T.
Soós, Chem. Eur. J. 2016, 22, 18101−18106.
[28] S. Grimme, L. Goerigk, R. F. Fink. WIRES Comput. Mol. Sci. 2012, 2,
886−906.
[29] Y. Zhao, D. G. Truhlar. Phys. Chem. Chem. Phys. 2008, 10,
2813−2818.
[30] R. F. Ribeiro, A. V. Marenich, C. J. Cramer, D. G. Truhlar. J. Phys.
Chem. B 2011, 115, 14556−14562.
[31] A. H. Asari, Y.-H. Lam, M. A. Tius, K. N. Houk. J. Am. Chem. Soc. 2015,
137, 13191−13199.
[32] N. Gulzar, K. M. Jones, H. Konnerth, M. Breugst, M. Klussmann. Chem.
Eur J. 2015, 21, 3367−3376.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
[33] K: G. Kishore, O. Ghashghaei, C. Estarellas, M. M. Mestre, C. Monturio,
N. Kielland, J. M. Kelly, A. F. Francisco, S. Jayawardhana, D. Muñoz-
Torrero, B. Pérez, F. J. Luque, R. Gámez-Montaño, R. Lavilla. Angew.
Chem. Int. Ed. 2016, 55, 8994−8998.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery,
Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M.
Cossi, N. Rega, N. J. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L.
Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J.
Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J.
V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc., Wallingford CT, 2010.
[34] E. Cancès, B. Mennucci, J. Tomasi, J. Chem. Phys. 1997, 107,
3032−3041.
[35] a) A. D. Becke, Phys. Rev. A 1988, 38, 3098−3100; b) C. Lee, W. Yang,
R. G. Parr, Phys. Rev. B 1988, 37, 785−789; c) P. J. Stephens, F. J.
Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994, 98,
11623−11627.
[36] Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel,
G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
…
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700610
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Carolina Estarellas, Federica Arioli,
Maria Pérez, Celeste Are, David Hevia,
Elies Molins, F. Javier Luque,* Joan
Bosch, and Mercedes Amat*
Page No. – Page No.
Origin of the Base-Dependent Facial
Selectivity in Annulation Reactions of
Nazarov-Type Reagents with
Unsaturated Indolo[2,3-
Text for Table of Contents
a]quinolizidine Lactams
The reversal of the facial selectivity observed when Cs2CO3 is used as the base instead of DBU in double Michael addition reactions
of the Nazarov reagent 4 with unsaturated Nind-Boc indoloquinolizidine lactams is rationalized by theoretical calculations. The
synthetic potential of these annulation reactions is illustrated with the enantioselective synthesis of 17a-carbaakuammigine.
Key topic: Stereoselectivity
This article is protected by copyright. All rights reserved.