Synthesis of the core ring system of the yuzurimine-type daphniphyllum alkaloids by cascade condensation, cyclization, cycloaddition chemistry

Article abstract of DOI:10.1021/jo2000868

Addition of hydroxylamine to substituted 4-chlorobutanals gives intermediate nitrones that undergo tandem cyclization and then intramolecular dipolar cycloaddition to give the core ring system of the yuzurimine-type natural products. Ring-opening of the isoxazolidines gives amino alcohols that can be converted to 1,3-oxazines, representing the tetracyclic core of alkaloids such as daphcalycic acid and daphcalycine.

Full text of DOI:10.1021/jo2000868

NOTE
pubs.acs.org/joc
Synthesis of the Core Ring System of the Yuzurimine-Type
Daphniphyllum Alkaloids by Cascade Condensation, Cyclization,
Cycloaddition Chemistry
Iain Coldham,*,† Luke Watson,† Harry Adams,† and Nathaniel G. Martin‡
†Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.
‡AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, U.K.
S Supporting Information
b
ABSTRACT: Addition of hydroxylamine to substituted 4-chlorobu-
tanals gives intermediate nitrones that undergo tandem cyclization
and then intramolecular dipolar cycloaddition to give the core ring
system of the yuzurimine-type natural products. Ring-opening of the
isoxazolidines gives amino alcohols that can be converted to 1,3-
oxazines, representing the tetracyclic core of alkaloids such as
daphcalycic acid and daphcalycine.
he Daphniphyllum alkaloids are a structurally diverse family
of natural products that are derived from evergreen shrubs
T
and trees found in Japan and southeast Asia.1-3 Many Daphni-
phyllum alkaloids have been discovered, and presently, there are
over 200 of these alkaloids from more than 10 species of the
genus Daphniphyllum. These alkaloids are generally classified by
the structures of daphniphylline, secodaphniphylline, yuzuri-
mine, daphnilactones A and B, and yuzurine, although other
structural types are also known. The biosynthesis of these
alkaloids arises from modification of squalene, and this has
inspired the biomimetic synthesis of some of the members of
these alkaloids.4-8 Despite the large number of these alkaloids,
there are only a few approaches to the core ring systems of these
structurally complex compounds.9-16
Figure 1. Some yuzurimine alkaloids.
dipolar cycloaddition for the forward direction suggests that we
could use the aldehyde 4. Condensation of this aldehyde with
hydroxylamine should give the desired isoxazolidine 3 by a
cascade of condensation to the oxime, cyclization to the nitrone,
and dipolar cycloaddition.27,28 This paper reports the results of
this study and the first synthesis of the core ring system of the
yuzurimine-type Daphniphyllum alkaloids.
We have recently reported a cascade of reactions involving
condensation of an aldehyde and primary amine, in situ cycliza-
tion, then cycloaddition of the resulting 1,3-dipole.17-22 This
chemistry allows an efficient stereoselective access to tricyclic
nitrogen-containing products. We therefore considered if this
strategy could access the core of some of the Daphniphyllum
alkaloids. In particular, the core tricyclic ring system of some of
the yuzurimine alkaloids caught our attention. These alkaloids
have two fused cyclopentane rings, one of which is spiro-fused to
a cyclohexane ring, and some representative examples are shown
in Figure 1. Daphcalycic acid23 and daphcalycine24 (and daphca-
lycinosidine A, in which R is an iridoid glucoside)23 have a 1,3-
oxazine ring, whereas other members of the yuzurimine type
alkaloids, such as daphnioldhanin A25 and daphlongamine D,26
have a tertiary alcohol group. We are not aware of any reported
syntheses or of any synthetic approaches toward these alkaloids.
The core ring system of these yuzurimine alkaloids and a
retrosynthesis is shown in Scheme 1. The 1,3-oxazine (N,O-
acetal) 1 and the amino alcohol 2 could be derived from the
isoxazolidine 3. Disconnection of the isoxazolidine 3 using a
We have recently reported that heating the aldehydes 5 with
i
hydroxylamine hydrochloride and Pr2NEt in toluene gave the
tricyclic products 6 or 7 (Scheme 2).19 When two of the three
rings in the new tricyclic product are five-membered then the all-
cis stereoisomer is formed.18 We therefore anticipated that the
cascade chemistry with the aldehyde 4 would lead to the desired
stereoisomer of the product 3.
Initially, we prepared the related aldehyde 10, starting from
6-heptenenitrile, using alkylation to give the alcohol 8, conver-
sion to the chloride 9, and DIBAL-H reduction (Scheme 3).
Disappointingly, no tricyclic product was obtained from heating
aldehyde 10 with hydroxylamine, and instead, the pyrrole 12 and
decomposed material were formed.
Received: January 20, 2011
Published: March 08, 2011
r
2011 American Chemical Society
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|

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NOTE
Scheme 1. Retrosynthetic Disconnection of the Core Ring
System 1
Scheme 4. Synthesis of the Aldehyde 17a
a Reagents and conditions: (i) LDA, 13, THF, -78 °C, 73%; (ii) LDA,
BrCH2CH2OTMS, THF, -78 °C, then HCl(aq), 88%; (iii) PPh3, N-
chlorosuccinimide, THF, 83%; (iv) DIBAL-H, CH2Cl2, -78 °C, then
HCl(aq), 56%.
Scheme 2. Previous Syntheses of Isoxazolidines19
Scheme 5. Cycloaddition Using the Aldehyde 17a
Scheme 3. Model Studies with the Aldehyde 10a
a Reagents and conditions: (i) LDA, BrCH2CH2OTMS, THF, -78 °C,
then HCl(aq), 65%; (ii) PPh3, N-chlorosuccinimide, THF, 67%; (iii)
a Reagents and conditions: (i) NH2OH HCl, iPr2NEt, PhMe, 110 °C,
3
60%; (ii) Zn, AcOH, H2O, 90 °C, 91%; (iii) (CH2O)n, 5 mol % TsOH,
CHCl3, 80 °C, 70%; (iv) MeCHO, 5 mol % TsOH, CHCl3, 80 °C, 57%.
DIBAL-H, CH2Cl2, -78 °C, then HCl(aq), 72%; (iv) NH2OH HCl,
3
iPr2NEt, PhMe, 110 °C, 29%.
acetic acid. This showed that the product had the desired
stereochemistry which must have arisen from cycloaddition to
the cis-fused product with suprafacial reaction of the cyclopen-
tene dipolarophile.
