Application of Electrocyclic Ring-Opening and Desymmetrizing Nucleophilic Trappings of meso-6,6-Dibromobicyclo[3.1.0]hexanes to Total Syntheses of Crinine and Haemanthamine Alkaloids

Article abstract of DOI:10.1021/acs.joc.9b00018

The thermally induced electrocyclic ring-opening of C₂-symmetric (meso) 6,6-dibromobicyclo[3.1.0]hexanes such as 10 in the presence of the chiral, nonracemic 1°-amine 28 afforded a ca. 1:1 mixture of the diastereoisomeric and chromatographically separable 1-amino-2-bromo-2-cyclohexenes 37 (42%) and 38 (45%). Each of these was elaborated over 13 steps, including Suzuki-Miyaura cross-coupling, radical cyclization, and Pictet-Spengler reactions, into (-)- or (+)-crinane (1 or ent-1, respectively). Variations on these protocols were applied to the total syntheses of (+)- and (-)-11-hydroxyvattitine [(+)- and (-)-3], (+)- and (-)-bulbispermine [(+)- and (-)-4], (+)- and (-)-haemanthamine [(+)- and (-)-5], (+)- and (-)-pretazettine [(+)- and (-)-6], and (+)- and (-)-tazettine [(+)- and (-)-7] as well as (±)-hamayne [(±)-8] and (±)-apohaemanthamine [(±)-9]. A number of these alkaloids were synthesized for the first time.

Full text of DOI:10.1021/acs.joc.9b00018

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Article
Application of Electrocyclic Ring-opening and Desymmetrizing
Nucleophilic Trappings of meso-6,6-Dibromobicyclo[3.1.0]hexanes
to Total Syntheses of Crinine and Haemanthamine Alkaloids
Ping Lan, Martin G Banwell, and Anthony C. Willis
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00018 • Publication Date (Web): 06 Feb 2019
Downloaded from http://pubs.acs.org on February 7, 2019
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Application of Electrocyclic Ring-opening and Desymmetrizing Nucleophilic Trappings of
meso-6,6-Dibromobicyclo[3.1.0]hexanes to Total Syntheses of Crinine and Haemanthamine
Alkaloids†
Ping Lan, Martin G. Banwell* and Anthony C. Willis‡
†
,§
,†,‡
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†Institute for Advanced and Applied Chemical Synthesis,
Jinan University, Zhuhai, 519070, China
‡Research School of Chemistry, Institute of Advanced Studies,
The Australian National University, Canberra, ACT 2601, Australia
and
§
Department of Food Science and Engineering,
Jinan University, Guangzhou, 510632, China
Abstract: The thermally-induced electrocyclic ring-opening of C -symmetric (meso) 6,6-
2
dibromobicyclo[3.1.0]hexanes such as 10 in the presence of the chiral, non-racemic 1°-amine
2
8 afforded a ca. 1:1 mixture of the diastereoisomeric and chromatographically separable 1-
amino-2-bromo-2-cyclohexenes 37 (42%) and 38 (45%). Each of these was elaborated, over
thirteen steps including Suzuki-Miyaura cross-coupling, radical cyclization and Pictet-
Spengler reactions, into (–)- or (+)-crinane (1 or ent-1, respectively). Variations on these
protocols have been applied to the total syntheses of (+)- and (–)-11-hydroxyvattitine [(+)-
and (–)-3], (+)- and (–)-bulbispermine [(+)- and (–)-4], (+)- and (–)-haemanthidine [(+)- and
(
–)-5], (+)- and (–)-pretazettine [(+)- and (–)-6] and (+)- and (–)-tazettine [(+)- and (–)-7] as
well as (±)-hamayne [(±)-8] and (±)-apohaemanthamine [(±)-9]. A number of these alkaloids
have been synthesized for the first time.
†
Decidated to the memory of Leo A. Paquette, organic chemist extraordinaire of The Ohio State
st
University, who passed away on Monday, January 21 , 2019
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INTRODUCTION
Within the vast collection of compounds isolated from the Amaryllidaceae family of herbaceous,
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perennial and bulbous flowering plants those embodying the 2,3,4,4a-tetrahydro-1H,6H--
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,10b-ethanophenanthridine skeleton 1 (Figure 1) or its -5,10b-ethano-bridged enantiomer
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ent-1) are defined as crinine or haemanthamine-type alkaloids, respectively.1,2
(
Figure 1: The 2,3,4,4a-tetrahydro-1H,6H--5,10b-ethanophenanthridine framework (1), the
labeling of the associated rings and its -5,10b-ethano-bridged enantiomer (ent-1)
So, for example, as shown in Figure 2, (–)-buphanisine [(–)-2] (isolated from the Central African
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plant Boöphane fischeri) is a member of the former class while its optical antipode (+)-
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buphanisine [(+)-2] (isolated from the widely distributed plant Sternbergia sicula) belongs to
the haemanthamine group of alkaloids.
Figure 2: Representative members, (–)-2, (+)-2, (+)-3, (+)-4, (–)-5, (+)-6, (+)-7, (+)-8, and
(+)-9, of the crinane and haemanthamine classes of alkaloids
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Other examples of such alkaloids relevant to the present discussion include the
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diastereoisomerically-related compounds (+)-11-hydroxyvattitine [(+)-3] and (+)-bulbispermine
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7,8
[
(+)-4] as well as (–)-haemanthidine [(–)-5] incorporating a hydroxy group in the B-ring and
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an established precursor to the alkaloids (+)-pretazettine [(+)-6] and (+)-tazettine [(+)-7]. (+)-
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Hamayne [(+)-8] as well as the structurally related ether (+)-apohaemanthamine [(+)-9] are
further examples with the latter being both naturally occurring11 and formed on treating
crinamine with hot mineral acid.12
The title alkaloids exert manifold biological effects13,14 including antimalarial, antiplasmodial,
apoptosis-inducing, antibacterial, antiviral, neuroprotective and antiproliferative ones. This
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situation has prompted a range of productive studies on analogues. Furthermore, it is also clear
that certain of these natural products can serve as synthetic as well as biogenetic precursors to
other classes of alkaloids.16
Such diverse properties have prompted extensive efforts to develop total syntheses of the crinane
and haemanthamine alkaloids. A range of approaches has been devised over the past four to five
decades.9,17,18 A particularly effective strategy involves the formation of C3a-arylated
perhydroindoles that embody the A-, C- and D-rings of the target framework 1 or ent-1.
Subjecting these perhydroindoles to a Pictet-Spengler reaction then establishes the required B-
ring and so completing the assembly these alkaloids.18g,19 Two key challenges associated with
implementing such protocols more broadly are, (i), the limited capacities currently available for
introducing functionality (oxygenation) at C11 within the ethano-bridge of alkaloids such as (+)-
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, (+)-5, (+)-6, (–)-7, (+)-8 and (+)-9 and, (ii), the restrictions on generating such systems in
enantiomerically pure form.
As an initial part of efforts to address the first of these deficiencies, we recently18g disclosed a
total synthesis of the racemic modification of the crinane [viz. (±)-1]. The key elements of the
approach are shown in Scheme 1 and involve, in the opening stages, the thermally-induced
electrocyclic ring-opening of the ring-fused cyclopropane 1020 with the ensuing and C2-
symmetric -allyl cation being intercepted by added benzylamine (11) and thereby delivering
compound (±)-12. Over six steps allylic amine (±)-12 was converted into the iodide (±)-13 that
upon exposure to n-Bu SnH resulted in the formation of the corresponding 1°-radical (±)-14 and
3
this was then engaged in a 5-exo-trig radical cyclization to afford the isomeric radical (±)-15 that
upon hydrogen abstraction afforded the C3a-arylated perhydroindole (±)-16. This last compound
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embodies the ACD-ring system of the target framework and over two steps involving
hydrogenolytic removal of the N-benzyl group, to give 2°-amine (±)-17, and reaction with
formic acid and formaldehyde to effect a Pictet-Spengler reaction (and so form the B-ring), (±)-
crinane was obtained.
