Stereocontrolled preparation of bicyclic alkaloid analogues: an approach towards the kinabalurine skeleton

Article abstract of DOI:10.1016/j.tet.2009.07.060

An approach towards the construction of bicyclic analogues of monoterpene alkaloids belonging to the kinabalurine, incarvilline and skytanthine families of natural products is reported. These syntheses rely on a stereoselective intramolecular Pauson-Khand

Full text of DOI:10.1016/j.tet.2009.07.060

Tetrahedron 65 (2009) 8259–8268
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Tetrahedron
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Stereocontrolled preparation of bicyclic alkaloid analogues: an approach
towards the kinabalurine skeleton
*
Yvonne Kavanagh, Matthew O’Brien, Paul Evans
Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
a r t i c l e i n f o
a b s t r a c t
Article history:
An approach towards the construction of bicyclic analogues of monoterpene alkaloids belonging to the
kinabalurine, incarvilline and skytanthine families of natural products is reported. These syntheses rely
on a stereoselective intramolecular Pauson–Khand cyclisation of a chiral pool-derived enyne in order to
prepare the bicyclic core. Stereoselective further elaboration generates diastereomeric analogues of the
naturally occurring alkaloids.
Received 3 February 2009
Received in revised form 30 June 2009
Accepted 23 July 2009
Available online 29 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
OH
H
O
H
OH
H
OH
H
In 1997 a new class of monoterpene alkaloids, named the kin-
abalurines, was isolated from Kopsia pauciflora.1 This species be-
longs to a larger family of trees and shrubs that are widespread
throughout Asia. The structures of this group of diastereomeric
compounds, exemplified by kinabalurines A 1, B 2 and F 3, were
determined by X-ray crystallography and NMR spectroscopy. These
compounds appear to belong to a wider family bearing a close
structural resemblance to other bicyclic alkaloids isolated from
different plant sources. For example, the incarvilline series was
isolated recently from Incarvillea sinensis Lam. and members of this
compound class exhibit analgesic properties.2 Recently reports
concerning the stereoselective synthesis of the incarvilline 4 family
of compounds have appeared.3 Tecomanine 5 from Tecoma stans
Juss. possesses hypoglycaemic properties.4 Tecostanine 6 is an iso-
mer of incarvilline 4 in which the oxidation is found on the methyl
substituent as opposed to the five-membered ring.5
H
H
H
H
N
N
N
N
Me
Me
Me
Me
Kinabalurine F (3)
Kinabalurine A (1) Kinabalurine B (2)
Incarvilline (4)
O
H
H
HO
H
H
H
N
N
N
N
Me
Me
Me
Tecomanine (5)
Tecostanine (6) α –Skytanthine (7) Actinidine (8)
Figure 1. Bicyclic monoterpene alkaloids.
In terms of the kinabalurine family, the presence of 5-contigu-
ous stereocentres and the trans-stereochemistry of the 4a/7a ring
junction represents an interesting and challenging synthetic
problem. Consequently, based on both their structure and potential
biological properties we considered this family of compounds as
interesting targets and envisaged using an intramolecular Pauson–
Khand cyclisation9 to install the bicyclic ring architecture (Fig. 2).
Retrosynthetically, from the target compound(s), manipulation
of the nitrogen-protecting group and two stereocontrolled re-
ductions lead to the cyclopentenone Pauson–Khand adduct 9. Ever
since Magnus’ seminal studies involving the intramolecular Pau-
son–Khand reaction it has been well appreciated that a stereogenic
centre adjacent to either the propargylic, or the allylic reactive
group typically engenders good stereocontrol on cyclisation.9–11
Finally, it was felt that the acyclic PKR precursor 10 would be readily
available following standard synthetic steps. Recently, Honda and
The majority of compounds, shown in Figure 1, possesses
a characteristic fused bicyclic ring structure and oxygenation in the
five-membered carbocyclic ring. Another structurally related class
of compounds that have generated interest are the skytanthine
alkaloids 7 that lack this oxygenation in the five-membered ring
but display the same structural framework.6 Similarly, related
compounds are found in which the heterocyclic ring is present as
a pyridine, exemplified by actinidine 8.7 In a more general sense,
since many natural products and pharmaceutically active agents
possess substituted piperidine ring systems the synthesis of this
class of functionalised heterocyclic compound remains of interest
to the general synthetic chemistry community.8
* Corresponding author.
E-mail address: paul.evans@ucd.ie (P. Evans).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.060

8260
Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
dichloromethane and the mixture was stirred for 1 h at room
X
H
O
temperature. TLC analysis indicated the consumption of 10 and the
formation of a less-polar, brown spot. The reaction mixturewas then
cooled to 0 ꢁC and NMO$H2O was added. Following purification of
the crude reaction mixture, 9a was isolated (80%) along with its
diastereomeric adduct 9b (10%). Under these conditions the PKR
proceeds in a diastereoselective manner and the stereochemistry of
the newly formed chiral centre was confirmed by NOE and X-ray
crystallography.15
H
H
4a
4a
7a
4
4
7a
2
2
N
N
N
Functional group
interconversions
Intramolecular
Pauson-Khand
Cycloaddition
Ts
10
Ts
9
Me
1, 3, 4 (X = OH);
7 (X = H)
Figure 2. Retrosynthetic analysis of bicyclic alkaloids based on an intramolecular
During this sequence we were somewhat concerned with the
integrity of the stereogenic methyl substituent since several com-
pounds potentially possess a labile proton. However, based on the
Flack parameters15,16 obtained for the X-ray structure and the
Pauson–Khand reaction.
Kaneda have reported a similar PKR based strategy as a means to
prepare both (ꢀ)-incarvilline and (þ)-
a-skytanthine as single
stereoisomers.12
consistent optical rotation values obtained for the bulk material
20
(9a: [
a]
¼ꢀ74.2) we believe that this fear was unfounded and that
D
minimal epimerisation occurs following this sequence. Thus, ad-
duct 9a may be prepared from 11 in seven linear steps (31% overall
yield) and isolated as a single diastereoisomer. The preferential
formation of 9a is consistent with a reactive conformer resembling
exo-18 (X¼H) in which the alkene moiety occupies a pseudo-
equatorial orientation (Fig. 3). Although this stereochemistry is
present in the natural product kinabalurine F (3), most members of
this family of compounds possess a cis-relationship between H-4
and H-4a (see Fig. 1). Therefore, we wished to investigate whether
the presence of a sulfonyl substituted alkene would reverse the
stereochemical outcome of the intramolecular PKR following work
from Carretero’s group.17 In these studies good to excellent levels of
diastereoselectivity were achieved, particularly during the forma-
tion of [3.3.0]bicyclic cyclopentenones. The rationale used to ex-
plain the change in stereochemical course for a series of enynes was
that according to the Magnus mechanistic model, the presence of
2. Results and discussion
Scheme 1 illustrates the preparation of the enyne PKR precursor
10 and its subsequent intramolecular PKR. Starting from the enan-
tiopure, chiral pool-derived alcohol 11, often termed the Roche es-
ter, a Mitsunobu reaction using a Weinreb-type reagent, under
standard conditions,13 installed the protected nitrogen atom. When
1 equiv of alcohol 11 was employed only moderate yields of adduct
12 were encountered (ca. 40–60%). It seems likely that these low
yields arise from a competitive elimination reaction, facilitated by
the ester functional group. Based on this hypothesis the use of
2 equiv of 11 significantly improved the isolated yield of 12 (94%).
The methyl ester moiety was then reduced using LiAlH4 to afford the
primary alcohol 13. This apparently straightforward reduction
proved troublesome and following initial attempts the desired
product 13 was formed in only moderate yield in conjunction with
compound 14 in which the tert-butyloxycarbamate group has been
lost. However, the formation of this side product can be minimised if
the reaction is conducted at low temperature and for only short
periods. Oxidation of the primary alcohol 13 to the aldehyde 15,
using PCC, proceeded smoothly and this material was converted
into the terminal alkene 16 using a standard Wittig reaction. An
excess of the phosphonium salt was used to ensure that the alde-
hyde 15, with its vulnerable asymmetric carbon, did not come into
contact with the base. However, under a variety of conditions only
moderated yields of 16 were obtained. Removal of the carbamate
protecting group with TFA and alkylation using but-2-ynyl bromide
proceeded without event and afforded the PKR precursor 10 in good
yield. This compound was treated under standard intramolecular
PKR conditions:11,14 thus, Co2(CO)8 was added to a solution of 10 in
H
H
H
Co
X
Co
Co
Me
X
Co
Me
Me
N
9a (X = H), 24 (X = SO2Ph)
Me
N
H
Ts
Me
Ts
H
18
exo-18
H
H
H
X
Co
H
Co
Me
Me
H
N
Co
Co
9b (X = H)
N
Ts
Ts
X
Me
19
endo-19
Figure 3. Possible explanation for observed stereochemistry (cobalt CO ligands
omitted for clarity).
TsNHBoc,
DIAD, PPh3,
Ts
Ts
LiAlH4, THF,
HO
BocN
BocN
OH TsHN
OH
CO2Me
CO2Me
THF, 0 °C to rt,
15 h, 94%
-78 °C, 10 min,
quant
11
12
13
14
PCC, DCM,
rt, 2.5 h, 90%
TFA, CH2Cl2,
1 h, 97%
Ph3PCH3Br,
Ts
BocN
Ts
O
TsHN
BocN
KHMDS, THF,
-78 °C to rt,
1.5 h, 56%
17
16
15
(1) NaH, DMSO, 0 ºC, 0.5 h;
(2) but-2-ynyl bromide, rt, 15 h, 84%
O
O
H
H
N
(1) Co2(CO)8, CH2Cl2, rt, 1 h;
(2) NMO·H2O , 0 °C to rt, 2 h
N
N
Ts
10
Ts
Ts
(
)-9a: 80%
(+)-9b: 10%
Scheme 1. Preparation of enyne 10 and its stereoselective intramolecular Pauson–Khand reaction.

Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
8261
(1) NaH, THF,
Ts
TFA, CH2Cl2, rt,
6 h, 98%
0 °C, 0.5 h;
TsHN
BocN
(EtO)2OP
SO2Ph
SO2Ph
SO2Ph
(2) 15, rt,
1 h, 68%
20
21
22
(1) NaH, DMSO, 0 °C, 0.5 h;
(2) but-2-ynyl bromide, rt, 1.5 h, 57%
O
O
PhO2S
5
H
H
SmI2, THF,
4a
(1) Co2(CO)8, CH2Cl2, rt, 1 h;
TsN
4
0 °C, 1 h, 79%
(2) NMO·H2O, 0 °C to rt, 15 h, 73%
SO2Ph
N
N
23
Ts
9a
Ts
24
Scheme 2. Intramolecular Pauson–Khand reaction of vinyl sulfone 23.
a sulfinyl, or sulfonyl alkenyl substituent leads to a developing
steric interaction between the allylic substituent in the proposed
transition state forming 18 when X¼SO2Ph. In contrast, it was ar-
gued that in the pseudo-axial conformer endo-19 when X¼SO2Ph
such steric interactions between the substituents are minimised on
formation of 19 (Fig. 3).
intramolecular PKR was not observed.17 Possible explanations for
this could be that allylic strain serves to minimise the population of
the reactive conformer endo-19,20 or alternatively the formation of
the metallocycle intermediate 19 may force the newly formed pi-
peridine ring into an unfavourable boat conformation.