The amino-alcohol 19 represents the core ring structure of
some of the yuzurimine type alkaloids (see Figure 1). The 1,3-
oxazine ring present in other yuzurimine type alkaloids was
formed from amino-alcohol 19 by simple heating with parafor-
maldehyde and p-toluenesulfonic acid to give 20, or with
acetaldehyde to give 21, which was formed as a single stereoiso-
mer. The stereochemistry of the acetal 21 was determined by 1H
NOESY experiments. This chemistry therefore provides a meth-
od to prepare the tetracyclic core of the alkaloid daphcalycic acid
(and its ester derivatives).
An attempt to remove the phenylthio group from the
cycloadduct 18 using sodium amalgam (Na/Hg, MeOH, Na2H-
PO4, room temperature) gave only the amino alcohol 19 (75%
yield). Rather than pursue alternative methods for desulfenyla-
tion, we decided to explore the preparation of the methyl-
substituted derivative 4 containing a phenylthio substituent to
block pyrrole formation.
The pyrrole 12 may arise from the ability of the nitrone
intermediate 11 to tautomerize followed by dehydration to the
aromatic ring system. Alternatively, formation of the oxime then
cyclization to a six-membered cyclic oxime (sometimes called a
dihydro-1,2-oxazine), followed by tautomerism, fragmentation
and recombination could lead to the pyrrole.29 To prevent this
process, we chose to block enamine formation with a phenylthio
substituent alpha to the aldehyde. Hence, starting with phe-
nylthioacetonitrile, alkylation with the known iodide 1330,31 gave
the nitrile 14. A second alkylation gave the alcohol 15 which was
converted to the chloride 16 and, hence, after DIBAL-H reduc-
tion, the aldehyde 17 (Scheme 4).
Heating the aldehyde 17 with hydroxylamine hydrochloride
and iPr2NEt in toluene under reflux gave the expected product 18
as a single stereoisomer (Scheme 5). Alternatively, heating at
60 °C gave the intermediate oxime (66% yield) that could be
converted to the cycloadduct 18 in high (95%) yield. The
stereochemistry of the product was determined by X-ray crystal
structure analysis of the amino alcohol 19 (see the Supporting
Information), formed after reductive ring-opening with zinc/
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Scheme 6. Synthesis of the Aldehyde 27a
Scheme 7. Cycloaddition Using the Aldehyde 27a
a Reagents and conditions: (i) NH2OH HCl, iPr2NEt, PhMe, 60 °C, 16
3
h, 72%; (ii) PhMe, 110 °C, 16 h, 80%.
a Reagents and conditions: (i) LDA, THF, 13, -78 °C, 98%; (ii) Bu4NF,
THF, 82%; (iii) iPrMgCl, THF, -78 °C, PhSSPh, 92% (or PhSSO2Ph,
85%); (iv) polymer-bound triphenylphosphine (diphenylphospinated
polystyrene cross-linked with divinylbenzene), CCl4, CH2Cl2, 90%; (v)
DIBAL-H, CH2Cl2, -78 °C, then HCl(aq), 65%.
Scheme 8. Alternative Synthesis of Nitrile 25a
The nitrile 22 (Scheme 6) was prepared from commercially
available methyl (R)-3-hydroxy-2-methylpropionate using a
known procedure.32 Alkylation using LDA and the iodide 13
proceeded smoothly to give the nitrile 23 as a mixture of
a Reagents and conditions: (i) Bu4NF, THF, 90%; (ii) iPrMgCl, THF, -
78 °C, PhSSPh, 80%; (iii) LDA, THF, 13, -78 °C, 83%.
1
diastereoisomers (dr 2:1 by H NMR spectroscopy, major iso-
mer unknown). Treatment of the nitrile 23 with LDA followed
by attempted sulfenylation with PhSSPh or PhSSO2Ph (or
alkylation with MeI) gave only recovered starting material 23.
We therefore removed the silyl protecting group to give the
nitrile 24. This compound also failed to undergo sulfenylation
using LDA, PhSSPh. However, following precedent from Fleming
Scheme 9. Completion of the Synthesis of the Core Ring
Systema
i
and co-workers,33 treatment with PrMgCl then sulfenylation
gave the desired product 25. Using PhSSO2Ph as the electro-
phile, the nitrile 25 was formed as a 1:1 (inseparable) mixture of
diastereoisomers, whereas PhSSPh as the electrophile gave the
nitrile 25 as a 2:1 mixture of diastereoisomers (major isomer
unknown at this stage).
We expected that, using the same procedure as before, the
nitrile 25 could be converted to the aldehyde 27. The product 26,
from chlorination of 25 (dr 2:1) with N-chlorosuccinimide and
PPh3 was inseparable from the byproduct Ph3PO and the
mixture was detrimental to the following reduction step. There-
fore, the chlorination was conducted using polymer-supported
phosphine and CCl4.34 Finally, reduction of the nitrile 26 with
DIBAL-H gave the desired aldehyde 27. This was formed as an
inseparable mixture of diastereoisomers (dr 7:3).
Heating the mixture of diastereoisomeric aldehydes 27 with
hydroxylamine hydrochloride at 60 °C gave the intermediate
oximes 28 that were heated under reflux in toluene to give two
separable cycloadducts 29 and 30 (ratio 7:3) (Scheme 7). The
stereochemistry of the minor isomer 30 was established by
single-crystal X-ray analysis (see the Supporting Information).
The stereochemistry of the major isomer 29 was determined by
1H NMR spectroscopy (NOESY).
The formation of the isomer 30 as the minor product indicates
that the sulfenylation reaction of the magnesium (di)anion of
nitrile 24 with PhSSPh took place to give predominantly the
undesired diastereoisomer of the nitrile 25 (dr 2:1). Therefore,
we attempted an inverse order of alkylation, where the phe-
nylthio group was added before the alkyl halide. Nitrile 31,
prepared by desilylation of nitrile 22, was converted to the nitrile
a Reagents and conditions: (i) Zn, AcOH, H2O, 90 °C, 99% for 33, 95%
for 35; (ii) (CH2O)n, 5 mol % TsOH, CHCl3, 65 °C, 79% for 34, 61%
for 36.
32 (dr 3:1, major isomer unknown) (Scheme 8). Subsequent
i
alkylation using PrMgCl (and the iodide 13) was unsuccessful
and gave the product 24 (60% yield, dr 2:1), formed by desulfe-
nylation then alkylation. Using LDA and iodide 13, the product 25
was formed; however, the diastereoisomer ratio was low (dr 2:1)
1
and the major diastereoisomer was the same (as judged by H
NMR spectroscopy) as that formed from nitrile 24 (Scheme 6).
The separated cycloadducts 29 and 30 were converted to the
amino alcohols 33 and 35 and hence to the 1,3-oxazines 34 and
36 (Scheme 9). The formation of the 1,3-oxazine 36 represents
the desired framework of the core of some of the yuzurimine
alkaloids, including daphcalycic acid and daphcalycine.