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Scheme 1: A synthesis of (±)-crinane [(±)-1 (R,R=CH )] from the C -symmetric ring-fused
2
2
gem-dibromocyclopropane 10
The C -symmetric nature of cyclopropane 10 and the -allyl cation derived from its
2
electrocyclic ring-opening means that carrying out such processes in the presence of chiral 1°-
amines would be expected to result, as shown in Scheme 2, in the formation of mixtures of
diastereoisomeric allylic amines. These should be capable of chromatographic separation under
conventional conditions and so affording the R- and S-configured products 18 and 19,
respectively. Given that heating at elevated temperatures will almost certainly be required to
effect the desired conversions, little if any diastereoselectivity would be expected. That said, if
the diastereoisomers 18 and 19 could be formed and separated at scale then useful routes to both
crinine or haemanthamine-type alkaloids could be realized.
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Scheme 2: A possible pathway for preparing enantiomerically pure crinane alkaloid D-ring
synthons of the general forms 18 and 19 from cyclopropane 10 and homochiral 1°-amines.
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The recent emergence of a significant suite of homochiral primary and secondary amines
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1
through the refinement of biocatalytic processes resulted in our first efforts being directed at
using these for the purposes of examining the stereochemical outcomes of the associated
desymmetrizing reactions shown immediately above. As is detailed below, certain of these
proved very successful and enabled the development of total syntheses, in enantiomerically pure
form, of various of the alkaloids shown in Figure 2. Some of these have been synthesized for the
first time.
RESULTS AND DISCUSSION
(i) Electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane (10) in the presence of
        ꢀꢁꢀꢂiral primary and secondary amines – formation of enantiopure
1
-amino-2-bromo-2-cyclohexenes of defined absolute configuration.
The suite of homochiral primary and secondary amines employed in examining the outcomes of
the type of electrocyclic ring-opening/nucleophilic trapping sequence proposed above are shown
in Figure 3. Two distinct sets of conditions were used in effecting these processes, namely a
microwave-promoted reaction of a THF solution of these reactants at 150 °C for 1.5 h (Method
A) and the more conventional heating of a neat mixture of the same at 55 °C for 8 h (Method B).
In each instance a four-fold excess of the relevant S-configured amine was used and a mixture of
the diastereoisomeric 1-amino-2-bromo-2-cyclohexene derivatives 18 and 19 was thus
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produced. In 15 of the 19 cases (see Table 1) these could be separated from one another by flash
chromatography (R approx. 0.05) and, in all but one instance (see entry 17), the more mobile
f
diastereoisomer had the more negative or less positive specific rotation. This trend was reversed
when the R-configured amine ent-28 was employed but not when compound ent-23 served as
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the trapping nucleophile. With some exceptions, in the H NMR spectra of the suites of
compounds of the general forms 18 and 19 the resonance due to H-1 appeared at lower field for
the chromatographically more mobile isomer while the reverse was so for the resonances due to
the olefinic proton H-3 (the integrations of which were used to determine the diastereoisomeric
ratio). The chromatographically less mobile and crystalline product derived from reaction of
cyclopropane 10 with amine 30 was subjected to single-crystal X-ray analysis [see Supporting
Information (SI) for details] and thus established to be compound 36 (Figure 4) possessing the
R-configuration at C-1.
Figure 3: The commercially available amines 20-23, ent-23, 23-28, ent-28, 28-35 and ent-35
used to trap the -allyl cation derived from thermally-induced electrocyclic ring-opening of
6
,6-dibromobicyclo[3.1.0]hexane (10).
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Table 1: Outcomes of the reaction of cyclopropane 10 with amines 20-23, ent-23, 23-28, ent-
2
8, 28-35 and ent-35 under two distinct reaction conditions
a a
Ratio
Ratio
Combined
Yield
[] of more
[] of less
D
D
Entry
Amine
18/19
Method A
18/19
Method B
mobile diastere- mobile diastere-
b
c
d
d
(ex. Method A)
oisomer
oisomer
1
2
3
4
5
6
7
8
9
20
21
0.96:1
0.95:1
93%
95%
95%
94%
89%
93%
94%
94%
91%
88%
84%
84%
88%
88%
96%
96%
89%
61%
No separation
No separation
1:1
1:1
–92.2
+52.3
22
1:1
1:1
–11.0
+70.8
23
1:1
1:1
–92.7
–18.4
ent-23
24
1:1
1:1
+96.5
+21.4
1:1
1:1
–96.9
–23.6
25
1:1
0.95:1
1:1
–90.6
–27.7
26
0.93:1
0.94:1
1:1
–87.5
+13.6
27
0.95:1
1:1
–86.0
–20.7
1
0
28
–93.5
–20.8
11
ent-28
29
1:1
1:1
+95.5
+18.5
1
1
1
1
2
3
4
5
0.82:1
0.9:1
0.9:1
1:1
0.95:1
0.9:1
0.9:1
1:1
–42.2
+33.6
30
–23.9
+40.0
31
–93.1
–22.7
32
No separation
+10.2
No separation
+64.4
16
33
0.95:1
1:1
0.95:1
1:1
1
7
34
+90.2
+21.1
18
35
0.74:1
0.73:1
NR
No separation
No separation
No separation
No separation
1
9
ent-35
NR
50%
a
1
b
ratio determined by H NMR spectroscopy (see text); Method A: microwave reaction conducted in THF at 150
c
°
C and 80 psi for 1.5 h; Method B: conventional reaction conducted with neat substrates at 55 °C for 8 h;
optical rotations were recorded in chloroform at 20 °C (c = 1 in most instances).
d
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Figure 4: The structure 36 (as established by single-crystal X-ray analysis) of the
chromatographically less mobile product arising from the reaction of cyclopropane 10 with
homochiral amine 30 using Method A
The various spectroscopic trends defined above, when considered in conjunction with the
outcomes of other single-crystal X-ray analyses undertaken (as delineated below), led to the
conclusion that the less mobile diastereoisomers likely possess the R-configuration at C-1 while
the more mobile ones are S-configured at the same center. Whether or not the products of the
reaction of compound 10 with amine 34 (entry 17, Table 1) conform to this “rule of thumb”
remains to be determined.
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Clearly the diastereoselectivities associated with the desymmetrizing electrocyclic ring-
opening/nucleophilic trapping processes shown in Scheme 2 are very low and all efforts to
improve upon these by varying the reaction conditions proved unsuccessful. However, this
situation was offset to some extent, at least, by the ease with which certain of the products could
be separated from one another, including at multi-gram-scale, using conventional flash
chromatographic techniques. As such, sufficient quantities of various of the product 1-amino-2-
bromo-2-cyclohexenes were available to explore their utility as building blocks for the assembly
of the title alkaloids. Initial studies of this type, as detailed in the following section, were
focused on developing the means for generating the parent systems 1 (R,R=CH ) and ent-1
2
(
R,R=CH ), which, while not natural products themselves, have previously been the targets of
2
chemical synthesis.18g
(ii)
Elaboration of 1-amino-2-bromo-2-cyclohexenes 37 and 38 into compounds
1(R,R=CH ) and ent-1(R,R=CH )
2
2
The opening stages of the reaction sequences used for the elaboration of the
chromatographically separable 1-amino-2-bromo-2-cyclohexenes 37 and 38 (derived from the
reaction of amine 28 with cyclopropane 10) into (–)-crinane [1 (R,R=CH )] and haemanthamine
2
[
aka (+)-crinane, ent-1 (R,R=CH )], respectively, are shown in Scheme 3. The initial focus of
2
our studies was on the removal of the chiral auxiliary at nitrogen in compounds 37 and 38.