With compound 9a in hand its conversion into the types of
natural products illustrated in Figure 1 was considered. To this end
a racemic model system, 29, not containing the stereogenic methyl
substituent present in 9a was prepared using an analogous PK
based route (Scheme 3). But-2-ynol 25 smoothly participated in
As Scheme 2 illustrates, PK precursor, enyne 23 was prepared
over three steps from aldehyde 15. A standard Horner–Wadsworth–
Emmons reaction between 2018 and 15 afforded the
a,b-unsaturated
sulfone 21 in reasonable yield with good control of alkenyl geometry
(E:Z; >95:5). This compound was converted into enyne 23 in two
steps. The alkylation of 22 proved problematic and only moderate
yields of 23 were obtained. The main side product formed from this
reaction was trans-3-methyl(buta-1,3-diene-1-sulfonyl)benzene,
resulting from elimination of the amino containing group. Use of
alternative conditions such as Cs2CO3 did not improve this yield.19
Notwithstanding, enyne 23 underwent an efficient intramolecular
PKR and compound 24 was isolated in 73% yield and no diastereo-
meric products were detected following this reaction.
The relative stereochemistry of 24 was uncovered by two
means; firstly, NOE experiments indicated an enhancement to H-5
to when H-4 was irradiated and to the 4-methyl substituent when
H-4a was irradiated. Secondly, this was further confirmed on con-
version of 24 into 9a on treatment with 2 equiv of SmI2. Mea-
surement of optical rotation value of the material isolated following
this sequence proved to be identical to values recorded from
material prepared via Scheme 1, again confirming the integrity of
the stereogenic centre bearing the methyl substituent.
a
Mitsunobu reaction with N-(tert-butoxycarbonyl)-p-toluene-
sulfonamide and, in this case, equimolar amounts of the reaction
partners delivered adduct 26 in good yield. The tert-butoxycarbonyl
protecting group was removed with TFA and the resultant sulfon-
amide 27 underwent alkylation with butenyl bromide to generate
the PKR precursor 28. Standard oxidative PK conditions using
NMO$H2O afforded the racemic fused cyclopentenone 29 (four
steps, 49%).
Compound 29 stereoselectively underwent a palladium-cata-
lysed hydrogenation to generate 30, whose relative stereochemis-
try, again, was probed using NOE experiments [irradiation of H-7a
enhanced H-4a and H-7]. In contrast, subsequent 1,2-reduction of
30 with sodium borohydride resulted in a non-stereoselective re-
action in which significant levels of 31a were formed in addition to
the expected diastereoisomer, 31b [irradiation of H-7 enhancement
to H-6 and H-7a]. Attempts to optimise the stereochemical out-
come of this reaction were not performed and the major di-
astereoisomer was converted into the N-methyl analogue (ꢂ)-32
over a two-step sequence involving reductive desulfonylation fol-
lowed by reductive amination using aqueous formaldehyde and
Thus, clearly in the case of our particular substrate 23 the ability
of an
a
,b
-unsaturated sulfone to reverse the stereochemistry of an
TsNHBoc,
DIAD, PPh3,
TFA, CH2Cl2,
(1) NaH, DMSO, 0 °C, 0.5 h;
Ts
HO
BocN
TsHN
THF, 0 °C to rt,
15 h, 94%
6 h, 85%
(2) butenyl bromide,
rt, 15 h, 70%
25
26
27
O
O
(1) Co2(CO)8, CH2Cl2,
rt, 1.5 h;
H
H
H2, Pd/C, EtOH,
rt, 15 h, 90%
NaBH4, MeOH,
H
(2) NMO·H2O, 0 °C to rt,
15 h, 87%
0 °C, 15 min, 81%
N
TsN
N
Ts
Ts
30
28
O
( )-29
OH
OH
H
OH
( )-29
H
N
H
H
Ts
(1) Li, NH3, -78 °C, 1 h;
H
O
H
H
H
(2) CH2O, NaBH(OAc)3,
rt, 15 h, 25%
N
N
N
TsN
CH3
( )-30
Me
Ts
31a: 21%
Ts
H
H
31b: 60%
( )-32
Scheme 3. Stereoselective synthesis of bicyclic alkaloid analogue (ꢂ)-32.

8262
Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
O
OH
H
OH
H
O
6
H
H
H
4
H
7a
H2, Pd/C, EtOH,
rt, 15 h, 90%
NaBH4, MeOH,
0 °C, 15 min, 59%
4a
H
2
N
N
N
N
Ts
9a
Ts
33
Ts
Ts
34a: 24%
34b: 35%
(1) Li, NH3, -78 ºC, 1 h;
(2) CH2O, NaBH(OAc)3, rt,
15 h, 38%
NaBH4, CeCl3, 0 °C to rt, 1 hr, quant;
or DIBAL, DCM, -78 °C to rt, 65%
OH
H
OH
OH
H
H
H2, CH2Cl2, rt, 1 - 15 h
H
H
N
PCy3
Me
N
N
Ir
PF6
N
Ts
36
Ts
38
( )-35
37
(5-10 mol%)
Scheme 4. Stereoselective synthesis of (ꢀ)-35.
sodium triacetoxyborohydride.21 The drastic change in the stereo-
facial efficiency between the alkenyl reduction of 29 and the car-
bonyl reduction of 30 appears to be consistent with the shift from
an sp2 hybridised junction, between the bicyclic system, to an sp3
hybridised cis-ring junction and can be understood on the basis of
their likely, respective conformations (as shown in Scheme 3).
Following the model study outlined in Scheme 3 attention was
turned towards the chiral pool-derived cyclopentenone 9a (Scheme 4).
As observed in Scheme 3, hydrogenation occurred stereoselectively
to afford the cis-fused bicyclic ring architecture 33 and subsequent
non-stereoselective carbonyl reduction gave a mixture of 34a and
34b [NOE main diastereoisomer: irradiation of H-7a enhancement
to H-7 and H-4a; irradiation of H-7 enhancement to H-6; irradia-
tion of H-6 enhancement to CH2A-5 and irradiation of CH2A-5 en-
hancement to H-4a]. The low yields observed for the purified
diastereomers 34a and 34b reflect the difficulty in obtaining pure
samples by column chromatography. Diastereomer 34b was con-
verted into compound 35, a diastereoisomer of kinabalurine F (3),
following N-sulfonyl deprotection and methylation.
Since only 3 of the 5 stereocentres present in compound 35 are
consistent with those of the natural product kinabalurine F (3) we
then attempted to make use of the intrinsic stereofacial bias of
compound 9a, observed in the palladium-catalysed hydrogenation,
by reducing the carbonyl group prior to alkenyl reduction. Pleas-
ingly, when 9a was treated under either DIBAL, or Luche22 reduction
conditions only one diastereoisomer was isolated, which proved to
possess the correct stereochemistry [NOE: irradiation of H-6 en-
hancement CH2A-5, which when irradiated showed an enhance-
ment to H-4a, irradiation of CH2B-5 showed enhancement only to
CH2A-5]. We felt that allylic alcohol 36 was now a perfect candidate
for a directed diastereoselective hydrogenation,23 which has been
reported to occur under the influence of Crabtree’s iridium hydro-
genation catalyst 37, even in cases involving sterically challenging
substrates.24 Thus, we hoped that following this reaction we would
install the remaining stereocentres required to complete the syn-
thesis of 3. However, unfortunately under standard conditions
(1–4 atm H2, 5–10 mol % 37), several attempts only led to the
formation of unidentified material and none of the hoped for
product 38.
Apart from the sterically hindered nature of the tetrasubstituted
alkene present in 36 an additional explanation for the failure of this
key reaction concerns our recent finding that related PKR derived
bicycles undergo rapid alkene isomerisation in the presence of 37
affording the corresponding N-sulfonyl enamine.25 The conjugate
reduction of enone 9 under dissolved metal conditions was also
briefly investigated based on the possibility that this mechanisti-
cally distinct process might lead to the formation of the desired 4a/
7a trans-stereochemistry.24b,26 However, due to concomitant
N-sulfonyl deprotection the results obtained from these studies
proved difficult to interpret.
An interesting observation was encountered when allylic alco-
hol 36 was treated under standard hydrogenation conditions
(Scheme 5). Following short reaction periods, loss of the secondary
hydroxyl group occurred more rapidly than addition of hydrogen to
the hindered alkene. The product 39, of this uncommon allylic re-
duction (hydrogenolysis) was subsequently converted into 40,
a diastereoisomer of the deoxygenated skytanthine monoterpene
alkaloid 7.
In summary, the stereoselective synthesis of a series of bicyclic
analogues related to naturally occurring monoterpene alkaloids has
been achieved employing the intramolecular Pauson–Khand re-
action. The majority of the bicyclic compounds belonging to this
class of natural product possesses the opposite stereochemistry at
C-4a, therefore, further synthetic studies will be focussed on in-
vestigating the stereoselectivity of the Pauson–Khand cyclisation.
3. Experimental
3.1. General
THF was dried over sodium-benzophenone under an atmo-
sphere of nitrogen. Dichloromethane was distilled under nitrogen
from calcium hydride. Dimethyl sulfoxide (DMSO) was dried over
4 Å molecular sieves. Reagents were obtained from commercial
OH
(1) H2, Pd/C, EtOH, rt, 15 h, 79%;
H
H
H
H2, Pd/C, EtOH,
rt, 1 h, 95%
(2) Li, NH3, -78 °C, 1h;
H
(3) CH2O, NaBH(OAc)3, rt, 15 h, 36%
N
N
N
Ts
39
Me
40
Ts
36
Scheme 5. Synthesis of (ꢀ)-40.

Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
8263
sources and were used without additional purification. N-Methyl-
morpholine N-oxide (NMO) was used as its monohydrate. 1H and
13C NMR spectra were referenced to either residual (CHCl3, dH
7.27 ppm; CDCl3, dC 77.0 ppm), or internal trimethylsilane (TMS, dH
0.00 ppm). Spectral assignments reported were based on DEPT and
2D correlation spectroscopy. Optical rotation measurements,
recorded in spectrophotometric grade chloroform, were performed
2.5 equiv). Stirring was continued for 2.5 h at room temperature.
TLC analysis indicated the consumption of starting material. Solvent
was removed under reduced pressure and the residue purified by
rapid flash column chromatography (Hex–EtOAc; 5:1). Thus the
aldehyde 15 (1.14 g, 90%) was obtained as a colourless viscous oil
and was used immediately in the following step; Rf¼0.35 (Hex–
EtOAc; 3:1); dH (400 MHz, CDCl3) 1.22 (3H, d, J 7.0 Hz, CH3),1.32 (9H,
s, CH3), 2.45 (3H, s, CH3), 2.89–2.95 (1H, m, CH), 3.95 (1H, dd, J 7.0,
15.0 Hz, CH2), 4.16 (1H, dd, J 7.0, 15.0 Hz, CH2), 7.32 (2H, d, J 8.0 Hz,
ArH), 7.78 (2H, d, J 8.0 Hz, ArH) and 9.71 (1H, d, J 2.5 Hz, CHO); dC
(100 MHz, CDCl3) 11.6 (CH3), 21.6 (CH3), 27.7 (CH3), 47.1 (CH), 47.2
(CH2), 84.9 (C), 127.9 (CH), 129.4 (CH), 136.9 (C), 144.6 (C), 150.9 (C)
and 202.7 (CH) ppm; nmax (film) 3419, 2982, 2938, 1730, 1598, 1496,
1458, 1395, 1369, 1355, 1292, 1257, 1179, 1149 and 1088 cmꢀ1; m/z
C16H23NO5SNa requires 364.1204 (MNaþ, 100%); found 364.1195
(þ2.6 ppm).
at 20 ꢁC and are given in units of deg cm2 gꢀ1
.