In summary, we have shown that a cascade of condensation,
cyclization then intramolecular dipolar cycloaddition reactions
can be used to construct the tricyclic core of the yuzurimine
alkaloids, including the spirocyclic cyclohexane and cyclopentane
rings. This tricyclic arrangement can be converted easily to the
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NOTE
tetracyclic core containing a 1,3-oxazine ring. A phenylthio group
was used to prevent pyrrole formation. The cascade chemistry, in
particular the cycloaddition step, is stereoselective for a single
stereoisomer of the tricyclic product. The results could form the
basis for a synthesis of this type of Daphniphyllum alkaloid.
phenythioacetonitrile (0.42 mL, 3.23 mmol) and then iodide 1330 (0.80
g, 3.39 mmol) were added, and the mixture was warmed to room
temperature. After 3 h, saturated aqueous ammonium chloride solution
(10 mL) was added, and the mixture was extracted with Et2O (3 ꢀ
30 mL), dried (MgSO4), and evaporated. Purification by column
chromatography, eluting with petroleum ether-EtOAc (99:1), gave
nitrile 14 (0.61 g, 73%) as an oil: IR νmax (film)/cm-1 2940, 2840, 2235,
1475, 1440; 1H NMR (400 MHz, CDCl3) δ 7.67-7.59 (m, 2H), 7.46-
7.38 (m, 3H), 5.40-5.35 (m, 1H), 3.73 (t, J 7 Hz, 1H), 2.36-2.28 (m,
2H), 2.28-2.20 (m, 2H), 2.18-2.11 (m, 2H), 1.94-1.81 (m, 4H),
1.80-1.67 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.3, 134.5,
130.5, 129.5 (overlapping signals), 124.5, 119.3, 37.1, 34.9, 32.4, 32.1,
30.2, 25.0, 23.4; HRMS (ES) found 258.1314, C16H20NS requires MHþ
258.1316.
5-Cyclopentenyl-2-(2-hydroxyethyl)-2-(phenylthio)penta-
nenitrile 15. In the same way as 8, n-butyllithium (0.96 mL, 2.4 mmol,
2.5 M in hexanes), diisopropylamine (0.37 mL, 2.63 mmol), nitrile 14
(0.59 g, 2.29 mmol), and 2-bromoethyl trimethylsilyl ether (0.58 g, 2.98
mmol) gave, after purification by column chromatography, eluting with
petroleum-EtOAc (17:3), nitrile 15 (0.59 g, 88%) as an oil: IR νmax
(film)/cm-1 3340, 2945, 2845, 2250, 1650, 1475, 1440; 1H NMR (400
MHz, CDCl3) δ 7.73-7.66 (m, 2H), 7.52-7.40 (m, 3H), 5.39-5.34
(m, 1H), 3.96 (q, J 6.5 Hz, 2H), 2.36-2.27 (m, 2H), 2.26-2.18 (m,
2H), 2.17-1.99 (m, 4H), 1.96-1.64 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 143.3, 137.1, 130.4, 129.3, 129.0, 124.5, 121.4, 59.1, 47.6, 39.1,
37.2, 34.5, 32.4, 30.6, 23.4, 22.9; HRMS (ES) found 302.1575,
C18H24NOS requires MHþ 302.1579.
’ EXPERIMENTAL SECTION
2-(2-Hydroxyethyl)hept-6-enenitrile 8. n-Butyllithium (9.60 mL,
24 mmol, 2.5 M) was added to diisopropylamine (3.55 mL, 25 mmol) in
THF (25 mL) at -78 °C. After 10 min, heptenenitrile (2.57 mL, 20 mmol)
then 2-bromoethyl trimethylsilyl ether (4.30 g, 22 mmol) were added, and
the mixture was warmed to room temperature. After 16 h, HCl (2 M,
10 mL) was added, and the mixture was extracted with Et2O (3 ꢀ 30 mL),
dried (MgSO4), and evaporated. Purification by column chromatography,
eluting with petroleum ether-EtOAc (9:1 to 0:1), gave nitrile 8 (1.96 g,
1
65%) as an oil: IR νmax (film)/cm-1 3270, 2940, 1435; H NMR (400
MHz, CDCl3) δ 5.81 (ddt, J 17, 10, 6.5 Hz, 1H), 5.11-4.98 (m, 2H), 3.86
(t, J 5.5 Hz, 2H), 2.91-2.80 (m, 1H), 2.19-2.07 (m, 2H), 1.90-1.80 (m,
2H), 1.75-1.53 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 137.7, 122.1,
115.3, 59.3, 34.7, 33.0, 31.4, 28.0, 26.2; HRMS (ES) found 154.1232,
C9H16NO requires MHþ 154.1236.
2-(2-Chloroethyl)hept-6-enenitrile 9. Alcohol 8 (1.90 g, 12.4
mmol) was added to PPh3 (4.88 g, 18.6 mmol) and N-chlorosuccinimide
(1.80 g, 13.6 mmol) in THF (25 mL) at 0 °C, and the mixture was
warmed to room temperature. After 16 h, the solvent was evaporated,
and water was added. The mixture was extracted with Et2O (3 ꢀ 30 mL),
dried (MgSO4), evaporated, filtered over Celite, and washed with
petroleum ether, and the solvent was evaporated. Purification by column
chromatography, eluting with petroleum ether-EtOAc (97:3), gave
nitrile 9 (1.43 g, 67%) as an oil: IR νmax (film)/cm-1 2960, 2235, 1460;
1H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J 17, 10, 6.5 Hz, 1H), 5.12-
4.98 (m, 2H), 3.78-3.66 (m, 2H), 2.96-2.86 (m, 1H), 2.21-2.07 (m,
3H), 2.05-1.94 (m, 1H), 1.75-1.53 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 137.5, 121.0, 115.6, 41.7, 35.0, 33.0, 31.1, 28.9, 26.2; HRMS
(ES) found 172.0893, C9H15N35Cl requires MHþ 172.0896.