Ultimately a two-step cleavage process proved necessary, the first involving their high-yielding
conversions, under standard conditions, into the corresponding trifluoroacetamides, 39 and 40,
respectively. Independent treatment of the latter compounds with triflic acid (TfOH) in the
presence of the anisole (serving as a benzyl cation scavenger) then afforded the enantiomerically
related and crystalline trifluoroacetamides 41 (90%) and ent-41 (90%), respectively, the
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structures, including absolute configurations, of which were confirmed by single-crystal X-ray
analyses (see SI for details).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
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4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3: Reaction of the C -symmetric gem-dibromocyclopropane 10 with amine 28 and
2
elaboration of the diastereoisomeric adducts 37 and 38 to the homochiral trifluoroacetamides 41
and ent-41
The straightforward means by which trifluoroacetamides 41 (90%) and ent-41 (90%) were
elaborated to targets 1 (RR=CH ) and ent-1 (RR=CH ) are shown in Scheme 4. Thus, sequential
2
2
treatment of a dichloromethane solution of the former amide with aqueous potassium hydroxide
in the presence of the phase transfer catalyst triethylbenzylammonium chloride (TEBAC)
followed by immediate reaction of the resulting 1°-amine with benzyl bromide (BnBr) in the
presence of potassium carbonate gave the R-configured form of compound 12 (63%), the
racemic modification of which has been converted, over nine steps, into (±)-crinane (viz. (±)-1
[
R,R=CH ]). Accordingly, the 2°-amine 1R-12 was subjected to the same reaction sequence [see
2
the Experimental Section for details], including the pivotal 5-exo-trig radical cyclization process
shown in Scheme 1 and thus affording, in 13% overall yield, compound 1R-1 (RR=CH ). The
2
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5
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5
5
6
specific rotation determined for this material was [] = –11.6 (c = 1, CHCl ). An analogous
D
3
sequence allowed for the conversion of compound ent-41, via 2°-amine 1S-12 (66%), into the
2,3,4,4a-tetrahydro-1H,6H--5,10b-ethanophenanthridine ent-1 (R,R=CH ) (16%), the specific
2
rotation for which {[] = +11.0 (c = 1, CHCl )} was a good match for that recently reported by
D
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
others17h {[] = +8.20 (c = 1, CHCl )}.
D
3
Scheme 4: Elaboration of Compound 41 and its Enantiomer to (–)- and (+)-Crinane
(
iii) Developing protocols for the formation of enantiomerically pure and oxygenated 1-
amino-2-bromo-2-cyclohexenes
Any efforts to adapt the protocols delineated immediately above to natural products such as
those shown in Figure 1 require a means for introducing both unsaturation and oxygenation
within the D-ring as well as, in most cases, oxygen (normally at C11) in the C-ring. While the
radical cyclisation protocols detailed above do not allow this, suitable modifications to our
previously reported synthesis of (±)-hamayne18d do. Accordingly, we set out to explore such
possibilities by examining the relevant behaviors of the known, oxygenated, ring-fused and C2-
symmetric gem-dibromocyclopropanes 42 (Scheme 5), each diastereoisomeric form of which
would be expected to undergo electrocyclic ring-opening to give a common -allyl cation. In
principle, the interception of such a cation by added homochiral amines could lead to four
diastereoisomeric products but in practice, as revealed below, only the trans-forms 43 and 44,
were generated in significant amounts. The outcomes of conducting the appropriate suite of
ring-opening experiments on compounds 42 and using the homochiral amines 20-23, ent-23, 23-
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2
8, ent-28, 28-35 and ent-35 as trapping nucleophiles (under the same pair of reaction conditions
as employed previously – See Table 1) are summarized in Table 2. As was observed in the non-
oxygenated series, where the diastereoisomeric products 43 and 44 could be separated from one
another (Table 2), the chromatographically more mobile one had the more negative or less
positive specific rotation, save for those cases (entries 5 and 11, Table 2) where the enantiomeric
form of the trapping amine was employed.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
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4
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5
5
5
5
5
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0
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9
0
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2
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9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 5: A possible pathway for preparing enantiomerically pure and oxygenated crinane
alkaloid D-ring synthons of the general forms 43 and 44 from cyclopropane 42 and
homochiral 1°-amines.
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Table 2: Outcomes of the reaction of cyclopropanes 42 with amines 20-23, ent-23, 23-28,
ent-28, 28-35 and ent-35 under two distinct reaction conditions
a
a
Ratio
Ratio
Combined
Yield
[] of more
[] of less
D
D
Entry
Amine
43/44
Method A
43/44
Method B
mobile diastere- mobile diastere-
b
c
d
d
(ex. Method A)
oisomer
oisomer
1
2
3
4
5
6
7
8
9
20
21
1:1
1:1
88%
87%
84%
88%
89%
86%
83%
81%
84%
89%
93%
85%
90%
89%
85%
88%
91%
59%
No separation
No separation
1:1
1:1
–15.2
+42.9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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9
0
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9
0
22
1:1
1:1
–24.5
+53.8
23
0.87:1
0.87:1
1:1
0.80:1
0.80:1
1:1
–70.4
–10.2
ent-23
24
+64.3
+5.8
–69.5
–19.1
25
1:1
1:1
–41.5
–16.1
26
0.88:1
0.88:1
0.84:1
0.85:1
1:1
0.82:1
0.82:1
0.81:1
0.84:1
1:1
–65.3
+10.3
27
–67.1
–27.2
1
1
0
1
28
–93.9
–11.5
ent-28
29
+85.9
+17.2
12
No separation
–69.7
No separation
+54.4
1
3
30
1:1
1:1
14
31
0.88:1
1:1
0.88:1
0.84:1
1:1
–64.6
–15.3
1
1
1
1
5
6
7
8
32
–87.0
–35.2
33
1:1
No separation
No separation
No separation
No separation
No separation
No separation
No separation
No separation
34
1:1
1:1
35
0.74:1
0.71:1
NR
19
ent-35
NR
61%
a
1
b
ratio determined by H NMR spectroscopy (see text); Method A: microwave reaction conducted in THF at 150 °C
c
d
and 80 psi for 1.5 h; Method B: conventional reaction conducted with neat substrates at 55 °C for 8 h; optical
rotations were recorded in chloroform at 20 °C (c = 1 in most instances).
On the basis of the foregoing and given that a single-crystal X-ray analysis of the less mobile
product from -allyl trapping with amine 30 (see Experimental Section and Supporting
Information for details) reveals that this is compound 45 (Figure 5), then the R-configuration is
provisionally assigned to the new stereogenic center in the similarly less mobile products arising
from the reactions shown in Table 2, except entries 5 and 11 (where the enantiomeric amines
where used in the trapping reactions).
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9
0
Figure 5: The structure 45 (as established by single-crystal X-ray analysis) of the
chromatographically less mobile product arising from the reaction of cyclopropane 42 with
homochiral amine 30.
With the conclusion of the methodological studies detailed above, attention turned to their
exploitation in the total synthesis of key members of the title families of alkaloids. The
successful outcomes of such studies are detailed in the following sections and these also serve to
reinforce the structural assignments made above.
(iv)
Total syntheses of (+)-11-hydroxyvattitine [(+)-3] and (+)-bulbispermine [(+)-4]
The synthetic sequences leading to alkaloids (+)-3 and (+)-4 are shown in Scheme 6 and start
with the two-step conversion of compound ent-21 into the sulfonamide 46 (83%) that was
subjected to Suzuki-Miyaura cross-coupling with the commercially available arylboronic acid
4
7 and thus forming the expected product 48 (90%). In keeping with earlier studies in the
racemic series,18b,d,e,f N-propargylation of the last compound using 1-bromo-2-butyne in the
presence of sodium hydride gave 1,6-enyne 49 (91%) that engaged in a palladium-catalyzed
Alder-ene reaction and so affording the C3a-arylated hexahydroindole 50 (70%). This pivotal
transformation introduces both D-ring unsaturation and C-ring functionality as required in
constructing targets (+)-3 and (+)-4. The oxidative cleavage of the exocyclic double-bond within
compound 50 was accomplished by treating it with a combination of N-methylmorpholine N-
1
8f
oxide (NMO) and K OsO •2H O in the presence of citric acid. The resulting diols were
2
4
2
immediately cleaved oxidatively using PhI(OAc) and so affording the ketone 51 albeit in just
2
3
8% yield, presumably because of competing dihydroxylation at the endo-cyclic double-bond in
the substrate 50. Reduction of ketone 51 with sodium borohydride gave a single alcohol that
upon acetylation afforded ester 52 in 81% yield. Treatment of this last compound with selenium
dioxide afforded the allylic alcohol 53 stereoselectively in 71% yield and the structure of which
was confirmed by single-crystal X-ray analysis (see SI for details). The associated tosyl group
was cleaved using sodium naphthalenide22 and the resulting secondary amine 54 (56%)
subjected to a Pictet-Spengler reaction using formaldehyde in the presence of trifluoroacetic acid
(TFA). Treatment of the ensuing pentacyclic diacetate with potassium carbonate in methanol
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5
6
then gave (+)-11-hydroxyvattitine [(+)-3]. The spectral data acquired on this compound matched
1
3
those reported for the natural product. A comparison of the relevant sets of C NMR data are
presented in the SI. Furthermore, the specific rotation of the synthetic material {[] = +11.3 (c
D
5
=
+
0.88, methanol)} compared favorably with the value reported for the natural product {[] =
D
0
1
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0
1
2
3
4
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0
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5
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9
0
1
2
3
4
5
6
7
8
9
0
11.0 (c = 0.88, methanol)}.