3.2. (D)-Methyl 3-[N-(tert-butoxycarbonyl)-N-(4-
methylphenylsulfamido)]-2S-methyl propanoate 1227
Under N2 S-11 (1.00 cm3, 9.08 mmol, 2 equiv) was added to a so-
lution of N-(tert-butyoxycarbonyl)-p-toluenesulfonamide (1.23 g,
4.54 mmol, 1 equiv), triphenylphosphine (1.78 g, 6.81 mmol,
1.5 equiv) and diisopropylazodicarboxylate (1.43 cm3, 7.26 mmol,
1.6 equiv) in THF (100 cm3) in a dropwise fashion at 0 ꢁC. The re-
action mixture was then stirred at room temperature for 15 h. The
solvent was removed under reduced pressure. Hexane (100 cm3)
was added to the resultant yellow mixture and a white solid
precipitate removed by filtration. The remaining solution was pre-
absorbed on silica gel (ca. 15 g) and purified by flash column chro-
matography (Hex–EtOAc; 9:1/3:1) affording the product 12 as
3.5. (D)-tert-Butyl N-(2R-methylbut-3-enyl)-N-(toluene-4-
sulfonyl)carbamate 16
Under N2 a slurry of Ph3PCH3Br (1.76 g, 4.92 mmol, 1.5 equiv) in
THF (30 cm3) was treated with a 0.5 M solution of KHMDS in tol-
uene (8.2 cm3, 4.10 mmol,1.25 equiv) at ꢀ78 ꢁC. The yellow/orange
solution was warmed to room temperature over 1 h before re-
cooling to ꢀ78 ꢁC and addition of the aldehyde 15 (1.12 g,
3.28 mmol, 1 equiv) in THF (10 cm3). Stirring was continued for
0.5 h at ꢀ78 ꢁC before warming to room temperature over 1 h.
Saturated NH4Cl (50 cm3) was added and the mixture was extrac-
ted with ether (3ꢃ50 cm3). The combined organic extracts were
dried over MgSO4 followed by filtration, solvent removal under
reduced pressure and purification by flash column chromatogra-
phy (Hex–EtOAc; 5:1). Thus, the alkene 16 (630 mg, 56%) was iso-
a colourless solid (1.59 g, 94%); mp¼64–66 ꢁC; Rf¼0.35 (Hex–EtOAc;
20
3:1); [
a
]
þ24.0 (c 0.36, CHCl3); dH (400 MHz, CDCl3) 1.27 (3H, d, J
D
7.5 Hz, CH3),1.34 (9H, s, CH3), 2.46 (3H, s, CH3), 2.99–3.08 (1H, m, CH),
3.70 (3H, s, CH3), 3.94 (1H, dd, J 7.5, 14.5 Hz, CH2), 4.11 (1H, dd, J 7.5,
14.5 Hz, CH2), 7.32 (2H, d, J 8.5 Hz, ArH) and 7.81 (2H, d, J 8.5 Hz, ArH)
ppm; dC (100 MHz, CDCl3) 14.6 (CH3), 21.6 (CH3), 27.8 (CH3), 39.8
(CH), 49.1 (CH2), 51.8 (CH3), 84.5 (C), 127.9 (CH), 129.2 (CH), 137.1 (C),
144.2 (C), 150.9 (C) and 174.7 (C) ppm; nmax (film) 2980, 2926, 2853,
1732, 1597, 1496, 1458, 1435, 1358, 1292, 1256, 1170, 1148 and
1088 cmꢀ1; m/z C17H25NO6SNa requires 394.1315 (MNaþ, 100%);
found 394.1300 (þ3.7 ppm); CHN analysis: C17H25NO6S requires C
54.99%, H 6.74%, N 3.77%; found C 55.04%, H 6.77%, N 3.76%.
lated as a viscous, slightly yellow oil; Rf¼0.35 (Hex–EtOAc; 5:1);
20
[
a
]
þ7.6 (c 0.95, CHCl3); dH (400 MHz, CDCl3) 1.08 (3H, d, J 6.5 Hz,
D
CH3), 1.34 (9H, s, CH3), 2.43 (3H, s, CH3), 2.69–2.77 (1H, m, CH),
3.73–3.84 (2H, m, CH2), 5.02–5.11 (2H, m, CH2), 5.70–5.79 (1H, m,
CH), 7.31 (2H, d, J 8.0 Hz, ArH) and 7.80 (2H, d, J 8.0 Hz, ArH) ppm; dC
(100 MHz, CDCl3) 16.9 (CH3), 21.1 (CH3), 27.4 (CH3), 38.3 (CH), 51.5
(CH2), 83.6 (C), 114.9 (CH2), 127.5 (CH), 128.6 (CH), 137.1 (C), 140.3
(CH), 143.5 (C) and 150.6 (C) ppm; nmax (film) 3079, 2978, 2932,
1723, 1643, 1598, 1456, 1421, 1367, 1356, 1157 and 1088 cmꢀ1; m/z
C17H25NO4SNa requires 362.1408 (MNaþ, 100%); found 362.1402
(þ1.7 ppm).
3.3. (D)-tert-Butyl N-(3-hydroxy-2S-methylpropyl)-N-
(toluene-4-sulfonyl)carbamate 1327
Under N2 a solution of 12 (6.186 g, 16.67 mmol, 1 equiv), in THF
(150 cm3), at ꢀ78 ꢁC was treated with solid LiAlH4 (2.53 g,
66.6 mmol, 4 equiv) in one portion. Stirring was continued for
10 min before TLC analysis indicated consumption of the starting
material. Saturated aqueous NH4Cl (100 cm3) was cautiously added
at ꢀ78 ꢁC. The mixture was stirred at room temperature before
extraction with ether (4ꢃ50 cm3). The combined organic extracts
were dried over MgSO4, filtered and the solvent was removed un-
der reduced pressure. Purification by flash column chromatography
3.6. (L)-4-Methyl-N-(2R-methylbut-3-
enyl)benzenesulfonamide 1727
At room temperature a solution of the alkene 16 (428 mg,
1.31 mmol, 1 equiv) in dichloromethane (20 cm3) was treated with
TFA (1.01 cm3, 13.11 mmol, 10 equiv) in a dropwise fashion. Stirring
was continued for 1 h before a saturated solution of NaHCO3
(50 cm3) was added. Extraction with ether (3ꢃ50 cm3) and drying
of the combined organic extracts over MgSO4, filtration and solvent
removal in vacuo gave the crude product. Purification by flash
(Hex–EtOAc; 3:1) afforded the alcohol 13 as a colourless oil (5.71 g,
20
100%); Rf¼0.20 (Hex–EtOAc; 3:1); [
a
]
þ6.4 (c 1.5, CHCl3); dH
D
(400 MHz, CDCl3) 1.04 (3H, d, J 7.0 Hz, CH3), 1.32 (9H, s, CH3), 2.08–
2.21 (1H, m, CH), 2.46 (3H, s, CH3), 2.57 (1H, s(br), OH), 3.52 (1H, dd,
J 4.0, 11.5 Hz, CH2), 3.73 (1H, dd, J 4.0, 11.5 Hz, CH2), 3.77 (1H, dd, J
5.5, 15.0 Hz, CH2), 3.88 (1H, dd, J 9.5, 15.0 Hz, CH2), 7.35 (2H, d, J
8.0 Hz, ArH) and 7.77 (2H, d, J 8.0 Hz, ArH) ppm; dC (100 MHz,
CDCl3) 14.6 (CH3), 21.6 (CH3), 27.8 (CH3), 36.4 (CH), 49.1 (CH2), 63.5
(CH2), 85.0 (C), 127.7 (CH), 129.3 (CH), 137.1 (C), 144.4 (C) and 152.0
(C) ppm; nmax (film) 3543, 3429, 2978, 2878, 1726, 1597, 1456, 1354,
1290, 1257, 1154 and 1088 cmꢀ1; m/z C16H25NO5SNa requires
366.1359 (MNaþ, 100%); found 366.1310 (þ2.1 ppm).
column chromatography (Hex–EtOAc; 5:1) gave 17 as a colourless
20
viscous oil (287 mg, 97%); Rf¼0.15 (Hex–EtOAc; 5:1); [
a]
ꢀ2.3 (c
D
0.258, CHCl3); dH (400 MHz, CDCl3) 0.98 (3H, d, J 6.5 Hz, CH3), 2.25–
2.32 (1H, m, CH), 2.45 (3H, s, CH3), 2.72–2.77 (1H, m, CH2), 2.94–
3.01 (1H, m, CH2), 4.44 (1H, t, J 5.0 Hz, NH), 5.01–5.05 (2H, m CH2),
5.48–5.57 (1H, m, CH), 7.33 (2H, d, J 8.0 Hz, ArH) and 7.75 (2H, d, J
8.0 Hz, ArH) ppm; dC (100 MHz, CDCl3) 17.1 (CH3), 21.1 (CH3), 37.5
(CH), 47.5 (CH2), 116.0 (CH2), 126.7 (CH), 129.3 (CH), 136.5 (C), 139.9
(CH) and 143.1 (C) ppm; nmax (film) 3340, 3293, 3109, 2971, 2928,
2872, 1642, 1453, 1423, 1324, 1306, 1289, 1160 and 1093 cmꢀ1; m/z
C12H18NO2S requires 240.1054 (MHþ, 100%); found 240.1058
(ꢀ1.8 ppm).
3.4. (D)-tert-Butyl N-(2S-methyl-3-oxopropyl)-3-(toluene-4-
sulfonyl)carbamate 15
A solution of the alcohol 13 (1.28 g, 3.73 mmol, 1 equiv) in
dichloromethane (60 cm3) was treated with PCC (2.00 g, 9.33 mmol,

8264
Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
3.7. (D)-N-But-2-ynyl-4-methyl-N-(2R-methylbut-3-
enyl)benzenesulfonamide 10
1159 cmꢀ1; m/z C17H20NO3S requires 318.1164 (MꢀHþ,100%); found
318.1176 (þ3.8 ppm).