2-(2-Chloroethyl)-5-cyclopentenyl-2-(phenylthio)penta-
nenitrile 16. In the same way as 9, PPh3 (0.78 g, 3.0 mmol), N-
chlorosuccinimide (0.29 g, 2.2 mmol), and alcohol 15 (0.58 g, 1.9
mmol) gave, after purification by column chromatography, eluting with
petrol-EtOAc (99:1), nitrile 16 (0.51 g, 83%) as an oil: IR νmax (film)/
1
cm-1 2945, 2840, 2250, 1475, 1440; H NMR (400 MHz, CDCl3)
δ 7.71-7.65 (m, 2H), 7.54-7.41 (m, 3H), 5.40-5.36 (m, 1H), 3.76
(td, J 10.5, 6 Hz, 1H), 3.70 (td, J 10.5, 6 Hz, 1H), 2.37-2.18 (m, 6H),
2.12 (bs, 2H), 1.93-1.59 (m, 6H); 13C NMR (100 MHz, CDCl3) δ
143.1, 137.1, 130.6, 129.5, 128.5, 124.5, 120.0, 48.2, 39.4, 38.9, 36.7, 34.9,
32.4, 30.5, 23.4, 22.9; HRMS (ES) found 320.1241, C18H23NS35Cl
requires MHþ 320.1240.
2-(2-Chloroethyl)-5-cyclopentenyl-2-(phenylthio)penta-
nal 17. In the same way as 10, DIBAL-H (3.12 mL, 3.12 mmol, 1.0 M
in hexanes) and nitrile 16 (0.50 g, 1.56 mmol) gave, after purification
by column chromatography, eluting with petroleum ether-EtOAc
(99:1), aldehyde 17 (0.28 g, 56%) as an oil: IR νmax (film)/cm-1 2945,
1715, 1475, 1440; 1H NMR (250 MHz, CDCl3) δ 9.32 (s, 1H), 7.46-
7.31 (m, 5H), 5.40-5.36 (m, 1H), 3.80 (td, J 10.5, 5.5 Hz, 1H), 3.58
(td, J 10.5, 5.5 Hz, 1H), 2.37-2.28 (m, 2H), 2.27-2.07 (m, 5H),
2.06-1.95 (m, 1H), 1.94-1.82 (m, 2H), 1.80-1.54 (m, 3H), 1.47-
1.30 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 193.9, 143.1, 137.1,
130.0, 129.3, 128.3, 124.5, 62.5, 39.5, 35.0, 32.4, 32.3, 31.1, 30.1, 23.4,
22.3; HRMS (ES) found 323.1237, C18H24OS35Cl requires MHþ
323.1236.
Cycloadduct 18. Aldehyde 17 (0.27 g, 0.84 mmol), hydroxylamine
hydrochloride (0.09 g, 1.26 mmol), and diisopropylethylamine
(0.67 mL, 2.52 mmol) in PhMe (8 mL) were heated to 60 °C. After
1.5 h, the mixture was adsorbed onto silica. Purification by column
chromatography, eluting with CH2Cl2-MeOH (49:1), gave the inter-
mediate oxime (0.19 g, 66%) as an oil (1:1 mixture of isomers): 1H NMR
(400 MHz, CDCl3) δ 7.60-7.53 (m, 2H), 7.49-7.37 (m, 3H), 6.84
(d, J 1.5 Hz, 0.5H), 6.84 (d, J 1.5 Hz, 0.5H), 5.39-5.36 (m, 1H), 3.70-
3.60 (m, 1H), 3.18-3.07 (m, 1H), 2.44-2.37 (m, 2H), 2.36-2.29 (m,
2H), 2.28-2.21 (m, 2H), 2.17-2.09 (m, 2H), 1.93-1.54 (m, 6H). This
oxime (0.18 g, 0.53 mmol) in PhMe (5.5 mL) was heated under reflux.
After 16 h, the mixture was adsorbed onto silica. Purification by column
2-(2-Chloroethyl)hept-6-enal 10. DIBAL-H (10 mL, 10 mmol,
1.0 M in hexanes) was added to nitrile 9 (1.40 g, 8.2 mmol) in CH2Cl2
(40 mL) at -78 °C. After 1.5 h, aqueous HCl (2 M, 5 mL) was added.
After 30 min, the mixture was warmed to room temperature, extracted
with Et2O (6 ꢀ 25 mL), dried (MgSO4), and evaporated. Purification by
column chromatography, eluting with petroleum ether-EtOAc (99:1),
gave aldehyde 10 (1.02 g, 72%) as an oil: IR νmax (film)/cm-1 2935,
1
1725, 1640, 1460; H NMR (400 MHz, CDCl3) δ 9.67 (s, 1H), 5.80
(ddt, J 17, 10, 6.5 Hz, 1H), 5.08-4.96 (m, 2H), 3.66-3.52 (m, 2H),
2.65-2.56 (m, 1H), 2.26-2.15 (m, 1H), 2.15-2.05 (m, 2H) 1.92-1.80
(m, 1H), 1.79-1.64 (m, 1H), 1.58-1.39 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 203.7, 137.9, 115.2, 48.9, 42.5, 33.6, 31.2, 27.9, 26.0;
HRMS (ES) found 175.0890, C9H16O35Cl requires MHþ 175.0883.
3-(Pent-4-enyl)-1H-pyrrole 12. The aldehyde 10 (0.50 g, 2.86
mmol), hydroxylamine hydrochloride (0.30 g, 4.29 mmol), and diiso-
propylethylamine (1.50 mL, 8.58 mmol) in PhMe (30 mL) were heated
under reflux. After 1.5 h, the mixture was adsorbed onto silica. Purifica-
tion by column chromatography, eluting with petroleum ether-EtOAc
(19:1), gave pyrrole 12 (0.14 g, 29%) as an oil: IR νmax (film)/cm-1
3370, 2925, 1680, 1640, 1440; 1H NMR (400 MHz, CDCl3) δ 8.02 (bs,
1H), 6.76 (q, J 2.5 Hz, 1H), 6.62 (d, J 1 Hz, 1H), 6.18-6.11 (m, 1H),
5.89 (ddt, J 17, 10, 6.5 Hz, 1H), 5.14-4.96 (m, 2H), 2.56 (t, J 7.5 Hz,
2H), 2.16 (q, J 7.5 Hz, 2H), 1.73 (quin, J 7.5 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 139.1, 124.2, 117.7, 115.0, 114.4, 108.6, 33.6, 30.4, 26.4;
HRMS (ES) found 135.1053, C9H13N requires MHþ 135.1048.