Engagement of compound 53 in a Mitsunobu reaction using acetic acid as the nucleophile and a
combination of Ph P and DBAD for alcohol activation afforded diacetate 55 (97%), the structure
3
of which was confirmed by single-crystal X-ray analysis (see SI for details). Subjection of this
diester to the same three steps employed in completing the synthesis of the previous target then
delivered (+)-bulbispermine [(+)-4] in 45% yield. Once again, all the NMR spectral data
acquired on this product matched those reported earlier30 while the specific rotation of the
synthetically-derived and enantiomerically pure material was in good agreement with that
2
3
reported for the natural product {[] = +108.9 (c 1.0, methanol); lit. [] = +106.7 (c 1.02,
D
D
methanol)}.
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Scheme 6: Syntheses of (+)-11-hydroxyvattitine [(+)-3] and (+)-bulbispermine [(+)-4] from
trifluoroacetamide ent-41
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(v)
Total syntheses of (–)-11-hydroxyvattitine [(–)-3] and (–)-bulbispermine [(–)-4]
A series of reactions analogous to that shown in Scheme 6 but now starting with homochiral
allylic amine 41 allowed for the syntheses of alkaloids (–)-3 and (–)-4. Full details of these
conversions are presented in the Experimental Section. All of the spectra obtained on the final
products matched those recorded for their enantiomers while the specific rotations of each were
of similar magnitude but opposite in sign to those of their optical antipodes. Furthermore, the
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5
5
5
5
5
5
5
5
6
structure of compound (–)-3 was confirmed through a single-crystal X-ray analysis of its picrate
salt.
(
vi)
Total syntheses of (–)-haemanthidine [(–)-5], (+)-pretazettine [(+)-6] and
(+)-tazettine [(+)-7]
0
1
2
3
4
5
6
7
8
9
0
1
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6
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8
9
0
1
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Alkaloids (–)-5, (+)-6 and (+)-7 were readily prepared from the homochiral intermediate 53
using the reaction sequence shown in Scheme 7. Thus, Purdie-Irvine O-methylation of alcohol
53 afforded ether 56 (56%) and the structure of the latter was confirmed through the single-
crystal X-ray analysis on the racemate obtained during preliminary studies. The tosyl group
associated with compound 56 was cleaved with sodium naphthalenide to give the corresponding
secondary amine. Treatment of this with ethyl formate then afforded the formamide 57 (58%
over two steps) that on exposure to POCl engaged in an intramolecular Vilsmaier-Haack-type
3
formylation reaction to deliver, after exposure of the initially-formed cyclization product to
aqueous THF then potassium carbonate, (–)-haemanthidine [(–)-5] in 47% yield. Treatment of
compound (–)-5 with methyl iodide, HCl then sodium bicarbonate afforded (+)-pretazzetine
9
[
(+)-6], as a single anomer, in 84% yield. Finally, exposure of acetal (+)-6 to sodium hydroxide
9
afforded (+)-tazettine [(+)-7] in 91% yield and the structure of which was confirmed through an
X-ray analysis of the readily derived picrate salt of the racemate obtained during preliminary
studies. All the spectral data acquired on compounds (–)-5, (+)-6 and (+)-7 were in complete
accord with the assigned structures and matched those reported previously (see SI for details).
1
3
Relevant comparisons of the C NMR data sets are also provided in the SI.
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Scheme 7: Total syntheses of (–)-haemanthidine [(–)-5], (+)-pretazettine [(+)-6] and (+)-
tazettine [(+)-7] from the C3a-arylated hexahydroindole 53
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
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2
3
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3
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3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
vii) Total syntheses of (+)-haemanthidine [(+)-5], (–)-pretazettine [(–)-6] and
–)-tazettine [(–)-7]
Starting from amide 41, compound ent-53 (Figure 6) could be prepared using the early steps
associated with the reaction sequence shown in Scheme 6 and this sulfonamide (the structure of
which was confirmed by single-crystal X-ray analysis) could then be converted, using the same
reaction steps as shown in Scheme 7, into the title compounds (+)-5, (–)-6 and (–)-7. Once
again, all the spectral data derived from this trio of hitherto unreported compounds accorded
with the assigned structures and compared favorably with those detailed previously for their
optical antipodes. Relevant comparisons are provided in the SI.
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Figure 6: The structures of compounds 41, ent-53, (+)-5, (–)-6 and (–)-7
(
viii) Total syntheses of (±)-hamayne [(±)-8] and (±)-apohaemanthamine [(±)-9]
Total syntheses of alkaloids (±)-8 and (±)-9 were accomplished using the ring
opening/nucleophilic trapping products derived from reaction of the oxygenated cyclopropane
4
2 and amine 28 (Scheme 8). Thus, using Method B a mixture of the four possible trapping
products, 58-61, and comprising the relevant pairs of cis- and trans-isomers, was obtained. Since
these could not be readily bseparated from one another at preparative scales by normal flash
chromatographic methods, this four-component mixture was carried through the illustrated eight
steps and thereby affording the epimeric and chromatographically separable nosylates (±)-62
and (±)-63. So, following the protocols defined in Scheme 3 and the early parts of Scheme 4, the
mixture 58-61 was treated with TFAA and pyridine and thereby forming the corresponding
mixture of trifluoroacetamides (90% combined yield) that also failed to separate under flash
chromatographic conditions. Treatment of these amides with TFA/TfOH in the presence of
anisole resulted in cleavage of the chiral auxiliaries and the resulting cis/trans pair of amides
(
67% combined yield) was treated with potassium hydroxide in the presence of TEBAC and so
affording the corresponding amino-alcohols and these were converted into the corresponding
nosylates on reaction with nosyl chloride in the presence of triethylamine and DMAP. Treatment
of these sulfonamides with TBS-Cl in the presence of imidazole resulted in the re-instatement of
the silyl ether cleaved in a preceding step. The diastereoisomeric mixture of sulfonamide/ethers
so-obtained (in 60% yield over three steps) was engaged in a Suzuki-Miyaura cross-coupling
with the aryl boronic acid 47 under conditions similar to those employed in the conversion 46 +
47  48 (Scheme 6) and so affording the expected product mixture (85%), the sulfonamide
nitrogen of which was propargylated using 1-bromo-2-butyne in the presence of sodium hydride.
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This mixture of product 1,6-enynes (88%) was then engaged in a palladium-catalyzed
intramolecular Alder-ene reaction analogous to that employed in the conversion 49  50
(Scheme 6) and so affording the now chromatographically separable C3a-arylated
hexahydroindoles (±)-62 (9%) and (±)-63 (56%).
1
1
1
1
1
1
1
1
1
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 8: The reaction of cyclopropane 42 with homochiral 1°-amine 28 and the elaboration
of products 58-61 to C3a-arylated hexahydroindoles (±)-62 and (±)-63
Of course, the less-than-desirable consequence of employing this reaction sequence was that
cleavage of the chiral amine-based residue occurred prior to any chromatographic separation of
the relevant diastereoisomers and so delivering racemates. Nevertheless, these could be
exploited in developing routes to the title compounds (±)-8 and (±)-9, the latter not having been
the subject of any previously successful total synthesis. So, for example, compound (±)-62 was
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converted (Scheme 9), through a three-step process and via intermediate (±)-64, into the ketone-
conjugated imine (±)-65. Reduction of this last compound with sodium borohydride at –40 °C
followed by immediate treatment of the resulting epimeric mixture of alcohols (±)-66 and (±)-67
with formaldehyde in formic acid afforded, after a work-up using ammonia-saturated methanol,
a chromatographically separable mixture of (±)-hamayne [(±)-8] (13%) and apohaemanthamine
0
1
2
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4
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7
8
9
0
1
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9
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8
9
0
[(±)-9] (40%). The structure of compound (±)-9 was confirmed by single-crystal X-ray analysis
(see SI for details). The spectral data derived from these final products were in accord with the
assigned structures and matched those reported previously (see the SI for relevant comparisons
of spectral data).