At room temperature a solution of the alkene 17 (435 mg,
1.91 mmol,1 equiv) inDMSO(40 cm3) wastreated with60% w/w NaH
in mineral oil (115 mg, 2.87 mmol,1.5 equiv). The mixture was stirred
for 0.5 h before 1-bromobut-2-yne (0.34 cm3, 3.83 mmol, 2 equiv)
was added dropwise. After stirring for 1 h the mixture was extracted
with ether (4ꢃ50 cm3). The combined organic extracts were dried
over MgSO4, filtered and the solvent was removed in vacuo. Purifi-
cation by flash column chromatography (Hex–EtOAc; 9:1/Hex–
3.9. (D)-trans-tert-Butyl N-(2R-methyl-4-
(phenylsulfonyl)but-3-enyl)-N-(toluene-4-sulfonyl)
carbamate 21
Solid 60% w/w NaH in mineral oil (100 mg; 2.52 mmol, 1.1 equiv)
was added portionwise to a solution of phosphonate ester 2028
(770 mg, 2.52 mmol, 1.1 equiv) in THF (100 cm3) at 0 ꢁC. After 0.5 h
aldehyde 15 (782 mg, 2.29 mmol, 1 equiv) was added at ambient
temperature. After stirring for 1 h a saturated solution of NH4Cl
(50 cm3) was added, and the mixture was extracted with ether
(4ꢃ50 cm3). The combined organic extracts were dried over MgSO4,
filtered and the solvent was removed in vacuo. Purification by flash
column chromatography (cyclohexane–EtOAc; 1:1) afforded 21
EtOAc; 1:1) afforded 10 (470 mg, 84%) as a colourless oil; Rf¼0.35
20
(Hex–EtOAc; 5:1); [
a
]
þ6.8 (c 0.302, CHCl3); dH (400 MHz, CDCl3)
D
1.05 (3H, d, J 6.5 Hz, CH3), 1.53 (3H, t, J 1.5 Hz, CH3), 2.42 (3H, s, CH3),
2.45–2.52 (1H, m, CH), 3.00–3.10 (2H, m, CH2), 4.00–4.12 (2H, m, CH2),
5.02–5.11 (2H, m, CH2), 5.70–5.79 (1H, m, CH), 7.29 (2H, d, J 8.0 Hz,
ArH) and 7.73 (2H, d, J 8.0 Hz, ArH) ppm; dC (100 MHz, CDCl3) 3.1
(CH3),17.4 (CH3), 21.4 (CH3), 36.0 (CH), 37.1 (CH2), 51.4 (CH2), 71.5 (C),
81.5 (C), 114.8 (CH2), 127.7 (CH), 129.1 (CH), 136.0 (C), 140.9 (CH) and
143.0 (C) ppm; nmax (film) 3095, 2972, 2921, 2868, 2224, 1598, 1495,
1346, 1331, 1306, 1183, 1158, 1118 and 1090 cmꢀ1; m/z C16H22NO2S
requires 292.1371 (MHþ, 100%); found 292.1371 (ꢀ0.2 ppm).
(743 mg, 68%) as a colourless oil; Rf¼0.40 (cyclohexane–EtOAc; 3:1);
20
[a]
¼þ17 (c 0.511, CHCl3); dH (500 MHz, CDCl3) 1.07 (3H, d, J 6.5 Hz,
D
CH3),1.25 (9H, s, CH3), 2.35 (3H, s, CH3), 2.82–2.87 (1H, m, CH), 3.72–
3.82 (2H, m, CH2), 6.30 (1H, dd, J 1.0, 15.0 Hz, CH), 6.87 (1H, dd, J 8.0
and 15.0 Hz, CH), 7.21 (2H, d, J 8.0 Hz, ArH), 7.43–7.47 (2H, m, ArH),
7.52–7.35 (1H, m ArH), 7.67 (2H, d, J 8.0 Hz, ArH) and 7.81–7.83 (2H,
m, ArH) ppm; dC (125 MHz, CDCl3) 16.6 (CH3), 21.6 (CH3), 27.8 (CH3),
37.1 (CH), 50.9 (CH2), 84.0 (C),127.7 (CH),127.8 (CH),129.2 (CH),129.3
(CH), 130.9 (CH), 133.3 (CH), 137.1 (C), 140.4 (C), 144.4 (CH), 147.9 (C)
and 150.9 (C); nmax (film) 3060, 2980, 2933, 1729, 1598, 1626, 1447,
1355, 1317, 1147, 1086 and 1008 cmꢀ1; m/z C23H29NO6SNa requires
502.1334 (MNaþ, 100%); found 502.1317 (ꢀ3.4 ppm).
3.8. (L)-(4R,4aR)-4,7-Dimethyl-2-(toluene-4-sulfonyl)-
1,2,3,4,4a,5-hexahydro[2]pyrindin-6-one 9a and (D)-(4R,4aS)-
4,7-dimethyl-2-(toluene-4-sulfonyl)-1,2,3,4,4a,5-
hexahydro[2]pyrindin-6-one 9b
At room temperature a solution of the enyne 10 (215 mg,
0.739 mmol, 1 equiv) in dichloromethane (25 cm3, 0.03 M) was
degassed with a steady stream of N2 for approximately 0.5 h.
Co2(CO)8 (316 mg, 0.924 mmol, 1.25 equiv) was added in one por-
tion. Stirring was continued for 1 h before TLC analysis indicated the
formation of the cobalt complex [brown spot; Rf¼0.45 (Hex–EtOAc;
5:1)]. The solution was cooled to 0 ꢁC before NMO$H2O (435 mg,
3.22 mmol, 4.5 equiv) was added in one portion. Stirring was con-
tinued at 0 ꢁC to room temperature over 2 h. TLC analysis indicated
the formation of a more polar spot. Silica (ca. 5 g) was added and the
solvent was removed under reduced pressure. The residue was
purified by flash column chromatography (Hex–EtOAc; 3:1/1:1).
Thus, the title compound 9a (188 mg, 80%) was isolated as a col-
ourless solid; crystals were formed from evaporation of a saturated
3.10. (D)-trans-N-(4-Benzenesulfonyl-2R-methylbut-3-enyl)-
4-methylbenzene sulfonamide 22
At room temperature a solution of the alkene 21 (3.34 g,
6.99 mmol,1 equiv) in dichloromethane (110 cm3) was treated with
TFA (5.35 cm3, 69.9 mmol, 10 equiv) in a dropwise fashion. Stirring
was continued for 6 h before a saturated solution of NaHCO3
(150 cm3) was added. Extraction with ether (3ꢃ100 cm3) and dry-
ing of the combined organic extracts over MgSO4, filtration and
solvent removal in vacuo gave the crude product. Purification by
flash column chromatography (cyclohexane–EtOAc; 3:1) gave 22 as
a colourless viscous oil (2.65 g; 98%); Rf¼0.25 (cyclohexane–EtOAc;
20
3:1); [
a
]
þ8.9 (c 0.725, CHCl3); dH (500 MHz, CDCl3) 1.05 (3H, d, J
D
solution of 9a in dichloromethane; mp¼120 ꢁC (CH2Cl2); Rf¼0.40
7.0 Hz, CH3), 2.43 (3H, s, CH3), 2.53–2.62 (1H, m, CH), 2.89–3.02 (2H,
m, CH2), 4.83 (1H, t, J 7.0 Hz, NH), 6.29 (1H, dd, J 1.5, 15.0 Hz, CH),
6.83 (1H, dd, J 7.0,15.0 Hz, CH), 7.30 (2H, d, J 8.0 Hz, ArH), 7.56 (2H, t,
J 7.5 Hz, ArH), 7.62–7.65 (1H, m, ArH), 7.72 (2H, d, J 8.0 Hz, ArH) and
7.88 (2H, d, J 7.5 Hz, ArH) ppm; dC (125 MHz, CDCl3) 16.4 (CH3), 21.5
(CH3), 36.4 (CH), 47.4 (CH2), 127.0 (CH), 127.6 (CH), 129.4 (CH), 129.3
(CH), 131.4 (CH), 133.5 (CH), 136.8 (C), 140.8 (C), 143.6 (C) and 147.5
(CH) ppm; nmax (film) 3277, 2969, 2926, 2360, 1736, 1625, 1446,
1320, 1306, 1299, 1146 and 1086 cmꢀ1; m/z C18H20NO4S2 requires
378.0829 (MꢀHþ, 100%); found 378.0834 (ꢀ1.3 ppm).
20
(Hex–EtOAc; 1:1); [
a]
ꢀ74.2 (c 0.225, CHCl3); dH (400 MHz, CDCl3)
D
0.97 (3H, d, J 6.5 Hz, 4-CH3), 1.49–1.53 (1H, m, 4-CH), 1.74 (3H, d, J
1.0 Hz, 7-CH3), 1.99 (1H, d, J 18.5 Hz, 5-CH2), 2.08–2.13 (1H, m(br),
4a-CH), 2.19 (1H, dd (app. t), J 12.0 Hz, 3-CH2), 2.45 (3H, s, CH3), 2.55
(1H, dd, J 6.5,18.5 Hz, 5-CH2), 3.07 (1H, d, J 13.5 Hz,1-CH2), 3.85 (1H,
ddd, J 2.0, 3.5,12.0 Hz, 3-CH2), 4.76 (1H, d, J 13.5 Hz,1-CH2), 7.36 (2H,
d, J 8.0 Hz, ArH), 7.71 and (2H, d, J 8.0 Hz, ArH) ppm; dC (100 MHz,
CDCl3) 7.9 (CH3), 17.3 (CH3), 21.5 (CH3), 37.7 (CH), 38.9 (CH2), 44.8
(CH), 45.2 (CH2), 52.2 (CH2), 127.6 (CH), 129.8 (CH), 132.9 (C), 135.6
(C), 144.8 (C), 163.3 (C) and 205.1 (C) ppm; nmax (film) 3042, 2960,
2925, 1705, 1666, 1597, 1457, 1344 and 1169 cmꢀ1; m/z C17H22NO3S
requires 320.1331 (MHþ, 100%); found 320.1320 (þ3.3 ppm). The
3.11. (D)-trans-N-(4-Benzenesulfonyl-2R-methylbut-3-enyl)-
N-(but-2-ynyl)-4-methyl benzenesulfonamide 23
other diastereoisomer 9b was also isolated (25 mg,10%) as a viscous
20
oil; Rf¼0.30 (Hex–EtOAc; 1:1); [
a
]
þ49.8 (c 1.016, CHCl3); dH
At 0 ꢁC a solution of the alkene 22 (42 mg, 0.11 mmol, 1 equiv) in
DMSO (6 cm3) was treated with 60% w/w NaH in mineral oil (4 mg,
0.11 mmol, 1 equiv). The mixture was stirred for 0.5 h before
1-bromobut-2-yne (0.02 cm3, 0.22 mmol, 2 equiv) was added
dropwise. After stirring for 1.5 h the mixture was extracted with
ether (3ꢃ20 cm3). The combined organic extracts were dried over
MgSO4, filtered and the solvent was removed in vacuo. Purification
by flash column chromatography (cyclohexane/cyclohexane–
D
(400 MHz, CDCl3) 0.84 (3H, d, J 6.5 Hz, 4-CH3), 1.74 (3H, s, 7-CH3),
2.13–2.21 (2H, m, 4-CH, 5-CH2), 2.34 (1H, d, J 6.5 Hz, 5-CH2), 2.44
(3H, s, CH3), 2.63 (1H, dd, J 2.5, 12.0 Hz, 3-CH2), 2.72 (1H, s(br), 4a-
CH), 3.05 (1H, d, J 13.5,1-CH2), 3.74 (1H, d, J 12.0, 3-CH2), 4.69 (1H, d,
J 13.5, 1-CH2), 7.35 (2H, d, J 8.0 Hz, ArH), and 7.68 (2H, d, J 8.0 Hz,
ArH) ppm; dC (100 MHz, CDCl3) 7.8 (CH3),10.7 (CH3), 21.5 (CH3), 31.2
(CH), 36.7 (CH2), 41.5 (CH), 45.7 (CH2), 52.1 (CH2), 127.6 (CH), 129.8
(CH),132.7 (C),136.8 (C), 143.9 (C),161.6 (C) and 208.2 (C) ppm; nmax
(film) 3020, 2966, 2924, 1702, 1634, 1597, 1454, 1344, 1305 and
EtOAc; 1:1) afforded 23 (27 mg, 57%) as a colourless oil; Rf¼0.50
20
(cyclohexane–EtOAc; 1:1); [
a
]
þ2.35 (c 1.70, CHCl3); dH (400 MHz,
D

Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
8265
CDCl3) 1.10 (3H, d, J 7.0 Hz, CH3), 1.53 (3H, t, J 2.5 Hz, CH3), 2.41 (3H,
s, CH3), 2.71–2.78 (1H, m, CH), 3.05–3.16 (2H, m, CH2), 3.89–3.93
(2H, m, CH2), 6.36 (1H, dd, J 1.5, 15.0 Hz, CH), 6.94 (1H, dd, J 7.5,
15.0 Hz, CH), 7.28 (2H, d, J 8.0 Hz, ArH), 7.52–7.55 (2H, m, ArH),
7.59–7.63 (1H, m, ArH), 7.67 (2H, d, J 8.0 Hz, ArH) and 7.89 (2H, d, J
7.0 Hz, ArH) ppm; dC (100 MHz, CDCl3) 3.2 (CH3), 16.4 (CH3), 21.4
(CH3), 35.1 (CH), 37.9 (CH2), 50.9 (CH2), 71.2 (C), 82.2 (C), 127.6 (CH),
127.7 (CH),129.2 (CH),129.3 (CH),130.8 (CH),133.3 (CH),135.5 (CH),
140.2 (C), 143.5 (C) and 148.3 (C) ppm; nmax (film) 3405, 3058, 2967,
2921, 1626, 1598, 1446, 1347, 1318, 1161, 1087 and 1024 cmꢀ1; m/z
C22H26NO4S2 requires 432.1305 (MHþ, 100%); found 432.1318
(þ3.4 ppm).