5-Cyclopentenyl-2-(phenylthio)pentanenitrile 14. n-Butyl-
lithium (1.36 mL, 3.7 mmol, 2.5 M in hexanes) was added to diisopro-
pylamine (0.52 mL, 3.4 mmol) in THF (5 mL) at -78 °C. After 10 min,
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NOTE
chromatography, eluting with CH2Cl2-MeOH (99.5:0.5), gave cy-
cloadduct 18 (0.15 g, 95%) as an oil: IR νmax (film)/cm-1 2935, 2855,
1475, 1440; 1H NMR (400 MHz, CDCl3) δ 7.60-7.51 (m, 2H), 7.44-
7.31 (m, 3H), 4.11 (d, J 5 Hz, 1H), 3.46 (td, J 12.5, 6 Hz, 1H), 3.39-3.32
(m, 1H), 3.31 (s, 1H), 2.22 (td, J 12.5, 6 Hz, 1H), 2.06-1.95 (m, 2H),
1.94-1.80 (m, 3H), 1.79-1.66 (m, 3H), 1.64-1.54 (m, 2H), 1.51-1.36
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 136.7, 132.7, 128.9, 128.7, 87.9,
79.6, 59.4, 59.0, 55.7, 43.1, 37.2, 36.3, 33.8, 33.0, 24.3, 19.0; HRMS (ES)
found 302.1568, C18H24NOS requires MHþ 302.1579.
(2R,3a0R,7a0S)-3a0-(Phenylthio)octahydrospiro[cyclopen-
tane-1,70-indol]-2-ol 19. Zn powder (0.26 g, 4.0 mmol) was added
to cycloadduct 18 (0.30 g, 1.0 mmol) in AcOH (1.6 mL) and H2O
(3.3 mL), and the mixture was heated at 100 °C. After 3 h, the mixture
was cooled to room temperature, filtered, washed with CH2Cl2, and
evaporated. Aqueous NH4OH (10 mL) was added, and the mixture was
extracted with CH2Cl2 (3 ꢀ 20 mL), dried (MgSO4), and evaporated to
give alcohol 19 (0.27 g, 91%), which was recrystallized from CH2Cl2-
petroleum ether as cubes: mp 96-98 °C; IR νmax (film)/cm-1 3335,
1445, 1250; 1H NMR (400 MHz, CDCl3) δ 7.59-7.49 (m, 2H), 7.39-
7.29 (m, 3H), 3.78 (d, J 4.5 Hz, 1H), 3.06-2.92 (m, 3H), 2.33-2.23 (m,
1H), 2.13-1.57 (m, 9H), 1.49-1.39 (m, 1H), 1.37-1.25 (m, 2H), 1.17
(td, J 13.5, 3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 136.5, 133.0,
128.6, 128.5, 82.4, 68.0, 56.3, 47.8, 43.3, 42.6, 34.1, 31.6, 31.4, 29.5, 22.5,
18.4; HRMS (ES) found 304.1730, C18H26NOS requires MHþ
304.1735. Anal. Calcd for C18H25NOS: C, 71.24; H, 8.30; N, 4.62; S,
10.57. Found: C, 71.44; H, 8.10; N, 4.70; S, 10.45.
0.65H), 2.79-2.67 (m, 0.35H), 2.35-2.28 (m, 2H), 2.27-2.20 (m,
2H), 2.16-2.09 (m, 2H), 2.02-1.43 (m, 7H), 1.01 (t, J 7 Hz, 3H),
0.93-0.90 (m, 9H), 0.09-0.07 (m, 6H); 13C NMR (100 MHz, CDCl3,
some peaks coalesce and/or are not observed) δ 143.6, 124.1, 122.1,
120.9, 65.6, 65.0, 37.6, 37.3, 34.9, 33.9, 33.1, 32.4, 30.6, 30.4, 29.9, 27.9,
25.6, 25.7, 23.4, 18.2, 14.3, 12.6, -5.5; HRMS (ES) found 322.2556,
C19H36NOSi requires MHþ 322.2566.
5-Cyclopentenyl-2-((S)-1-hydroxypropan-2-yl)pentaneni-
trile 24. Tetrabutylammonium fluoride (7.8 mL, 7.8 mmol, 1.0 M in
THF) was added to ether 23 (1.00 g, 3.11 mmol, dr 2:1) in THF
(30 mL) with 4 Å molecular sieves. After 1 h, the mixture was filtered and
evaporated. Purification by column chromatography, eluting with pet-
roleum ether-EtOAc (3:1), gave alcohol 24 (0.53 g, 82%) as an oil (dr
1
2:1): IR νmax (film)/cm-1 3360, 2950, 1460; H NMR (400 MHz,
CDCl3) δ 5.40-5.35 (m, 1H), 3.75-3.55 (m, 2H), 3.01-2.94 (m,
0.65H), 2.73-2.66 (m, 0.35H), 2.36-2.28 (m, 2H), 2.27-2.20 (m,
2H), 2.18-2.10 (m, 2H), 2.03-1.46 (m, 7H), 1.09 (d, J 7 Hz, 1H), 1.05
(d, J 7 Hz, 2H); 13C NMR (100 MHz, CDCl3, some peaks coalesce and/
or are not observed) δ 143.6, 124.1, 120.7, 65.5, 65.0, 37.3, 37.2, 34.9,
34.2, 33.3, 32.4, 30.5, 30.0, 28.4, 25.7, 25.6, 23.4, 14.6, 12.6; HRMS (ES)
found 208.1695, C13H22NO requires MHþ 208.1701.
5-Cyclopentenyl-2-((R)-1-hydroxypropan-2-yl)-2-(phenyl-
thio)pentanenitrile 25. PrMgCl (2.40 mL, 4.80 mmol, 2.0 M in
i
THF) was added to nitrile 24 (0.20 g, 0.97 mmol) in THF (2 mL) at
-78 °C. After 5 min, the mixture was warmed to room temperature.
After 30 min, the mixture was cooled to -78 °C, diphenyl disulfide (1.05 g,
4.80 mmol) in THF (2 mL) was added, and the mixture was warmed to
room temperature. After 16 h, saturated aqueous ammonium chloride
solution (10 mL) was added, the mixture was extracted with Et2O (3 ꢀ
30 mL), dried (MgSO4), and evaporated. Purification by column
chromatography, eluting with petroleum ether-EtOAc (4:1), gave
nitrile 25 (0.28 g, 92%) as an oil (dr 2:1): IR νmax (film)/cm-1 3420,
Acetal 20. Paraformaldehyde (20 mg, 0.65 mmol) and TsOH H2O
3
(1.5 mg, 0.05 mmol) were added to amino alcohol 19 (50 mg, 0.16
mmol) in CHCl3 (3 mL), and the mixture was heated to 65 °C. After 16
h, the mixture was adsorbed onto silica. Purification by column
chromatography, eluting with CH2Cl2-MeOH (99.5:0.5), gave acetal
20 (35 mg, 70%) as an oil: IR νmax (film)/cm-1 2925, 2860, 2800, 1475,
1440; 1H NMR (400 MHz, CDCl3) δ 7.57-7.50 (m, 2H), 7.39-7.30
(m, 3H), 4.39 (d, J 7 Hz, 1H), 3.94 (d, J 7 Hz, 1H), 3.77 (t, J 9 Hz, 1H),
3.01 (td, J 8, 3 Hz, 1H), 2.47 (ddd, J 13, 8, 5 Hz, 1H), 2.36-2.19 (m,
3H), 2.09-1.55 (m, 9H), 1.55-1.42 (m, 2H), 1.30-1.22 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 136.1, 132.9, 128.7, 128.4, 84.0, 79.4, 67.3,
56.0, 46.9, 42.1, 39.4, 34.6, 34.1, 33.2, 25.4, 20.4, 19.9; HRMS (ES)
found 316.1723, C19H26NOS requires MHþ 316.1735.