Scheme 9: Elaboration of the C3a-arylated hexahydroindole (±)-62 to (±)-hamayne [(±)-8]
and (±)-apohaemanthamine [(±)-9]
A somewhat more efficient route to apohaemanthamine [(±)-9] arose from analogous
manipulations of substrate (±)-63 as shown in Scheme 10. So, when the by now standard two-
step oxidation cleavage protocol was applied to this starting material then ketone (±)-68 (51%)
was obtained and on treating this with K CO an E1cb reaction took place and so delivering the
2
3

-azaenone (±)-69 (82%). Reduction of this last compound took place stereoselectively to afford
alcohol (±)-70 (81%) that when treated with formaldehyde in hot formic acid gave
apohaemanthamine [(±)-9] in 68% yield. In contrast, on treating alcohol (±)-70 with
formaldehyde and trifluoroacetic acid (TFA) at 60 °C then a Pictet-Spengler reaction took place
2
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and this was accompanied by silyl ether cleavage and thus affording (±)-11-hydroxyvattitine
1
13
[(±)-3] in 50% yield. The H and C NMR spectral data derived from this material matched
those obtained for its enantiomerically pure counterpart and its structure was confirmed by
single-crystal X-ray analysis (see Experimental Section and SI for details).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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3
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3
3
4
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5
6
0
1
2
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4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 10: Elaboration of the C3a-arylated hexahydroindole (±)-63 to
(±)-11-hydroxyvattitine [(±)-3] and (±)-apohaemanthamine [(±)-9]
CONCLUSION
The thermally-induced electrocyclic ring-opening of the meso-cyclopropanes 10 and 42 and the
in situ nucleophilic trapping of the resulting -allyl cations using commercially available,
homochiral amines has allowed for the formation of diastereoisomeric pairs of 2-
bromocyclohex-2-en-1-amines. Various of these can be separated at multi-gram scale by
conventional chromatographic methods and the individual isomers then manipulated so as to
afford homochiral 2-bromocyclohex-2-en-1-amines. Elaboration of simple derivatives of these
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using a range of protocols, most notably palladium-catalyzed intramolecular Alder-ene
reactions, then allows for their conversion into either crinine or haemanthamine-type alkaloids.
Given the broad synthetic utility of the electrocyclic ring-opening/nucleophilic trapping
reactions of ring-fused gem-dihalocyclopropanes in the synthesis of biologically relevant
1
8
0
1
2
3
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8
9
0
1
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0
1
2
3
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9
0
1
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9
0
motifs, the protocols defined here should find application in a wide range of settings, including
for the purposes of establishing syntheses of enantiomerically pure forms of various erythrina24
25
and aeruginosin-type alkaloids.
EXPERIMENTAL SECTION
General Experimental Protocols
1
1
13
Unless otherwise specified, proton ( H) and proton-decoupled carbon ({ H} C) NMR
spectra were recorded at room temperature in base-filtered CDCl on a Varian spectrometer
3
1
operating at 400 MHz for proton and 100 MHz for carbon nuclei. For H NMR spectra,
signals arising from the residual protio-forms of the solvent were used as the internal
1
standards. H NMR data are recorded as follows: chemical shift (δ) [multiplicity, coupling
constant(s) J (Hz), relative integral] where multiplicity is defined as: s = singlet; d = doublet;
t = triplet; q = quartet; m = multiplet or combinations of the above. The signal due to residual
CHCl appearing at δ 7.26 and the central resonance of the CDCl “triplet” appearing at δ
3
H
3
C
1
13
7
7.0 were used to reference H and C NMR spectra, respectively. The signal due to residual
CH OH appearing at δ 3.31 and the central resonance of the CD OD “multiplet” appearing
3
H
3
1
13
at δ 49.0 were used to reference H and C NMR spectra, respectively. Infrared spectra
C
(λmax) were recorded on a Perkin–Elmer 1800 Series FTIR Spectrometer. Samples were
analyzed as thin films on KBr plates. Low-resolution ESI mass spectra were recorded on a
single quadrupole liquid chromatograph-mass spectrometer, while high-resolution
measurements were conducted on a time-of-flight instrument. Low- and high-resolution EI
mass spectra were recorded on a magnetic-sector machine. Melting points were measured on
an Optimelt automated melting point system and are uncorrected. Analytical thin layer
chromatography (TLC) was performed on aluminum-backed 0.2 mm thick silica gel 60 F254
plates as supplied by Merck while silica gel 60 (40–63 μm) was used for the column
chromatography. Eluted plates were visualized using a 254 nm UV lamp and/or by treatment
2
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with a suitable dip followed by heating. These dips included phosphomolybdic acid : ceric
sulfate : sulfuric acid (conc.) : water (37.5 g : 7.5 g : 37.5 g : 720 mL) or potassium
permanganate : potassium carbonate : 5% sodium hydroxide aqueous solution : water (3 g :
2
0 g: 5 mL : 300 mL). Flash chromatographic separations were carried out following
2
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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3
3
3
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5
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5
6
0
1
2
3
4
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7
8
9
0
1
2
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4
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6
7
8
9
0
1
2
3
4
5
6
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8
9
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1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
protocols defined by Still et al. with silica gel 60 (40–63 μm) as the stationary phase and
using the AR- or HPLC-grade solvents indicated. Starting materials and reagents were
generally available from the Sigma–Aldrich, Merck, TCI, Strem or Lancaster Chemical
Companies and were used as supplied. Drying agents and other inorganic salts were
purchased from the AJAX, BDH or Unilab Chemical Companies. Tetrahydrofuran (THF),
diethyl ether, methanol and dichloromethane were dried using a Glass Contour solvent
purification system that is based upon a technology originally described by Grubbs et al.27
Where necessary, reactions were performed under an nitrogen atmosphere.
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Specific Experimental Protocols
Electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane (10) in the presence of
homochiral primary and secondary amines 20-23, ent-23, 23-28, ent-28, 28-35 and ent-35
Method A:
0
1
2
3
4
5
6
7
8
9
0
1
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8
9
0
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9
0
A solution of gem-dibromocyclopropane 10 (1.0 mmol, 1 equiv) in THF (2 mL) was treated
with the relevant homochiral primary or secondary amine 20-35 (4 equiv) and the ensuing
solution, that was contained in a sealed tube equipped with a fiber optic temperature senor
immersed in the reaction vessel, subjected to microwave irradiation (200 W, 150 °C, 80 psi)
for 1.5 h in a CEM Discover microwave reactor. The cooled reaction mixture was diluted
with ethyl acetate (20 mL) and the resulting solution then washed with water (1 x 20 mL) and
brine (1 x 20 mL) before dried (Na SO ), filtered and concentrated under reduced pressure.
2
4
The generally light-yellow oil thus obtained was subjected to flash chromatography (silica,
0:1 v/v hexane/ethyl acetate elution) to afford, in the majority of cases, two fractions with a
1
ΔR of approximately 0.05. In all instances except that involving compound 36, the products
f
were isolated as clear, colorless oils.
Method B:
The gem-dibromocyclopropane 10 (0.3 mmol, 1 equiv) was treated with the relevant
homochiral primary or secondary amine 20-35 (4 equiv) and the ensuing mixture stirred at 55
°
C (bath temperature) for 8 h. A portion of the cooled mixture was dissolved in CDCl and
3
1
the resulting solution subjected to H NMR spectroscopic analysis. The diastereoisomeric
ratio of products 18 and 19 was established by integration of the relevant resonances,
normally those due to the olefinic or allylic protons, viz. H-3 or H-1 respectively.