20.5 mmol, 1.1 equiv) in THF (250 cm3) in a dropwise fashion at 0 ꢁC.
The reaction mixture was then stirred at room temperature for 15 h.
The solvent was removed under reduced pressure. Cyclohexane
(100 cm3) was added to the resultant yellow mixture and the white
precipitate was filtered. The remaining solution was pre-absorbed on
silica gel (ca. 15 g) and purified by flash column chromatography
(cyclohexane/cyclohexane–EtOAc; 3:1) affording the product 26 as
a white solid (6.02 g, 100%); mp¼103 ꢁC; Rf¼0.40 (cyclohexane–
EtOAc; 3:1); dH (500 MHz, CDCl3) 1.31 (9H, s, CH3), 2.35 (3H, t, J 2.5 Hz,
CH3), 2.41 (3H, s, CH3), 4.54 (2H, q, J 2.5 Hz, CH2), 7.27 (2H, d, J 8.0 Hz,
ArH) and 7.87 (2H, d, J 8.0 Hz, ArH) ppm; dC (125 MHz, CDCl3) 3.3
(CH3), 21.4 (CH3), 27.7 (CH3), 36.1 (CH2), 74.2 (C), 79.8 (C), 84.5 (C),
128.1 (CH), 128.9 (CH), 136.8 (C), 144.1 (C) and 150.2 (C) ppm; nmax
(film) 3035, 2982, 2923, 2233,1919,1729,1598,1496,1457,1359,1313,
1280, 1246, 1173, 1089 and 1067 cmꢀ1; m/z C16H22NO4S requires
324.1270 (MHþ, 100%); found 324.1285 (þ4.8 ppm).
3.12. (L)-(4R,4aR,5S)-5-Benzenesulfonyl-4,7-dimethyl-2-
(toluene-4-sulfonyl)-1,2,3,4,4a,5-hexahydro[2]pyrindin-
6-one 24
At room temperature a solution of the enyne 23 (666 mg,
1.54 mmol, 1 equiv) in dichloromethane (200 cm3) was degassed
with a steady stream of N2 for approximately 0.5 h. Co2(CO)8
(792 mg, 2.31 mmol, 1.5 equiv) was then added in one portion.
Stirring was continued for 1 h before TLC analysis indicated the
formation of the cobalt complex [brown spot; Rf¼0.80 (cyclohex-
ane–EtOAc; 1:1)]. The solution was cooled to 0 ꢁC before NMO$H2O
(903 mg, 6.69 mmol, 4.5 equiv) was added in one portion. The re-
action was stirred from 0 ꢁC to room temperature over 15 h. TLC
analysis indicated the formation of a more polar spot. Silica (ca. 7 g)
was added the solvent removed under reduced pressure and the
residue purified by flash column chromatography (cyclohexane/
cyclohexane–EtOAc; 1:1). Thus, the title compound 24 (518 mg,
3.15. N-But-2-ynyl-4-methylbenzenesulfonamide 27
At room temperature a solution of the alkyne 26 (1.65 g,
5.09 mmol, 1 equiv) in dichloromethane (100 cm3) was treated
with TFA (3.9 cm3, 50.9 mmol, 10 equiv) in a dropwise fashion.
Stirring was continued for 6 h before a saturated solution of
NaHCO3 (100 cm3) was added. Extraction with ether (3ꢃ75 cm3)
and drying of the combined organic extracts over MgSO4, filtration
and solvent removal in vacuo gave the crude product. Purification
by flash column chromatography (cyclohexane–EtOAc; 3:1) gave 27
as a colourless solid (1.07 g; 95%); mp¼61 ꢁC; Rf¼0.35 (cyclohex-
ane–EtOAc; 3:1); dH (500 MHz, CDCl3) 1.47 (3H, t, J 2.5 Hz, CH3),
2.32 (3H, s, CH3), 3.64–3.67 (2H, m, CH2), 5.11 (1H, t, J 5.5 Hz, NH),
7.20 (2H, d, J 8.5 Hz, ArH) and 7.69 (2H, d, J 8.5 Hz, ArH) ppm; dC
(125 MHz, CDCl3) 3.0 (CH3), 21.2 (CH3), 33.1 (CH2), 73.2 (C), 80.7 (C),
127.2 (CH), 129.3 (CH), 136.7 (C) and 143.3 (C) ppm; nmax (film)
3258, 3063, 2954, 2919, 2851, 2299, 2228, 1598, 1494, 1325, 1245,
1160, 1092 and 1046 cmꢀ1; m/z C11H14NO2S requires 224.1745
(MHþ, 100%); found 224.0751 (þ0.6 ppm).
73%) was isolated as a colourless solid; mp¼87 ꢁC; Rf¼0.60 (cy-
20
clohexane–EtOAc; 1:1); [
a]
ꢀ33.6 (c 1.15, CHCl3); dH (500 MHz,
D
CDCl3) 1.13 (3H, d, J 7.0 Hz, 4-CH3),1.57–1.64 (1H, m, 4-CH),1.74 (3H,
s, 7-CH3), 2.31 (1H, t, J 12.0 Hz, 3-CH2), 2.46 (3H, s, CH3), 2.86 (1H, d,
J 11.0 Hz, 4a-CH), 3.13 (1H, d, J 13.5 Hz, 1-CH2), 3.61 (1H, d, J 2.0 Hz,
5-CH), 3.87–3.90 (1H, m, 3-CH2), 4.74 (1H, d, J 13.5 Hz, 1-CH2), 7.36
(2H, d, J 8.0 Hz, ArH), 7.57 (2H, t, J, 8.0 Hz, ArH), 7.69 (3H, d, J 8.0 Hz,
ArH) and 7.85 (2H, d, J 8.0 Hz, ArH) ppm; dC (125 MHz, CDCl3) 8.3
(CH3), 17.4 (CH3), 21.6 (CH3), 37.8 (CH), 45.3 (CH2), 45.6 (CH), 52.4
(CH2), 70.1 (CH), 127.6 (CH), 129.0 (CH), 129.3 (CH), 129.9 (CH), 132.9
(C), 134.3 (CH), 135.5 (C), 137.6 (C), 144.3 (C), 163.6 (C) and 195.9 (C)
ppm; nmax (film) 3026, 2964, 2927, 2360, 1715, 1665, 1598, 1448,
1387, 1346, 1309, 1163, 1008 and 1001 cmꢀ1; m/z C23H25NO5S2 re-
quires 460.1252 (MHþ, 100%); found 460.1233 (ꢀ4.2 ppm).
3.16. N-But-3-enyl-N-but-2-ynyl-4-methylbenzene-
sulfonamide 28
Under N2 a solution of the alkyne 27 (1.16 g, 5.20 mmol, 1 equiv)
in DMSO (70 cm3) was treated with 60% w/w NaH in mineral oil
(260 mg, 6.50 mmol, 1.25 equiv) at ambient temperature. The
mixture was stirred for 0.5 h before 4-bromobut-1-ene (0.79 cm3,
7.80 mmol, 1.5 equiv) was added dropwise. After stirring for 15 h
saturated aqueous NH4Cl (100 cm3) was added. The mixture was
extracted with ether (4ꢃ75 cm3). The combined organic extracts
were dried over MgSO4, filtered and the solvent was removed in
vacuo. Purification by flash column chromatography (cyclohex-
ane/cyclohexane–EtOAc; 3:1) afforded 28 (1.01 g, 70%) as a col-
ourless oil; Rf¼0.60 (cyclohexane–EtOAc; 3:1); dH (500 MHz, CDCl3)
1.55 (3H, t, J 2.5 Hz, CH3), 2.30–2.35 (2H, m, CH2), 2.41 (3H, s, CH3),
3.23 (2H, t, J 7.5 Hz, CH2), 4.05–4.06 (2H, m, CH2), 5.03–5.12 (2H, m,
CH2), 5.73–5.81 (1H, m, CH), 7.28 (2H, d, J 8.0 Hz, ArH) and 7.22 (2H,
d, J 8.0 Hz, ArH) ppm; dC (125 MHz, CDCl3) 3.1 (CH3), 21.4 (CH3), 32.2
(CH2), 36.8 (CH2), 45.7 (CH2), 71.7 (C), 81.4 (C), 116.9 (CH2), 127.7
(CH), 129.2 (CH), 134.6 (C), 136.1 (C) and 143.1 (CH) ppm; nmax (film)
3077, 2978, 2921, 2867, 2298, 2224, 1920, 1642, 1598, 1495, 1455,
1325, 1288, 1233, 1170, 1092 and 1046 cmꢀ1; m/z C15H20NO2S re-
quires 278.1215 (MHþ, 100%); found 278.1210 (ꢀ1.7 ppm).
3.13. (D)-(4R,4aR)-4,7-Dimethyl-2-(toluene-4-sulfonyl)-
1,2,3,4,4a,5-hexahydro[2]pyrindin-6-one 9a
A solution of the enone 24 (49 mg, 0.106 mmol, 1 equiv) in THF
(5 cm3) was degassed under a steady stream of N2 for 10 min. A
0.1 M solution of SmI2 in hexanes (2.24 cm3, 0.224 mmol, 2.1 equiv)
was added dropwise at 0 ꢁC. After stirring for 1 h, NaHCO3 (10 cm3)
was added and the mixture extracted with diethyl ether
(3ꢃ10 cm3). The extract was dried over MgSO4, filtered and solvent
removed under reduced pressure. Purification by flash column
chromatography (cyclohexane/cyclohexane–EtOAc; 1:1) yielded
9a as a colourless solid (27 mg, 79%) whose data was in agreement
with that described above.
3.14. tert-Butyl N-but-2-ynyl(toluene-4-sulfonyl)-
carbamate 26
3.17. ( )-7-Methyl-2-(toluene-4-sulfonyl)-1,2,3,4,4a,5-
hexahydro-[2]pyrindin-6-one 29
Under N2, diisopropylazodicarboxylate (4.40 cm3, 22.3 mmol,
1.2 equiv) was added to a solution of N-(tert-butyoxycarbonyl)-p-
toluenesulfonamide (5.06 g,18.6 mmol,1 equiv), triphenylphosphine
(5.86 g, 22.3 mmol, 1.2 equiv) and 2-butyn-1-ol 25 (1.53 cm3,
At room temperature a solution of the enyne 28 (824 mg,
2.97 mmol, 1 equiv) in dichloromethane (100 cm3, 0.029 M) was

8266
Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
degassed with a steady stream of N2 for approximately 0.5 h.