1
2945, 2850, 2250, 1440; H NMR (400 MHz, CDCl3) δ 7.78-7.60
(m, 2H), 7.54-7.34 (m, 3H), 5.39-5.31 (m, 1H), 4.11-3.98 (m, 1H),
3.78-3.69 (m, 1H), 2.34-2.26 (m, 2H), 2.26-2.17 (m, 2H), 2.11-
2.01 (m, 2H), 1.91-1.58 (m, 7H), 1.28 (d, J 7 Hz, 1H), 1.25 (d, J 7 Hz,
2H); 13C NMR (100 MHz, CDCl3, some peaks coalesce and/or are not
observed) δ 143.4, 143.3, 137.3, 137.0, 130.3, 129.3, 128.8, 124.4, 120.5,
64.6, 64.3, 52.8, 40.4, 40.2, 35.0, 34.9, 34.5, 34.0, 32.4, 30.7, 23.4, 23.1,
22.6, 12.8, 12.6; HRMS (ES) found 316.1732, C19H26NOS requires
MHþ 316.1735.
Acetal 21. Acetaldehyde (0.04 mL, 0.65 mmol) and TsOH H2O
3
(1.5 mg, 0.05 mmol) were added to amino alcohol 19 (50 mg, 0.16
mmol) in CHCl3 (3 mL), and the mixture was heated to 65 °C. After
16 h, the mixture was adsorbed onto silica. Purification by column
chromatography, eluting with CH2Cl2-MeOH (99.5:0.5), gave acetal
21 (30 mg, 57%) as an oil: IR νmax (film)/cm-1 2930, 2880, 2800, 1475,
1440; 1H NMR (400 MHz, CDCl3) δ 7.57-7.48 (m, 2H), 7.38-7.29
(m, 3H), 3.97 (q, J 7 Hz, 1H), 3.78 (t, J 8.5 Hz, 1H), 3.05-2.98 (m, 1H),
2.55-2.45 (m, 1H), 2.29-2.18 (m, 3H), 2.13-2.03 (m, 1H), 2.00-
1.71 (m, 4H), 1.70-1.55 (m, 4H), 1.54-1.38 (m, 2H), 1.30-1.18 (m,
4H); 13C NMR (100 MHz, CDCl3) δ 136.0, 132.9, 128.6, 128.4, 84.8,
83.9, 67.7, 56.2, 47.3, 41.9, 39.4, 34.3, 33.9, 33.1, 26.0, 20.4, 20.2, 19.9;
HRMS (ES) found 330.1889, C20H28NOS requires MHþ 330.1892.
2-((S)-1-(tert-Butyldimethylsilyloxy)propan-2-yl)-5-cyclo-
pentenylpentanenitrile 23. n-Butyllithium (5.52 mL, 13.8 mmol,
2.5 M in hexanes) was added to diisopropylamine (2.13 mL, 15.1 mmol)
in THF (15 mL) at -78 °C. After 10 min, nitrile 2232 (2.80 g, 13.1
mmol) and then iodide 1330 (4.65 g, 19.7 mmol) were added, and the
mixture was warmed to room temperature. After 16 h, saturated aqueous
ammonium chloride solution (25 mL) was added, the mixture was
extracted with Et2O (3 ꢀ 60 mL), dried (MgSO4), and evaporated.
Purification by column chromatography, eluting with petroleum ether-
EtOAc (99:1), gave nitrile 23 (4.11 g, 98%) as an oil (dr 2:1): IR νmax
(film)/cm-1 2930, 2860, 2250, 1460, 1260; 1H NMR (400 MHz,
CDCl3) δ 5.39-5.35 (m, 1H), 3.68-3.44 (m, 2H), 3.01-2.90 (m,
2-((S)-1-Chloropropan-2-yl)-5-cyclopentenyl-2-(phenyl-
thio)pentanenitrile 26. The alcohol 25 (0.63 g, 2.0 mmol, dr 2:1)
was added to polymer-bound triphenylphosphine (1.30 g, 4.0 mmol, ∼3
mmol g-1, 2% cross-linked with divinylbenzene) and CCl4 (4.90 mL,
3
40 mmol) in CH2Cl2 (4 mL) at 0 °C, and the mixture was warmed to
room temperature. After 3 d, the mixture was filtered, washed with
CH2Cl2, evaporated, and adsorbed onto silica. Purification by column
chromatography, eluting with petroleum ether-EtOAc (99:1), gave
nitrile 26 (0.60 g, 90%) as an oil (dr 2:1): IR νmax (film)/cm-1 2945,
2850, 2250, 1440; 1H NMR (400 MHz, CDCl3) δ 7.73-7.64 (m, 2H),
7.54-7.40 (m, 3H), 5.40-5.34 (m, 1H), 4.12 (dd, J 11, 2.5 Hz, 0.65H),
4.02 (dd, J 11, 2.5 Hz, 0.35H), 3.50 (t, J 11 Hz, 0.35H), 3.43 (t, J 11 Hz,
0.65H), 2.36-2.27 (m, 2H), 2.27-2.18 (m, 2H), 2.15-2.05 (m, 2H),
1.93-1.66 (m, 6H), 1.64-1.51 (m, 1H), 1.37 (d, J 6.5 Hz, 1H), 1.32 (d,
J 6.5 Hz, 2H); 13C NMR (100 MHz, CDCl3, some peaks coalesce and/
or are not observed) δ 143.1, 137.4, 137.1, 130.6, 130.5, 129.4, 128.4,
124.6, 119.8, 53.8, 53.3, 46.5, 46.0, 41.2, 34.9, 34.9, 33.9, 33.7, 32.4, 30.6,
30.6, 23.4, 23.3, 22.5, 13.5, 13.2; HRMS (ES) found 334.1408,
C19H25NS35Cl requires MHþ, 334.1396.