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(10) in the presence of amine 20. Inseparable diastereoisomers (227 mg, 93%) (R = 0.8 in
f
1
10:1 v/v hexane/ethyl acetate). H NMR (400 MHz, CDCl ) δ (mixture of diastereoisomers)
3
6
.09 (m, 2H), 3.36 (s, 0.5H), 3.37 (s, 0.5H), 2.10−1.96 (complex m, 3H), 1.81−1.76 (complex
m, 1H), 1.75−1.65 (complex m, 2H), 1.64−1.55 (complex m, 2H), 1.16 (d, J = 8.4 Hz, 1.5H),
1.13 (d, J = 4.8 Hz, 1.5H), 0.78−0.69 (complex m, 1H), 0.49−0.38 (complex m, 1.5H),
0
.32−0.26 (complex m, 0.5H), 0.17−0.15 (complex m, 0.5H), 0.12−0.05 (complex m, 0.5H);
1
3
C NMR (100 MHz, CDCl ) δ (mixture of diastereoisomers) 131.5, 131.4, 126.4, 126.3,
3
5
2
1;
8.3, 57.0, 56.9, 56.5, 31.6, 30.2, 27.8(2), 27.8(0), 21.5, 20.6, 18.4, 18.1, 17.2, 16.9, 4.3, 4.2,
.4, 1.9; IR (KBr): νmax 3343, 3075, 2999, 2933, 2864, 1642, 1446, 1129, 1017, 986, 871 cm–
MS (EI, 70 eV): m/z 245 and 243 (M , 100 and 95%); HRMS M Calcd for C H1879BrN:
+•
+•
1
1
2
43.0623, Found: 243.0623; Calcd for C H1881BrN: 245.0602, Found: 245.0606.
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Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(10) in the presence of amine 21. Separable diastereoisomers. More mobile diastereoisomer
1
(
117 mg, 47.5%) (R = 0.8 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
6
.11 (t, J = 4.0 Hz, 1H), 3.24 (m, 1H), 2.38 (m, 1H), 2.08−2.01 (complex m, 2H), 1.79−1.71
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(complex m, 2H), 1.66 (m, 1H), 1.59−1.51 (complex m, 2H), 1.01 (d, J = 6.4 Hz, 3H), 0.89
1
3
(
t, J = 6.4 Hz, 6H) (resonance due to one proton obscured or overlapping); C NMR (100
MHz, CDCl ) δ 131.7, 126.3, 56.7, 56.5, 33.6, 30.1, 28.0, 19.09, 18.2, 16.7, 16.5; IR (KBr):
3
ν
3
3
3
1
,
3
0
3
9
,
2
9
5
6
,
2
8
7
1
,
1
6
4
3
,
1
4
6
5
,
1
4
5
0
,
1
3
7
2
,
1
1
6
0
,
1
1
1
8
,
1
0
9
7
,
1
0
6
6
,
9
8
1
,
7
4
1
c
m
–
m
a
x
1
+•
+
; MS (EI, 70 eV): m/z 247 and 245 (M , both 20%), 232 and 230 [(M−Me•) , 97 and 100];
HRMS M Calcd for C H BrN: 245.0779, Found: 245.0771; Calcd for C H2081BrN:
+
•
79
1
1
20
11
2
47.0759, Found: 247.0743; [α]D20 = −92.2 (c = 1, CHCl3).
1
Less mobile diastereoisomer (117 mg, 47.5%) (R = 0.75 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 6.09 (t, J = 4.0 Hz, 1H), 3.24 (broad s, 1H), 2.61 (m, 1H),
3
2
.08−2.00 (complex m, 2H), 1.81−1.77 (complex m, 2H), 1.72−1.66 (complex m, 2H),
1.59−1.53 (complex m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.89 (d, J =
1
3
6
.8 Hz, 3H) (resonance due to one proton obscured or overlapping); C NMR (100 MHz,
CDCl ) δ 131.4, 126.5, 56.9, 56.6, 31.2, 30.7, 27.9, 19.6, 17.2, 17.1, 16.4; IR (KBr): ν
3
max
–
1
3
339, 3038, 2957, 2871, 1641, 1465, 1445, 1385, 1373, 1115, 982, 742 cm ; MS (EI, 70
+
•
+
+•
eV): m/z 247 and 245 (M , both 20%), 232 and 230 [(M−Me•) , 98 and 100]; HRMS M
Calcd for C H BrN: 245.0779, Found: 245.0785; Calcd for C H2081BrN: 247.0759,
7
9
1
1
20
11
Found: 247.0766; [α]D20 = +52.3 (c = 1, CHCl3).
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(10) in the presence of amine 22. Separable diastereoisomers. More mobile diastereoisomer
1
(
124 mg, 47.5%) (R = 0.8 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
6.10 (s, 1H), 3.21 (s, 1H), 2.14 (m, 1H), 2.06−2.02 (complex m, 2H), 1.82−1.76 (complex m,
2
H), 1.59−1.49 (complex m, 2H), 1.05 (d, J = 7.8 Hz, 3H), 0.89 (s, 9H) (resonance due to one
13
proton obscured or overlapping); C NMR (100 MHz, CDCl ) δ 132.0, 126.0, 59.8, 57.0,
3
34.3, 29.6, 26.6, 26.5, 16.3, 14.6; IR (KBr): νmax 3331, 3040, 2954, 2867, 1644, 1463, 1373,
–
1
+
+
1
105, 981 cm ; MS (ESI, +ve): m/z 262 and 260 [(M+H] , 98 and 100%]; HRMS [M+H]
Calcd for C H BrN: 260.1014, Found: 260.1012; Calcd for C H2381BrN: 262.0993,
7
9
1
2
23
12
Found: 262.0996; [α]D20 = −11.0 (c = 1, CHCl3).
1
Less mobile diastereoisomer (124 mg, 47.5%) (R = 0.75 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 6.07 (t, J = 4.0 Hz, 1H), 3.19 (s, 1H), 2.40 (q, J = 6.4 Hz, 1H),
3
2
.09−2.01 (complex m, 2H), 1.80−1.64 (complex m, 2H), 1.60−1.54 (complex m, 2H), 0.98
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
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3
3
3
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5
5
5
5
6
13
(
d, J = 6.8 Hz, 3H), 0.93 (s, 9H) (resonance due to one proton obscured or overlapping); C
NMR (100 MHz, CDCl ) δ 131.3, 126.6, 61.8, 59.4, 35.3, 31.4, 27.9, 26.6, 17.7, 16.9; IR
3
–
1
(
KBr): νmax 3372, 3048, 2954, 2866, 1641, 1479, 1452, 1372, 1128, 1115, 985 cm ; MS (EI,
+•
+
+•
7
0 eV): m/z 261 and 259 (M , both 10%), 246 and 244 [(M−Me•) , 98 and 100]; HRMS M
Calcd for C H BrN: 259.0936, Found: 259.0927; Calcd for C H2281BrN: 261.0915,
7
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
22
12
Found: 261.0919; [α]D20 = +70.8 (c = 1, CHCl3).
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(
10) in the presence of amine 23. Separable diastereoisomers. More mobile diastereoisomer
1
(132 mg, 47%) (R = 0.8 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
7
3
.32 (m, 2H), 7.23 (m, 2H), 7.15 (m, 1H), 6.02 (t, J = 6.4 Hz, 1H), 3.97 (q, J = 8.8 Hz, 1H),
.16 (broad s, 1H), 2.01−1.84 (complex m, 2H), 1.56−1.52 (complex m, 1H), 1.49−1.45
(complex m, 2H), 1.38 (m, 1H), 1.30 (d, J = 8.0 Hz, 3H) (resonance due to one proton
1
3
obscured or overlapping); C NMR (100 MHz, CDCl ) δ 146.4, 131.5, 128.2, 126.8, 126.7,
3
1
26.3, 58.1, 58.0, 31.4, 27.8, 24.5, 17.2; IR (KBr): νmax 3344, 3026, 2957, 2928, 1640, 1450,
–
1
+•
1270, 1112, 996, 977, 762, 741, 701 cm ; MS (EI, 70 eV): m/z 281 and 279 (M , 5 and 4%),
66 and 264 ([M−Me•] , 99 and 100); HRMS M Calcd for C H1879BrN: 279.0623, Found:
+
+•
2
2
14
79.0627; Calcd for C H 81BrN: 281.0602, Found: 281.0614; [α]D20 = −92.7 (c = 1, CHCl3).