Co2(CO)8 (1.52 g, 4.45 mmol, 1.5 equiv) was added in one portion.
Stirring was continued for 1.5 h before TLC analysis indicated the
formation of the cobalt complex [brown spot; Rf¼0.9 (cyclohexane–
EtOAc; 1:1)]. The solution was cooled to 0 ꢁC before NMO$H2O
(2.60 g, 19.26 mmol, 6.5 equiv) was added in two portions. Stirring
was continued at 0 ꢁC to room temperature overnight. Silica (ca.
12 g) was added, the solvent was removed under reduced pressure
and the residue purified by flash column chromatography (cyclo-
hexane–EtOAc; 1:1) to afford the colourless solid 29 (790 mg, 87%);
mp¼116 ꢁC; Rf¼0.35 (cyclohexane–EtOAc; 1:1); dH (400 MHz,
CDCl3) 1.32–1.43 (1H, m, 4-CH2), 1.74 (3H, s, 7-CH3), 1.95 (1H, d, J
16.5 Hz, 5-CH2), 2.10 (1H, d(br), J 15.0 Hz, 4-CH2), 2.45 (3H, s, CH3),
2.53–2.59 (3H, m, 3-CH2, 4a-CH2, 5-CH2), 3.13 (1H, d, J 13.5 Hz, 1-
CH2), 3.93 (1H, d, J 12.0 Hz, 3-CH2), 4.75 (1H, d, J 13.5 Hz, 1-CH2),
7.37 (2H, d, J 8.0 Hz, ArH) and 7.68 (2H, d, J 8.0 Hz, ArH) ppm; dC
(100 MHz, CDCl3) 7.6 (CH3), 21.3 (CH3), 31.8 (CH2), 37.3 (CH2), 40.1
(CH), 45.5 (CH2), 45.7 (CH2), 127.4 (CH), 129.6 (CH), 132.8 (C), 135.4
(C), 143.8 (C), 163.6 (C) and 207.4 (C) ppm; nmax (film) 3064, 2956,
2923, 2847, 1712, 1629, 1598, 1494, 1464, 1410, 1342, 1228, 1199,
1164, 1103 and 1004 cmꢀ1; m/z C16H20NO3S requires 306.1164
(MHþ, 100%); found 306.1159 (ꢀ1.6 ppm).
2857, 2360, 1727, 1638, 1598, 1531, 1464, 1342, 1267, 1161, 1094 and
1025 cmꢀ1; m/z C16H24NO3S requires 310.1477 (MHþ, 100%); found
310.1470 (ꢀ2.2 ppm). The other diastereoisomer 31a was isolated
as a colourless oil (30 mg, 21%); Rf¼0.25 (cyclohexane–EtOAc; 1:1);
dH (400 MHz, CDCl3) 1.02 (3H, d, J 7.5 Hz, CH3), 1.51–1.59 (2H, m, 4-
CH2, 5-CH2), 1.79–1.98 (4H, m, 1-CH2, 4-CH2, 5-CH2, 7-CH), 2.17–
2.23 (1H, m, 7a-CH), 2.38–2.41 (2H, m, 3-CH2, 4a-CH), 2.44 (3H, s,
CH3), 3.46–3.54 (2H, m, 1-CH2, 3-CH2), 3.81–3.86 (1H, m, 6-CH),
7.34 (2H, d, J 8.0 Hz, ArH) and 7.64 (2H, d, J 8.0 Hz, ArH) ppm; dC
(100 MHz, CDCl3) 12.9 (CH3), 21.5 (CH3), 26.2 (CH2), 34.1 (CH), 36.2
(CH2), 41.7 (CH2), 41.8 (CH), 44.2 (CH2), 46.7 (CH2), 78.6 (CH), 127.5
(CH), 129.6 (CH), 133.5 (C) and 143.4 (C) ppm; nmax (film) 3497,
3401, 2923,1648,1598, 1463, 1340, 1162,1092,1057 and 1003 cmꢀ1
;
m/z C16H24NO3S requires 310.1477 (MHþ, 100%); found 310.1472
(ꢀ1.6 ppm).
3.20. ( )-(4aS,6R,7S,7aS)-2,7-Dimethyloctahydro[2]pyrindin-
6-ol 32
Alcohol 31b (70 mg, 0.23 mmol, 1 equiv) in THF (5 cm3) was
added dropwise to a solution of lithium (59 mg, 8.42 mmol,
38 equiv) in NH3 (40 cm3) at ꢀ78 ꢁC. Stirring was continued at
ꢀ78 ꢁC for 40 min. Solid NH4Cl (ca. 10 mg) was added and the
mixture was stirred at room temperature for 1 h. Water (10 cm3)
and dichloromethane (15 cm3) were added and the solution was
basified to pH 14 (1 M NaOH) and extracted with dichloromethane
(3ꢃ15 cm3). The combined extracts were dried over MgSO4, filtered
and the solvent was removed in vacuo. Mass spectrometry con-
firmed the presence of the amine [C9H18NO requires 156.1388
(MHþ, 100%); found 156.1381 (ꢀ4.7 ppm)]. The residue was taken
up in THF (5 cm3). To this, formaldehyde, 38% in water (19 mg,
0.25 mmol, 1.1 equiv) was added. The mixture was stirred for
10 min before sodium triacetoxyborohydride (72 mg, 0.34 mmol,
1.5 equiv) was added. After 15 h water (10 cm3) and dichloro-
methane (10 cm3) were added. Basification of the water layer from
pH of 5–14 (1 M NaOH) was followed by extraction with dichloro-
methane (3ꢃ15 cm3). The combined extracts were dried over
MgSO4, filtered and solvent removed under reduced pressure. Pu-
rification by flash column chromatography (CH2Cl2/CH2Cl2–
MeOH; 1:1) gave the tertiary amine 32 as a yellow oil (9 mg, 25%);
Rf¼0.10 (CH2Cl2–MeOH; 1:1); dH (500 MHz, CDCl3) 0.99 (3H, d, J
7.0 Hz, 7-CH3), 1.56–1.64 (2H, m, 4-CH2, 5-CH2), 1.86–1.96 (1H, m, 4-
CH2), 1.98–2.23 (5H, m, 1-CH2, 4a-CH, 5-CH2, 7-CH, 7a-CH), 2.27
(3H, s, 2-CH3), 2.38 (1H, dt, J 4.5, 12.0 Hz, 3-CH2), 2.47–2.53 (2H, m,
1-CH2, 3-CH2) and 4.08–4.12 (1H m, 6-CH) ppm; dC (125 MHz,
CDCl3) 9.5 (CH3), 25.8 (CH2), 33.6 (CH), 38.5 (CH2), 42.2 (CH), 42.9
(CH), 46.3 (CH3), 50.1 (CH2), 52.1 (CH2) and 74.5 (CH) ppm; nmax
(film) 3401, 2926, 2780, 2684, 2229, 1659, 1454, 1334, 1263, 1117
and 1034 cmꢀ1; m/z C9H20NO requires 170.1545 (MHþ, 100%);
found 170.1543 (ꢀ1.1 ppm).
3.18. ( )-(4aS,7S,7aS)-7-Methyl-2-(toluene-4-
sulfonyl)octahydro[2]pyrindin-6-one 30
A solution of enone 29 (233 mg, 0.76 mmol, 1 equiv) in ethanol
(20 cm3) was degassed with a steady stream of N2 for 20 min. To
this, Pd/C 10% w/w catalyst (81 mg, 10 mol %) was added. Stirring
was continued overnight under an atmosphere of H2. Filtration
through Celite, followed by purification by flash column chroma-
tography (cyclohexane–EtOAc; 1:1) afforded 30 as colourless solid
(211 mg, 90%); mp¼119 ꢁC; Rf¼0.55 (cyclohexane–EtOAc; 1:1); dH
(400 MHz, CDCl3) 0.98 (3H, d, J 7.5 Hz, 7-CH3), 1.72–1.77 (2H, m, 1-
CH2, 4-CH2), 1.86–1.94 (1H, m, 5-CH2), 2.02–2.10 (1H, m, 4-CH2),
2.17–2.31 (2H, m, 3-CH2, 5-CH2), 2.39–2.48 (5H, m, 4a-CH, 7-CH,
CH3), 2.56–2.63 (1H, m, 7a-CH), 3.61–3.65 (2H, m, 1-CH2, 3-CH2),
7.32 (2H, d, J 8.0 Hz, ArH) and 7.60 (2H, d, J 8.0 Hz, ArH) ppm; dC
(100 MHz, CDCl3) 8.2 (CH3), 21.3 (CH3), 25.7 (CH2), 30.3 (CH), 36.8
(CH2), 38.9 (CH), 40.9 (CH2), 43.7 (CH2), 48.7 (CH), 127.6 (CH), 129.6
(CH), 132.6 (C), 143.6 (C) and 218.3 (C) ppm; nmax (film) 3041, 2968,
2945, 2925, 1737, 1596, 1492, 1453, 1388, 1325, 1308, 1295, 1180,
1154, 1092, 1076, 1035 and 1005 cmꢀ1; m/z C16H22NO3S requires
308.1320 (MHþ, 100%); found 308.1311 (ꢀ3.1 ppm).