2-((S)-1-Chloropropan-2-yl)-5-cyclopentenyl-2-(phenylthio)-
pentanal 27. In the same way as 10, DIBAL-H (4.20 mL, 4.2 mmol,
1.0 M in hexanes) and nitrile 26 (0.70 g, 2.10 mmol, dr 2:1) gave, after
purification by column chromatography, eluting with petrol-EtOAc
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NOTE
(99:1), gave aldehyde 27 (0.46 g, 65%) as an oil (dr 7:3): IR νmax (film)/
cm-1 2940, 2845, 1715, 1440; 1H NMR (400 MHz, CDCl3) δ 9.53 (s,
0.3H), 9.44 (s, 0.7H), 7.46-7.31 (m, 5H), 5.38-5.31 (m, 1H), 4.09
(dd, J 10.5, 3 Hz, 0.7H), 3.87 (dd, J 10.5, 3 Hz, 0.3H), 3.59-3.51 (m,
0.3H), 3.47-3.40 (m, 0.7H), 2.39-2.26 (m, 2H), 2.26-2.16 (m, 2H),
2.08-1.96 (m, 2H), 1.87 (quin, J 7.5 Hz, 2H), 1.79-1.67 (m, 1H),
1.65-1.35 (m, 4H), 1.32 (d, J 7 Hz, 0.9H), 1.26 (d, J 7 Hz, 2.1H); 13C
NMR (100 MHz, CDCl3, some peaks coalesce and/or are not observed)
δ 194.1, 193.2, 143.5, 137.5, 137.2, 130.0, 129.4, 128.9, 128.2, 124.3,
65.9, 47.3, 47.2, 38.9, 38.3, 35.0, 32.4, 31.6, 29.5, 23.4, 22.4, 22.3, 13.4;
HRMS (ES) found 337.1394, C19H26OS35Cl requires MHþ 337.1393.
2-((S)-1-Chloropropan-2-yl)-5-cyclopentenyl-2-(phenylthio)-
pentanal Oxime 28. Aldehyde 27 (0.44 g, 1.31 mmol, dr 7:3),
hydroxylamine hydrochloride (0.14 g, 1.97 mmol), and diisopropylethy-
lamine (0.69 mL, 3.93 mmol) were heated in PhMe (13 mL) at 60 °C.
After 16 h, the solvent was evaporated and the mixture was adsorbed
onto silica. Purification by column chromatography, eluting with
CH2Cl2-MeOH (49:1), gave oxime 28 (0.33 g, 72%) as an oil (dr
7:3): IR νmax (film)/cm-1 3280, 2930, 1455, 1275; 1H NMR (400 MHz,
CDCl3) δ 7.58-7.47 (m, 2H), 7.44-7.32 (m, 3H), 6.88 (s, 0.3H), 6.70
(s, 0.7H), 5.38 (s, 0.3H), 5.34 (m, 0.7H), 3.80 (dd, J 13.5, 8.5 Hz, 1H),
3.51-3.42 (m, 1H), 2.81-2.70 (m, 1H), 2.37-2.16 (m, 4H), 2.15-
2.03 (m, 2H), 1.94-1.58 (m, 5H), 1.55-1.41 (m, 1H), 1.31 (d, J 7.5 Hz,
2.1H), 1.13 (d, J 7.5 Hz, 0.9H); 13C NMR (100 MHz, CDCl3, some
peaks coalesce and/or are not observed) δ 143.5, 139.4, 137.5, 137.2,
129.7, 129.6, 129.5, 129.3, 129.2, 124.3, 68.5, 68.0, 64.5, 63.3, 38.8, 38.5,
36.8, 34.9, 33.4, 32.4, 31.3, 31.0, 23.4, 23.2, 13.1, 11.9; HRMS (ES)
found 316.1725, C19H26NOS requires MHþ 316.1735.
118.2, 64.4, 64.0, 40.9, 40.2, 38.4, 38.3, 14.1, 13.5; HRMS (ES) found
208.0788, C11H14NOS requires MHþ 208.0796.
(1S,2R,30R,3a0R,7a0S)-30-Methyl-3a0-(phenylthio)octahy-
drospiro[cyclopentane-1,70-indol]-2-ol 33. In the same way as
19, cycloadduct 29 (0.10 g, 0.32 mmol) and Zn powder (0.08 g, 1.27
mmol) at 70 °C for 2 h gave alcohol 33 (0.10 g, 99%) as an oil, which was
used without further purification: IR νmax (film)/cm-1 3360, 2930,
2870, 1435; 1H NMR (400 MHz, CDCl3) δ 7.49-7.41 (m, 2H), 7.36-
7.24 (m, 3H), 3.83 (d, J 4 Hz, 1H), 3.39 (dd, J 11, 6 Hz, 1H), 3.07
(s, 1H), 2.75 (dd, J 11, 6 Hz, 1H), 2.31-2.21 (m, 1H), 2.04-1.59 (m, 8H),
1.48-1.39 (m, 1H), 1.36-1.12 (m, 3H), 1.28 (d, J 7 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 133.7, 133.0, 128.8, 127.7, 82.1, 65.5, 61.8, 52.2, 47.9,
43.4, 34.7, 31.7, 31.1, 29.9, 21.9, 18.9, 18.3; HRMS (ES) found 318.1888,
C19H28NOS requires MHþ 318.1892.
Acetal 34. In the same way as 20, alcohol 33 (0.09 g, 0.28 mmol),
paraformaldehyde (0.034 g, 1.12 mmol), and TsOH H2O (3 mg, 0.01
3
mmol) gave, after purification by column chromatography, eluting with
CH2Cl2-MeOH (99.5:0.5), acetal 34 (0.07 g, 79%) as an oil: [R]21
-
D
100 (c 0.5, CHCl3); IR νmax (film)/cm-1 2925, 1475, 1440; 1H NMR
(400 MHz, CDCl3) δ 7.44-7.37 (m, 2H), 7.33-7.21 (m, 3H), 4.40 (d,
J 6.5 Hz, 1H), 3.99 (d, J 6.5 Hz, 1H), 3.70 (t, J 8 Hz, 1H), 3.40 (t, J 7.5 Hz,
1H), 2.55-2.44 (m, 1H), 2.24 (s, 1H), 2.18 (q, J 7.5 Hz, 1H), 2.04 (td,
J 13, 3.5 Hz, 1H), 1.96-1.85 (m, 2H), 1.85-1.71 (m, 4H), 1.70-1.59
(m, 1H), 1.59-1.42 (m, 2H), 1.40-1.32 (m, 1H), 1.27 (d, J 7.5 Hz,
3H), 1.22 (bs, 1H); 13C NMR (100 MHz, CDCl3) δ 134.2, 132.8, 128.6,
126.7, 84.6, 79.9, 65.4, 56.7, 56.6, 42.5, 41.9, 34.7, 33.1, 32.8, 26.0, 20.8,
20.2, 20.1; HRMS (ES) found 330.1890, C20H28NOS requires MHþ,
330.1892. Anal. Calcd for C20H27NOS: C, 72.90; H, 8.26; N, 4.25; S,
9.73. Found: C, 72.84; H, 8.56; N, 4.12; S, 9.66.
Cycloadducts 29 and 30. The oxime 28 (0.32 g, 0.91 mmol, dr
7:3) was heated in PhMe (9 mL) under reflux. After 16 h, the solvent was
evaporated and the residue was adsorbed onto silica. Purification by
column chromatography, eluting with CH2Cl2-MeOH (99.5:0.5), gave
cycloadducts 29 and 30 (0.23 g, 80%) (ratio 7:3) partially separated.