1
4
18
1
Less mobile diastereoisomer (132 mg, 47%) (R = 0.75 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 7.29−7.16 (complex m, 5H), 6.05 (t, J = 4.0 Hz, 1H), 3.83 (q, J =
3
8
.6 Hz, 1H), 3.03 (m, 1H), 1.99−1.92 (complex m, 2H), 1.77−1.70 (complex m, 2H),
.64−1.57 (complex m, 2H), 1.58−1.48 (complex m, 1H),1.30 (d, J = 8.0 Hz, 3H) (resonance
1
1
3
due to one proton obscured or overlapping); C NMR (100 MHz, CDCl ) δ 145.0, 131.9,
3
1
2
28.4, 126.9, 126.7, 126.3, 55.5, 54.8, 28.8, 27.9, 25.3, 17.5; IR (KBr): νmax 3401, 3026,
–1
928, 2860, 1642, 1450, 1267, 1114, 908, 733, 701 cm ; MS (EI, 70 eV): m/z 281 and 279
+
•
+
+•
(M , both 5 and 4 %), 266 and 264 ([M−Me•] , both 98 and 100); HRMS M Calcd for
C H BrN: 279.0623, Found: 279.0622; Calcd for C H1881Br N: 281.0602, Found:
7
9
1
4
18
14
2
81.0592; [α]D20 = −18.4 (c = 1, CHCl3).
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(
10) in the presence of amine ent-23. Separable diastereoisomers. More mobile
1
diastereoisomer (125 mg, 44.5%) (R = 0.80 in 10:1 v/v hexane/ethyl acetate): H NMR (400
f
MHz, CDCl ) δ 7.40 (m, 2H), 7.30 (m, 2H), 7.23 (m, 1H), 6.09 (broad s, 1H), 4.06 (m, 1H),
3
3
.23 (broad s, 1H), 2.08−1.92 (complex m, 2H), 1.66−1.63 (complex m, 1H), 1.57−1.53
(
complex m, 2H), 1.47−1.43 (complex m, 1H), 1.38 (d, J = 6.4 Hz, 3H) (resonance due to one
13
proton obscured or overlapping); C NMR (100 MHz, CDCl ) δ 146.4, 131.6, 128.3, 126.9,
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26.8, 126.2, 58.1, 58.0, 31.4, 27.8, 24.5, 17.3; IR (KBr): νmax 3344, 3026, 2928, 1640, 1450,
–
1
+•
1369, 1350, 1271, 1112, 995, 977, 762 cm ; MS (EI, 70 eV): m/z 281 and 279 (M , both
%), 266 and 264 ([M−Me•] , both 100); HRMS M Calcd for C H1879BrN: 279.0623,
+
+•
5
14
Found: 279.0623; Calcd for C H1881BrN: 281.0602, Found: 281.0601; [α]D20 = +96.5 (c = 1,
1
4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CHCl3).
1
Less mobile diastereoisomer (125 mg, 44.5%) (R = 0.75 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 7.37−7.22 (complex m, 5H), 6.12 (t, J = 4.0 Hz, 1H), 3.90 (q, J =
3
6
.8 Hz, 1H), 3.06 (broad s, 1H), 2.10−1.95 (complex m, 2H), 1.91−1.77 (complex m, 2H),
1
3
1.72−1.64 (complex m, 2H), 1.55−1.49 (complex m, 1H), 1.37 (d, J = 6.4 Hz, 3H); C NMR
100 MHz, CDCl ) δ 145.0, 132.0, 128.4, 126.9, 126.7, 126.2, 55.4, 54.8, 28.8, 27.9, 25.2,
(
3
1
7.5; IR (KBr): νmax 3332, 3024, 2929, 1642, 1450, 1368, 1352, 1268, 1115, 978, 805, 762,
–
1
+•
+
700 cm ; MS (EI, 70 eV): m/z 281 and 279 (M , both 5%), 266 and 264 ([M−Me•] , both
00); HRMS M+• Calcd for C H1879BrN: 279.0623, Found: 279.0623; Calcd for
1
1
4
C H1881BrN: 281.0602, Found: 281.0599; [α]D20 = +21.4 (c = 1, CHCl3).
1
4
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(10) in the presence of amine 24. Separable diastereoisomers. More mobile diastereoisomer
1
(144 mg, 46.5%) (R = 0.70 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
7.22 (m, 1H), 6.97 (broad s, 2H), 6.76 (m, 1H), 6.09 (t, J = 4.0 Hz, 1H), 4.00 (q, J = 6.4 Hz,
1H), 3.80 (s, 3H), 3.22 (broad s, 1H), 2.02−1.93 (complex m, 2H), 1.56−1.50 (complex m,
1H), 1.49−1.46 (complex m, 2H), 1.46−1.42 (complex m, 1H), 1.36 (d, J = 6.4 Hz, 3H)
(
resonance due to one proton obscured or overlapping); 13C NMR (100 MHz, CDCl ) δ
3
159.6, 148.3, 131.6, 129.2, 126.3, 119.3, 112.3, 112.2, 58.2, 58.1, 55.2, 31.5, 27.8, 24.6, 17.3;
IR (KBr): νmax 3344, 2995, 2934, 2833, 1600, 1585, 1485, 1466, 1274, 1254, 1115, 1046, 781
–1
+•
+
cm ; MS (EI, 70 eV): m/z 311 and 309 (M , both 30%), 296 and 294 [(M−Me•] , both 100];
HRMS M Calcd for C H BrNO: 309.0728, Found: 309.0725; Calcd for C H2081BrNO:
+
•
79
1
5
20
15
3
11.0708, Found: 311.0707; [α]D20 = −96.9 (c = 1, CHCl3).
1
Less mobile diastereoisomer (144 mg, 46.5%) (R = 0.65 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 7.23 (m, 1H), 6.97 (broad s, 1H), 6.91 (d, J = 7.6 Hz, 1H), 6.78
3
(m, 1H), 6.13 (t, J = 4.4 Hz, 1H), 3.90 (q, J = 6.4 Hz, 1H), 3.82 (s, 3H), 3.08 (m, 1H),
2
.11−1.97 (complex m, 2H), 1.81 (m, 1H), 1.71−1.66 (complex m, 2H), 1.53 (m, 1H), 1.36
1
3
(d, J = 6.4 Hz, 3H) (resonance due to one proton obscured or overlapping); C NMR (100
MHz, CDCl ) δ 159.8, 146.8, 132.0, 129.3, 126.3, 119.2, 112.6, 111.8, 55.4, 55.2, 54.7, 28.7,
3
2
1
7.9, 25.3, 17.5; IR (KBr): νmax 3333, 2995, 2936, 2860, 2833, 1642, 1599, 1485, 1466, 1452,
–1
435, 1273, 1253, 1172, 1116, 1045, 979, 873, 743 cm ; MS (EI, 70 eV): m/z 310 and 308
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5
5
5
5
5
5
6
+
+
+•
[
M–H•) , 95 and 64%], 296 and 294 [(M−Me•] , both 100]; HRMS M Calcd for
C H BrNO: 309.0728, Found: 309.0727; Calcd for C H2081BrNO: 311.0708, Found:
7
9
1
5
20
15
3
11.0703; [α]D20 = −23.6 (c = 1, CHCl3).
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(10) in the presence of amine 25. Separable diastereoisomers. More mobile diastereoisomer
1
(
143 mg, 46%) (R = 0.70 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
7
.46 (d, J = 7.6 Hz, 1H), 7.20 (m, 1H), 6.94 (t, J = 7.6 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.09
(
t, J = 4.0 Hz, 1H), 4.32 (q, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.26 (broad s, 1H), 2.05−2.00
(complex m, 2H), 1.66 (broad s, 1H), 1.62−1.56 (complex m, 2H), 1.50−1.46 (complex m,
1
3
1
H), 1.37 (d, J = 6.8 Hz, 3H) (resonance due to one proton obscured or overlapping); C
NMR (100 MHz, CDCl ) δ 156.7, 135.0, 134.3, 131.4, 126.7, 126.6, 120.5, 110.4, 57.8, 55.2,
3
51.7, 30.8, 27.8, 22.1, 17.4; IR (KBr): νmax 3347, 3032, 2934, 2863, 2834, 1641, 1599, 1586,
–
1
+•
1
489, 1464, 1237, 1092, 1031 cm ; MS (EI, 70 eV): m/z 311 and 309 (M , 9 and 10%), 296
and 294 [(M−Me•) , 97 and 100]; HRMS M Calcd for C H2079BrNO: 309.0728, Found:
+
+•
1
5
309.0728; Calcd for C H 81BrNO: 311.0708, Found: 311.0707; [α]D20 = −90.6 (c 1, CHCl3).