3.19. ( )-(4aS,6R,7S,7aS)-7-Methyl-2-(toluene-4-
sulfonyl)octahydro[2]pyrindin-6-ol 31b and ( )-
(4aS,6S,7S,7aS)-7-methyl-2-(toluene-4-
sulfonyl)octahydro[2]pyrindin-6-ol 31a
Sodium borohydride (44 mg, 1.15 mmol, 2.5 equiv) was added to
a solution of ketone 30 (141 mg, 0.46 mmol, 1 equiv) in methanol
(40 cm3) at ꢀ78 ꢁC. After stirring for 15 min, water (30 cm3) was
added and the mixture was extracted with ether (3ꢃ25 cm3). The
organic layer was washed with brine (20 cm3), dried over MgSO4
and filtered. Purification by flash column chromatography (cyclo-
hexane/cyclohexane–EtOAc; 3:1) yielded 31b as a colourless oil
(85 mg, 60%); Rf¼0.30 (cyclohexane–EtOAc; 1:1); dH (400 MHz,
CDCl3) 0.97 (3H, d, J 7.5 Hz, 7-CH3), 1.32–1.39 (1H, m, 5-CH2), 1.58
(1H, d, J 13.5 Hz, 4-CH2), 1.91–2.16 (5H, m, 4-CH2, 4a-CH, 5-CH2, 7-
CH, 7a-CH), 2.42 (3H, s, CH3), 2.43–2.52 (2H, m, 1-CH2, 3-CH2),
3.53–3.57 (2H, m, 1-CH2, 3-CH2), 4.14–4.18 (1H, m, 6-CH), 7.29 (2H,
d, J 8.0 Hz, ArH) and 7.63 (2H, d, J 8.0 Hz, ArH) ppm; dC (100 MHz,
CDCl3) 8.9 (CH3), 21.4 (CH3), 26.1 (CH2), 34.7 (CH), 36.8 (CH2), 41.5
(CH), 41.6 (CH2), 42.3 (CH), 44.2 (CH2), 74.0 (CH), 127.4 (CH), 129.6
(CH), 133.9 (C) and 143.2 (C) ppm; nmax (film) 3513, 3060, 2928,
3.21. (D)-(4aS,4aR,7S,4aS)-4,7-Dimethyl-2-(toluene-4-
sulfonyl)octahydro[2]pyrindin-6-one 33
A solution of enone 9a (135 mg, 0.42 mmol, 1 equiv) in ethanol
(15 cm3) was degassed under a steady stream of N2 for 20 min. To
this Pd/C 10% w/w (45 mg, 10 mol %) was added. Stirring was con-
tinued overnight under an atmosphere of H2. Filtration through
Celite, followed by purification by flash column chromatography
(cyclohexane/cyclohexane–EtOAc; 1:1) afforded 33 as colourless
solid (122 mg, 90%); mp (decomp.)¼117 ꢁC; Rf¼0.65 (cyclohexane–
20
EtOAc; 1:1); [
a]
þ39.5 (c 2.4, CHCl3); dH (400 MHz, CDCl3) 0.99
D
(3H, d, J 7.5 Hz, 7-CH3), 1.22 (3H, d, J 7.5 Hz, 4-CH3), 1.86–1.95 (3H,
m, 4-CH, 5-CH2, 1-CH2), 2.09–2.16 (1H, m, 4a-CH), 2.22–2.29 (1H, m,
5-CH2), 2.32–2.39 (1H, m, 7-CH), 2.42 (3H, s, CH3), 2.54 (1H, dd, J
3.0, 11.5 Hz, 3-CH2), 2.68–2.76 (1H, m, 7a-CH), 3.26 (1H, d, J 11.5 Hz,

Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
8267
3-CH2), 3.56 (1H, dd, J 5.5, 12.0 Hz, 1-CH2), 7.30 (2H, J 8.0 Hz, ArH)
and 7.58 (2H, d, J 8.0 Hz, ArH) ppm; dC (100 MHz, CDCl3) 8.8 (CH3),
18.4 (CH3), 21.4 (CH3), 30.0 (CH), 35.7 (CH), 37.7 (CH), 38.6 (CH2),
41.2 (CH2), 47.1 (CH2), 48.2 (CH), 127.3 (CH), 129.7 (CH), 132.9 (C),
143.6 (C) and 218.4 (C) ppm; nmax (film) 2962, 2925, 2854, 1738,
the water layer from pH of 6–14 (1 M NaOH) was followed by ex-
traction with dichloromethane (3ꢃ10 cm3). The extracts were dried
over MgSO4, filtered and solvent removed under reduced pressure.
Purification by flash column chromatography (CH2Cl2/CH2Cl2–
MeOH; 1:1) gave the tertiary amine 35 as an oil (8 mg, 38%); Rf¼0.10
20
1598, 1463, 1379, 1344, 1306, 1261, 1163, 1091, 1067 and 1018 cmꢀ1
;
(CH2Cl2–MeOH; 1:1); [
a]
ꢀ5.6 (c 0.16, CHCl3); dH (500 MHz, CDCl3)
D
m/z C17H24NO3S requires 322.1477 (MHþ, 100%); found 322.1469
(ꢀ2.5 ppm).
1.00 (3H, d, J 7.5 Hz, 7-CH3), 1.12 (3H, d, J 7.5 Hz, 4-CH3), 1.55–1.61
(1H, m, 5-CH2), 1.70–1.76 (1H, m, 4a-CH), 1.77–1.83 (1H, m, 4-CH),
1.95–2.02 (1H, m, 7-CH), 2.12–2.19 (3H, m, 1-CH2, 5-CH2, 7a-CH),
2.23–2.29 (4H, m, 2-CH3, 3-CH2), 2.43–2.46 (2H, m, 1-CH2, 3-CH2)
and 4.11–4.15 (1H, m, 6-CH) ppm; dC (125 MHz, CDCl3) 9.5 (CH3),
21.7 (CH3), 31.3 (CH), 38.9 (CH), 39.5 (CH2), 41.2 (CH), 42.5 (CH), 46.9
(CH3), 53.7 (CH2), 57.9 (CH2) and 74.2 (CH) ppm; nmax (film) 3581,
3412, 2926, 2880, 2970, 1645, 1598, 1458, 1381, 1339, 1256, 1202,
1129 and 1037 cmꢀ1; m/z C11H22NO requires 184.1701 (MHþ, 100%);
found 184.1706 (þ2.5 ppm).
3.22. (D)-(4R,4aR,6R,7S,7aS)-4,7-Dimethyl-2-(toluene-4-
sulfonyl)octahydro[2]pyrindin-6-ol 34b and (D)-
(4R,4aS,6R,7S,7aS)-4,7-dimethyl-2-(toluene-4-
sulfonyl)octahydro[2]pyrindin-6-ol 34a
Sodium borohydride (11 mg, 0.29 mmol, 1.2 equiv) was added to
a solution of ketone 33 (78 mg, 0.24 mmol, 1 equiv) in methanol
(10 cm3) at ꢀ78 ꢁC. After stirring for 15 h, water (15 cm3) was added
and the mixture extracted with ether (3ꢃ20 cm3). The organic layer
was washed with brine (10 cm3), dried over MgSO4 and filtered.
Purification by flash column chromatography (cyclohexane–EtOAc;
3.24. (L)-(4R,4aR,6R)-4,7-Dimethyl-2-(toluene-4-sulfonyl)-
2,3,4,4a,5,6-hexahydro-1H-[2]pyrindin-6-ol 36
1:1/cyclohexane–EtOAc; 3:1) yielded 34b as
oil (35 mg, 45%); Rf¼0.60 (cyclohexane–EtOAc; 1:1); [
a
colourless
Cerium(III) chloride heptahydrate (347 mg, 0.93 mmol, 2 equiv)
was added to a solution of the enone 9a (150 mg, 0.47 mmol,
1 equiv) in methanol (35 cm3), at ꢀ78 ꢁC. After stirring for 10 min,
sodium borohydride (21 mg, 0.56 mmol, 1.2 equiv) was added. The
mixture was allowed to warm up to ambient temperature over
a period of 1 h before water (20 cm3) was added. This was extracted
using ether (3ꢃ20 cm3). The combined organic extracts were
washed with brine (15 cm3), dried over MgSO4 and filtered. The
solvent was removed under reduced pressure. Purification by flash
column chromatography (cyclohexane–EtOAc; 1:1) yielded 36 as
20
a
]
þ13.7
D
(c 2.15, CHCl3); dH (400 MHz, CDCl3) 0.98 (3H, d, J 7.0 Hz, 7-CH3),1.11
(3H, d, J 7.0 Hz, 4-CH3), 1.31–1.41 (1H, m, 5-CH2), 1.65–1.72 (1H, m,
4a-CH), 1.74–1.80 (1H, m, 4-CH), 1.95–2.00 (1H, m, 7-CH), 2.13–2.24
(2H, m, 5-CH2, 7a-CH), 2.43 (3H, s, CH3), 2.66 (1H, t, J 11.5 Hz, 1-
CH2), 2.76 (1H, dd, J 3.5, 11.5 Hz, 3-CH2), 3.09–3.14 (1H, m, 3-CH2),
3.45 (1H, dd, J 6.5, 11.5 Hz, 1-CH2), 4.11–4.16 (1H, m, 6-CH), 7.30 (2H,
d, J 8.0 Hz, ArH) and 7.63 (2H, d, J 8.0 Hz, ArH); dC (100 MHz, CDCl3)
9.3 (CH3), 19.3 (CH3), 21.5 (CH3), 31.2 (CH), 37.9 (CH2), 38.6 (CH),
42.0 (CH), 42.1 (CH), 44.2 (CH2), 48.1 (CH2), 74.1 (CH), 127.4 (CH),
129.5 (CH), 134.2 (C) and 143.1 (C) ppm; nmax (film) 3530, 3025,
a colourless solid (150 mg, 100%); mp (decomp.)¼130 ꢁC; Rf¼0.35
20
(cyclohexane–EtOAc; 1:1); [
a
]
ꢀ38.3 (c 2.45, CHCl3); dH (400 MHz,
D
2961, 2928, 1598, 1462, 1337, 1260, 1225, 1160, 1092 and 1024 cmꢀ1
;
CDCl3) 0.86 (3H, d, J 6.5 Hz, 4-CH3), 1.07–1.13 (1H, m, 5-CH2), 1.42–
1.53 (1H, m, 4-CH),1.71 (3H, d, J 1.0 Hz, 7-CH3),1.75–1.78 (1H, m, 4a-
CH), 2.01 (1H, t, J 12.0 Hz, 3-CH2), 2.43 (3H, s, CH3), 2.54–2.62 (1H, m,
5-CH2), 2.76–2.79 (1H, m, 1-CH2), 3.73–3.77 (1H, m, 3-CH2), 4.45
(1H, d, J 13.0 Hz, 1-CH2), 4.54 (1H, s(br), 6-CH), 7.33 (2H, d, J 8.0 Hz,
ArH) and 7.67 (2H, d, J 8.0 Hz, ArH) ppm; dC (100 MHz, CDCl3) 10.7
(CH3), 16.9 (CH3), 21.5 (CH3), 38.5 (CH2), 38.9 (CH), 44.8 (CH2), 48.3
(CH), 52.5 (CH2), 79.3 (CH), 127.7 (CH), 129.6 (CH), 132.0 (C), 133.3
(C), 135.1 (C) and 143.5 (C) ppm; nmax (film) 3412, 3029, 2921, 2852,
1598, 1453, 1342, 1088, 1039 and 1003 cmꢀ1; m/z C17H24NO3S re-
quires 322.1477 (MHþ, 100%); found 322.1489 (þ3.8 ppm).
m/z C17H26NO3S requires 324.1633 (MHþ, 100%); found 324.1629
(ꢀ1.4 ppm). The other diastereoisomer 34a was isolated as a col-
20
ourless oil (24 mg, 31%); Rf¼0.45 (cyclohexane–EtOAc; 1:1); [
a]
D
þ15.3 (c 0.9, CHCl3); dH (400 MHz, CDCl3) 1.03–1.07 (6H, m, 4-CH3,
7-CH3), 1.63–1.68 (2H, m, 4-CH, 4a-CH), 1.79–1.87 (2H, m, 5-CH2),
1.91–1.97 (1H, m, 7-CH), 2.32–2.42 (2H, m, 1-CH2, 7a-CH), 2.44 (3H,
s, CH3), 2.84–2.86 (2H, m, 3-CH2), 3.28 (1H, q, J 4.5, Hz,1-CH2), 3.83–
3.88 (1H, m, 6-CH), 7.32 (2H, d, J 8.0 Hz, ArH) and 7.64 (2H, d, J
8.0 Hz, ArH) ppm; dC (100 MHz, CDCl3) 13.6 (CH3), 18.9 (CH3), 21.5
(CH3), 31.8 (CH), 37.6 (CH), 38.5 (CH2), 41.6 (CH2), 44.4 (CH2), 46.1
(CH), 48.6 (CH), 78.6 (CH), 127.5 (CH), 129.6 (CH), 133.6 (C) and
143.3 (C) ppm; nmax (film) 3512, 3035, 2958, 2977, 2301, 1598, 1462,
1341, 1162, 1092, 1066 and 1019 cmꢀ1; m/z C17H26NO3S requires
324.1633 (MHþ, 100%); found 324.1624 (ꢀ2.9 ppm).