29 (107 mg) as an oil: [R]21D -3.5 (c 0.09, CHCl3); IR νmax (film)/
cm-1 2930, 2860, 1460, 1440; 1H NMR (400 MHz, CDCl3) δ 7.57-
7.50 (m, 2H), 7.41-7.33 (m, 3H), 4.06 (d, J 6 Hz, 1H), 3.70 (s, 1H), 3.39
(dd, J 13, 6.5 Hz, 1H), 3.23 (t, J 13 Hz, 1H), 2.70-2.64 (m, 1H), 2.15 (dd,
J 14, 1.5 Hz, 1H), 1.92-1.76 (m, 3H), 1.72-1.62 (m, 1H), 1.59-1.33 (m,
5H), 1.27-1.17 (m, 1H), 1.12 (d, J 7 Hz, 3H), 1.00 (td,
J 13, 3.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 137.2, 132.5, 128.8,
128.7, 87.8, 79.6, 62.9, 62.3, 59.7, 42.8, 40.4, 33.6, 33.5, 33.2, 24.1, 19.2,
10.5; HRMS (ES) found 316.1732, C19H26NOS requires MHþ 316.1735.
29 and 30 (98 mg) (1:1 mixture) as an oil.
Acetal 36. In the same way as 33, cycloadduct 30 (23 mg, 0.073
mmol) and Zn powder (19 mg, 0.29 mmol) gave the alcohol 35 (23 mg,
0.07 mmol), which was not characterized but was taken on directly.
Paraformaldehyde (9 mg, 0.29 mmol) and TsOH H2O (0.70 mg, 0.003
3
mmol) were added to 35 in CHCl3 (1.5 mL), and the mixture was
heated to 65 °C. After 16 h, the mixture was adsorbed onto silica.
Purification by column chromatography, eluting with CH2Cl2-MeOH
(99.5:0.5), gave acetal 36 (14 mg, 58% over two steps) as an oil: [R]21
D
þ90 (c 0.5, CHCl3); IR νmax (film)/cm-1 2925, 2855, 1440; 1H NMR
(400 MHz, CDCl3) δ 7.60-7.52 (m, 2H), 7.44-7.30 (m, 3H), 4.32 (d,
J 7 Hz, 1H), 3.95 (d, J 7 Hz, 1H), 3.71 (t, J 8 Hz, 1H), 2.67-2.51 (m,
2H), 2.45 (t, J 8 Hz, 1H), 2.41-2.32 (m, 2H), 2.08-1.43 (m, 10H),
1.32-1.20 (m, 1H), 0.73 (d, J 7 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 137.5, 131.9, 129.0, 128.6, 84.5, 79.6, 66.4, 57.8, 54.0, 43.3, 40.7, 34.1,
33.0, 28.1, 26.1, 20.4, 20.0, 13.2; HRMS (ES) found 330.1877,
C20H28NOS requires MHþ 330.1892.
30 (28 mg) as an oil, which crystallized on standing to give cubes: mp
89-91 °C; [R]21 þ4.3 (c 0.25, CHCl3);IR νmax (film)/cm-1 2930,
D
2860, 1440; 1H NMR (400 MHz, CDCl3) δ 7.57-7.48 (m, 2H), 7.43-
7.30 (m, 3H), 4.31-4.25 (m, 1H), 3.34 (dd, J 11.5, 7.5 Hz, 1H), 3.26 (s,
1H), 2.81 (t, J 11.5 Hz, 1H), 2.36-2.17 (m, 2H), 1.94-1.69 (m, 7H),
1.66-1.52 (m, 4H), 1.01 (d, J 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 137.9, 130.9, 129.2, 128.9, 87.2, 77.4, 61.6, 57.2, 56.1, 42.9, 42.0, 35.0,
27.1, 24.3, 23.4, 16.7, 10.7; HRMS (ES) found 316.1737, C19H26NOS
requires MHþ 316.1735. Anal. Calcd for C19H25NOS: C, 72.34; H, 7.99;
N, 4.44; S, 10.16. Found: C, 72.44; H, 7.97; N, 4.46; S, 10.00.
’ ASSOCIATED CONTENT
S
Supporting Information. Crystallographic information
b
files (CIFs) and ORTEP diagrams for the amino alcohol 19
and the cycloadduct 30 (CCDC reference nos. 806620 and
806619, respectively) and copies of NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(3R)-4-Hydroxy-3-methyl-2-(phenylthio)butanenitrile 32.
i
In the same way as 25, nitrile 3135 (0.30 g, 3.03 mmol), PrMgCl
’ AUTHOR INFORMATION
(4.55 mL, 9.10 mmol, 2.0 M in THF), and PhSSPh (1.99 g, 9.10 mmol)
gave, after purification by column chromatography, eluting with petro-
leum ether-EtOAc (4:1), nitrile 32 (0.50 g, 80%) as an oil (dr 3:1): IR
νmax (film)/cm-1 3420, 2945, 2850, 2250, 1440; 1H NMR (400 MHz,
CDCl3) δ 7.66-7.57 (m, 2H), 7.42-7.32 (m, 3H), 4.15 (d, J 5.5 Hz,
0.75H), 3.98 (d, J 5.5 Hz, 0.25H), 3.83-3.72 (m, 1H), 3.62-3.55 (m,
1H), 2.31-2.14 (m, 2H), 1.21 (d, J 7 Hz, 0.75H), 1.18 (d, J 7 Hz,
2.25H); 13C NMR (100 MHz, CDCl3, some peaks coalesce and/or are
not observed) δ 134.0, 133.7, 131.7, 131.6, 129.5, 129.3, 129.2, 119.2,
Corresponding Author
*E-mail: i.coldham@sheffield.ac.uk.
’ ACKNOWLEDGMENT
We thank the EPSRC, AstraZeneca, and the University of
Sheffield, U.K., for support of this work.
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The Journal of Organic Chemistry
NOTE
’ REFERENCES
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