1
5
20
1
Less mobile diastereoisomer (149 mg, 48%) (R = 0.70 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 7.32 (d, J = 7.6 Hz, 1H), 7.19 m, 1H), 6.94 (t, J = 7.6 Hz, 1H),
3
6
.85 (d, J = 7.6 Hz, 1H), 6.12 (m, 1H), 4.16 (m, 1H), 3.84 (s, 3H), 2.99 (m, 1H), 2.12−2.06
(
complex m, 2H), 1.99 (m, 1H), 1.84−1.65 (complex m, 2H), 1.49 (m, 1H), 1.40 (d, J = 6.8
Hz, 3H) (resonance due to one proton obscured or overlapping); 13C NMR (100 MHz,
CDCl ) δ 157.4, 132.0, 131.9, 127.9, 127.6, 126.3, 120.5, 110.4, 55.5, 55.2, 50.3, 28.7, 28.0,
3
23.0, 17.6; IR (KBr): νmax 3334, 2935, 2861, 1642, 1598, 1489, 1464, 1438, 1237, 1119,
–
1
+•
1
092, 1048, 1030, 753 cm ; MS (EI, 70 eV): m/z 311 and 309 (M , 9 and 10%), 296 and
94 [(M−Me•] , 98 and 100]; HRMS M Calcd for C H2079BrNO: 309.0728, Found:
+
+•
2
1
5
309.0728; Calcd for C H 81BrNO: 311.0708, Found: 311.0708; [α]D20 = −27.7 (c = 1,
1
5
20
CHCl3).
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(10) in the presence of amine 26. Separable diastereoisomers. More mobile diastereoisomer
1
(
155 mg, 47%) (R = 0.70 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
8
.30 (d, J = 8.4 Hz, 1H), 7.88 (m, 1H), 7.80 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.54
(
m, 1H), 7.49−7.46 (complex m, 2H), 6.12 (t, J = 4.0 Hz, 1H), 4.90 (q, J = 6.8 Hz, 1H), 3.33
broad s, 1H), 2.10−2.04 (complex m, 2H), 2.03−1.94 (complex m, 1H), 1.70−1.63 (complex
(
m, 2H), 1.53 (d, J = 6.8 Hz, 3H), 1.48−1.43 (complex m, 1H) (resonance due to one proton
13
obscured or overlapping); C NMR (100 MHz, CDCl ) δ 142.0, 133.9, 131.6, 131.1, 128.8,
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27.1, 126.2, 125.6(0), 125.5(5), 125.2, 123.7, 123.2, 58.3, 53.8, 31.2, 27.8, 23.8, 17.3; IR
–
1
(KBr): νmax 3335, 3047, 2927, 2860, 1641, 1444, 1176, 1115, 799, 778 cm ; MS (EI, 70 eV):
m/z 331 and 329 (M , 98 and 100%); HRMS M Calcd for C H2079BrN: 329.0779, Found:
+
•
+•
1
8
3
29.0778; Calcd for C H2081BrN: 331.0759, Found: 331.0756; [α]D20 = −87.5 (c = 1, CHCl3).
18
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Less mobile diastereoisomer (155 mg, 47%) (R = 0.65 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 8.22 (d, J = 7.6 Hz, 1H), 7.91 (m, 1H), 7.86 (d, J = 7.2 Hz, 1H),
3
7
4
.77 (d, J = 8.4 Hz, 1H), 7.56 (m, 1H), 7.52−7.48 (complex m, 2H), 6.18 (t, J = 4.0 Hz, 1H),
.85 (q, J = 6.4 Hz, 1H), 3.23 (broad s, 1H), 2.03−1.98 (complex m, 2H), 1.86 (m, 1H),
1.70−1.66 (complex m, 2H), 1.64 (m, 1H), 1.53 (d, J = 6.8 Hz, 3H) (resonance due to one
1
3
proton obscured or overlapping); C NMR (100 MHz, CDCl ) δ 140.6, 133.9, 132.1, 131.3,
3
1
29.0, 127.1, 126.3, 125.7(4), 125.7(0), 125.2, 123.4, 122.7, 55.6, 49.6, 29.1, 27.9, 24.9,
17.6; IR (KBr): νmax 3344, 3047, 2928, 2862, 2831, 1641, 1595, 1510, 1444, 1177, 1113, 799,
–
1
+•
+•
7
78 cm ; MS (EI, 70 eV): m/z 331 and 329 (M , 98 and 100%); HRMS M Calcd for
C H BrN: 329.0779, Found: 329.0780; Calcd for C H2081BrN: 331.0759, Found:
79
1
8
20
18
331.0761; [α]D20 = +13.6 (c = 1, CHCl3).
Products obtained from the electrocyclic ring-opening of 6,6-dibromobicyclo[3.1.0]hexane
(10) in the presence of amine 27. Separable diastereoisomers. More mobile diastereoisomer
1
(145 mg, 44%) (R = 0.70 in 10:1 v/v hexane/ethyl acetate): H NMR (400 MHz, CDCl ) δ
f
3
7
1
.84−7.81 (complex m, 4H), 7.58 (m, 1H), 7.49−7.42 (complex m, 2H), 6.11 (t, J = 4.0 Hz,
H), 4.23 (q, J = 6.4 Hz, 1H), 3.29 (broad s, 1H), 2.09−1.93 (complex m, 2H), 1.71−1.61
(complex m, 2H), 1.57−1.51 (complex m, 2H), 1.46 (d, J = 6.8 Hz, 3H) (resonance due to one
1
3
proton obscured or overlapping); C NMR (100 MHz, CDCl ) δ 144.0, 133.4, 132.8, 131.6,
3
1
28.0, 127.7, 127.6, 126.3, 125.9, 125.4, 125.3, 58.5, 58.2, 31.6, 27.8, 24.6, 17.3 (one signal
obscured or overlapping); IR (KBr): νmax 3344, 3053, 2927, 2861, 1600, 1442, 1130, 1112,
–
1
+•
997, 979, 856, 819, 747 cm ; MS (EI, 70 eV): m/z 331 and 329 (M , both 5%), 316 and 314
(M−Me•) , 98 and 100]; HRMS M Calcd for C H2079BrN: 329.0779, Found: 329.0781;
+
+•
[
18
Calcd for C H2081BrN: 331.0759, Found: 331.0753; [α]D20 = −86.0 (c = 1, CHCl3).
18
1
Less mobile diastereoisomer (155 mg, 47%) (R = 0.65 in 10:1 v/v hexane/ethyl acetate): H
f
NMR (400 MHz, CDCl ) δ 7.87−7.80 (complex m, 4H), 7.57 (m, 1H), 7.46−7.45 (complex
3
m, 2H), 6.15 (t, J = 4.0 Hz, 1H), 4.14 (q, J = 6.4 Hz, 1H), 3.12 (broad s, 1H), 2.07 (m, 1H),
2
3
1
2
.02−1.84 (complex m, 2H), 1.73−1.67 (complex m, 2H), 1.54 (m, 1H), 1.47 (d, J = 6.8 Hz,
1
3
H) (resonance due to one proton obscured or overlapping); C NMR (100 MHz, CDCl ) δ
3
42.6, 133.4, 132.0, 128.3, 127.7(1), 127.6(8), 126.3, 125.9, 125.5, 125.4, 124.9, 55.6, 54.9,
8.8, 27.9, 25.3, 17.6 (one signal obscured or overlapping); IR (KBr): νmax 3334, 3052, 2928,
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