3.25. (L)-(4R,4aR)-4,7-Dimethyl-2-(toluene-4-sulfonyl)-
2,3,4,4a,5,6-hexahydro-1H-[2]pyrindine 39
A solution of alcohol 36 (99 mg, 0.31 mmol, 1 equiv) in ethanol
(15 cm3) was degassed under a steady stream of N2 for 15 min. To
this solution Pd/C 10% w/w (33 mg, 10 mol %) was added. Stirring
was continued for 45 min under an atmosphere of H2. Filtration
through Celite, followed by purification by flash column chroma-
tography (cyclohexane–EtOAc; 3:1) afforded 39 as a colourless solid
3.23. (D)-(4R,4aR,6R,7S,7aS)-2,4,7-Trimethyl-
octahydro[2]pyrindin-6-ol 35
Lithium (8 mg, 1.08 mmol, 10 equiv) was added to a solution of
alcohol 34b (35 mg, 0.1 mmol, 1 equiv) in THF (5 cm3) and NH3
(30 cm3) at ꢀ78 ꢁC. The mixture was stirred at ꢀ78 ꢁC for 1 h. Solid
NH4Cl (ca. 10 mg) was added, and stirring was continued at room
temperature for 1 h. Water (7 cm3) and dichloromethane (10 cm3)
were added. The water layer was basified to pH 14 (1 M NaOH) and
extracted with dichloromethane (3ꢃ10 cm3). The combined ex-
tracts were dried over MgSO4, filtered and the solvent was removed
in vacuo. Mass spectrometry confirmed the presence of the amine
[C10H20NO requires 170.1545 (MHþ, 100%); found 170.1538
(ꢀ4.1 ppm)]. The residue was taken up in THF (5 cm3) and 38%
aqueous formaldehyde (9 mg, 0.12 mmol, 1.2 equiv) was added. The
mixture was stirred for 10 min before sodium triacetoxyborohy-
dride (34 mg, 0.16 mmol, 1.5 equiv) was added. After 15 h water
(10 cm3) and dichloromethane (10 cm3) were added. Basification of
(89 mg, 95%); mp (decomp.)¼106 ꢁC; Rf¼0.75 (cyclohexane–EtOAc;
20
1:1); [
a
]
ꢀ36.8 (c 2.17, CHCl3); dH (400 MHz, CDCl3) 0.82 (3H, d, J
D
6.5 Hz, 4-CH3), 1.21–1.28 (1H, m, 5-CH2), 1.31–1.34 (1H, m, 4-CH),
1.64 (3H, s, 7-CH3), 1.90–1.99 (2H, m, 3-CH2, 4a-CH), 2.00–2.04 (1H,
m, 5-CH2), 2.19–2.25 (2H, m, 6-CH2), 2.41 (3H, s, CH3), 2.71 (1H, d, J
12.5 Hz, 1-CH2), 3.69 (1H, dd, J 2.5, 11.5 Hz, 3-CH2), 4.43 (1H, d, J
12.5 Hz, 1-CH2), 7.30 (2H, d, J 8.0 Hz, ArH) and 7.65 (2H, d, J 8.0 Hz,
ArH) ppm; dC (100 MHz, CDCl3) 13.7 (CH3), 16.9 (CH3), 21.4 (CH3),
27.3 (CH2), 37.1 (CH2), 38.9 (CH), 45.1 (CH2), 51.7 (CH), 52.5 (CH2),
127.7 (CH), 128.7 (C), 129.5 (CH), 133.2 (C), 133.4 (C) and 143.3 (C)
ppm; nmax (film) 3035, 2957, 2928, 1710, 1598, 1495, 1458, 1342,
1226,1160,1090 and 1023 cmꢀ1; m/z C17H24NO2S requires 306.1528
(MHþ, 100%); found 306.1522 (ꢀ1.9 ppm).

8268
Y. Kavanagh et al. / Tetrahedron 65 (2009) 8259–8268
3.26. (D)-(4R,4aR,7R,7aR)-4,7-Dimethyl-2-(toluene-4-
Acknowledgements
sulfonyl)octahydro[2]pyrindine
We thank Science Foundation Ireland (SFI) and the University
College Dublin for financial support. Valuable input from Drs.
Tom McCabe (Trinity College Dublin), X-ray crystallography and
Jimmy Muldoon (UCD), NOE measurements, is gratefully acknow-
ledged.
A solution of 39 (358 mg, 1.16 mmol, 1 equiv) in ethanol
(40 cm3) was degassed with a steady stream of N2 for 15 min. To
this Pd/C 10% w/w catalyst (250 mg, 20 mol %) was added. Stirring
was continued for 72 h, under an atmosphere of H2. Filtration
through Celite, followed by purification by flash column chroma-
tography (cyclohexane–EtOAc; 3:1) afforded the title compound as
References and notes
an amorphous solid (285 mg, 79%); Rf¼0.75 (cyclohexane–EtOAc;
20
1:1); [
a]
þ13.9 (c 2.28, CHCl3); dH (600 MHz, CDCl3) 0.94 (3H, d, J
1. Kam, T.-S.; Yoganathan, K.; Wei, C. J. Nat. Prod. 1997, 60, 673–676.
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chemistry 1992, 31, 2930–2932.
3. (a) Ichikawa, M.; Takahashi, M.; Aoyagi, S.; Kibayashi, C. J. Am. Chem. Soc. 2004,
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1988–1998.
D
7.0 Hz, 7-CH3), 1.08 (3H, d, J 6.5 Hz, 4-CH3), 1.08–1.91 (1H, m, 6-
CH2), 1.33–1.40 (1H, m, 5-CH2), 1.59–1.66 (1H, m, 5-CH2), 1.68–1.71
(1H, m, 4-CH),1.72–1.77 (2H, m, 4a-CH, 6-CH2), 2.02–2.07 (1H, m, 7-
CH), 2.11–2.15 (1H, m, 7a-CH), 2.25 (1H, t, J 11.5 Hz,1-CH2), 2.43 (3H,
s, CH3), 2.71 (1H, dd, J 3.5,11.5 Hz, 3-CH2), 3.03 (1H, dd, J 3.5,11.5 Hz,
3-CH2), 3.34 (1H, dd, J 5.5, 11.5 Hz, 1-CH2), 7.31 (2H, d, J 8.0 Hz, ArH)
and 7.63 (2H, d, J 8.0 Hz, ArH) ppm; dC (150 MHz, CDCl3) 15.6 (CH3),
19.4 (CH3), 21.4 (CH3), 26.9 (CH2), 30.4 (CH2), 30.9 (CH), 36.6 (CH),
38.9 (CH2), 43.7 (CH), 44.2 (CH), 48.1 (CH2), 127.5 (CH), 129.5 (CH),
133.8 (C) and 143.1 (C) ppm; m/z C17H26NO2S requires 308.1684
(MHþ, 100%); found 308.1685 (þ0.2 ppm).
9. (a) Magnus, P.; Principe, L. M. Tetrahedron Lett. 1985, 26, 4851–4854; (b)
Magnus, P.; Exon, C.; Albaugh-Robertson, P. Tetrahedron 1985, 41, 5861–5869;
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3.27. (L)-(4R,4aR,7R,7aR)-2,4,7-Trimethyloctahydro-
[2]pyrindine 40
Lithium (33 mg, 4.51 mmol, 10 equiv) was added to a solution of
the above dimethylpyridine (139 mg, 0.45 mmol, 1 equiv) in THF
(5 cm3) and NH3 (30 cm3) at ꢀ78 ꢁC. The mixture was stirred at
ꢀ78 ꢁC for 1 h. Solid NH4Cl (ca. 15 mg) was added, and stirring
continued at room temperature for 1 h. Water (10 cm3) and
dichloromethane (15 cm3) were added. The water layer was basified
to pH 14 (1 M NaOH) and extracted with dichloromethane
(3ꢃ15 cm3). The combined extracts were dried over MgSO4, filtered
and the solvent removed in vacuo. High resolution mass spectrom-
controls the axial stereochemistry of a Vollhardt cyclisation see: Stara´, I. G.;
ˇ
´
I.; Saman, D.; Budesˇı´nsky, M.;
Alexandrova, Z.; Teply, F.; Sehnal, P.; Stary,
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´
ˇ
Cvacka, J. Org. Lett. 2005, 7, 2547–2550.
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5292; (b) Jeong, N.; Chung, Y. K.; Lee, B. Y.; Lee, S. H.; Yoo, S.-E. Synlett 1991,
204–206.
etry confirmed the presence of the intermediate amine [C10H20
N
requires 154.1596 (MHþ, 100%); found 154.1589 (ꢀ4.4 ppm)]. The
residue was taken up in THF (5 cm3). To this, formaldehyde, 38% in
water (39 mg, 0.49 mmol, 1.1 equiv), was added. The mixture was
stirred for 10 min before sodium triacetoxyborohydride (144 mg,
0.68 mmol, 1.5 equiv) was added. At 2 h water (15 cm3) and
dichloromethane (20 cm3) were added. Basification of the water
layer from pH of 6–14 (1 M NaOH) was followed by extraction with
dichloromethane (3ꢃ15 cm3). The extracts were dried over MgSO4,
filtered and the solvent was removed under reduced pressure. Pu-
rification by flash column chromatography (CH2Cl2/CH2Cl2–
15. X-ray deposition number for 9a CCDC 670403: Formula: C17H21NO3S: Unit cell
parameters: a 5.5026(5); b 9.1774(8); c 16.7670(16);
P21.
b 96.814(2); space group
16. Flack, H. D.; Bernardinelli, G. Acta Crystallogr. 1999, A55, 908–915.
17. Adrio, J.; Rodrı´guez Rivero, M.; Carretero, J. C. Angew. Chem., Int. Ed. 2000, 39,
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MeOH; 1:1) gave the tertiary amine 40 as an oil (27 mg, 36%);
20
Rf¼0.25 (CH2Cl2–MeOH; 1:1); [
a
]
ꢀ5.04 (c 1.35, CHCl3); dH
D
(600 MHz, CDCl3) 0.93 (3H, d, J 7.0 Hz, 7-CH3), 1.14 (3H, d, J 7.0 Hz, 4-
CH3), 1.28–1.32 (1H, m, 6-CH2), 1.53–1.59 (1H, m, 5-CH2), 1.66–1.70
(2H, m, 4-CH, 5-CH2), 1.75–1.81 (3H, m, 1-CH2, 4a-CH, 6-CH2), 2.02–
2.06 (1H, m, 7-CH), 2.13–2.16 (1H, m, 7a-CH), 2.24–2.28 (1H, m, 3-
CH2), 2.27 (3H, s, 2-CH3), 2.38 (1H, d, J 12.0 Hz, 3-CH2) and 2.55 (1H,
dd, J 5.0, 11.0 Hz, 1-CH2) ppm; dC (150 MHz, CDCl3) 15.4 (CH3), 21.0
(CH3), 27.3 (CH2), 30.4 (CH2), 31.2 (CH), 37.1 (CH), 39.1 (CH), 43.8 (CH),
47.1 (CH3), 53.5 (CH2) and 57.8 (CH2) ppm; nmax (film) 2952, 2941,
2783,1745,1664,1462,1376,1250,1153,1041, 886 and 829 cmꢀ1; m/z
C11H22N requires 168.1752 (MHþ, 70%); found 168.1744 (ꢀ4.9 ppm).
25. Kavanagh, Y.; Chaney, C. M.; Muldoon, J.; Evans, P. J. Org. Chem. 2008, 73, 8601–
8604.
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2558–2563.
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