A tandem Horner-Emmons olefination-gonjugate addition approach to the synthesis of 1,5-Disubstituted-6-azabicyclo[3.2.1]octanes based on the AE ring structure of the norditerpenoid alkaloid methyllycaconitine

Article abstract of DOI:10.1021/jo9519672

A novel Horner-Emmons olefination conjugate addition reaction of N-acetylamides to form 1,5-disubstituted-6-azabicyclo[3.2.1]octanes with two bridgehead quarternary carbon centers is reported. This reaction is a key step in an approach to the synthesis of small ring analogues based on the AE ring structure of the Delphinium norditerpenoid, methyllycaconitine (MLA) (1). Initially, 3-(hydroxymethyl)cyclohex-2-en-1-one (10) was selected as the starting material to these structures, but its generation proved inefficient. In contrast, the synthesis of 3-[(phenylthio)methyl]cyclohex-2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex-2-en-1-one (11) proceeded in good yield. Subsequent hydrocyanation, ketalization, reduction, acetylation, deprotection of the acetal, and Horner-Emmons olefination-conjugate addition reaction to form 1-[(phenylthio)methyl]-5-[(ethoxycarbonyl)methyl]-6-acetamido-6-azabicyclo[3.2. 1]octane(28), 1-(1,3-dithian-2-yl)-5-[(ethoxycarbonyl)methyl]-6-acetyl-6-azabicyclo[3.2.1] octane (29), respectively, are reported, as well as for readily available 3-methylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent desulfurization and reduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40) and then selective protection to form a protected hydroxyethyl N-ethyl (hydroxymethyl)azabicyclo-[3.2.1]octane (3) are also described.

Full text of DOI:10.1021/jo9519672

4634
J . Org. Chem. 1996, 61, 4634-4640
A Ta n d em Hor n er -Em m on s Olefin a tion -Con ju ga te Ad d ition
Ap p r oa ch to th e Syn th esis of
1,5-Disu bstitu ted -6-a za bicyclo[3.2.1]octa n es Ba sed on th e AE Rin g
Str u ctu r e of th e Nor d iter p en oid Alk a loid Meth yllyca con itin e
David J . Callis,† Noel F. Thomas,*,† David P. J . Pearson,‡ and Barry V. L. Potter†
School of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK and
Zeneca Agrochemicals, J ealott’s Hill Research Station, Bracknell, Berkshire RG42 6ET, UK
Received November 6, 1995X
A novel Horner-Emmons olefination conjugate addition reaction of N-acetylamides to form 1,5-
disubstituted-6-azabicyclo[3.2.1]octanes with two bridgehead quarternary carbon centers is reported.
This reaction is a key step in an approach to the synthesis of small ring analogues based on the
AE ring structure of the Delphinium norditerpenoid, methyllycaconitine (MLA) (1). Initially,
3-(hydroxymethyl)cyclohex-2-en-1-one (10) was selected as the starting material to these structures,
but its generation proved inefficient. In contrast, the synthesis of 3-[(phenylthio)methyl]cyclohex-
2-en-1-one (6) and 3-(1,3-dithian-2-yl)cyclohex-2-en-1-one (11) proceeded in good yield. Subsequent
hydrocyanation, ketalization, reduction, acetylation, deprotection of the acetal, and Horner-Emmons
olefination-conjugate addition reaction to form 1-[(phenylthio)methyl]-5-[(ethoxycarbonyl)methyl]-
6-acetamido-6-azabicyclo[3.2.1]octane (28), 1-(1,3-dithian-2-yl)-5-[(ethoxycarbonyl)methyl]-6-acetyl-
6-azabicyclo[3.2.1]octane (29), respectively, are reported, as well as for readily available 3-meth-
ylcyclohex-2-en-1-one (12). Studies on the Pummerer rearrangement of 28 and subsequent
desulfurization and reduction to form an hydroxymethyl-substituted azabicyclo[3.2.1.]octane (40)
and then selective protection to form a protected hydroxyethyl N-ethyl (hydroxymethyl)azabicyclo-
[3.2.1]octane (3) are also described.
In tr od u ction
is not well documented.6 The formation of these hetero-
cycles would be of value in the course of our synthetic
studies in the structure-activity relationships of the
Delphinium norditerpenoid methyllycaconitine (MLA)
(1). Previously, construction of the AE ring system of
this potent nicotinic acetylcholine receptor7 antagonist
used a double Mannich reaction on a keto ester to form
the required azabicyclo[3.3.1]nonanes.8 This bicyclic
structure forms a crucial part of the rigid homocholine
motif of the proposed MLA pharmacophore. Its relation-
ship to acetylcholine9 (2) is shown in Figure 1. However,
in order to synthesize the related azabicyclo[3.2.1]octane
system of our target (3) (Figure 2), to explore the effect
of ring contraction upon antagonist activity, a different
strategy was required. Our synthetic strategy is il-
lustrated by the retrosynthetic analysis shown below
(Scheme 1).
Azabicyclo[3.2.1]octanes are invaluable intermediates
in natural product synthesis.1 For example, Speckamp
et al.2 reported the formation of a 6-azabicyclo[3.2.1]-
octanone by silicon-assisted N-acyliminium ion cycliza-
tion as a key step in the synthesis of the Aristotelia
alkaloid peduncularine. Holmes et al.3 reported a ste-
reoselective synthesis of (()-actinbolamine, the main
degradation product of the antitumour compound, acti-
nobolin, via a 6-azabicyclo[3.2.1]octane. Carroll et al.4
have described a concise synthesis of (+)-6-methyl-6-
azabicyclo[3.2.1]octan-3-ol, a key intermediate for the
preparation of azaprophen (a novel conformationally
restricted, highly potent antimuscarinic analogue of
atropine). Shibanuma et al.5 have published a synthetic
approach to kobusine, a diterpene alkaloid whose BD ring
system is a 6-azabicyclo[3.2.1]octane. Notwithstanding
these achievements, stereocontrolled generation of 1,5
disubstituted 6-azabicyclo[3.2.1]octanes containing two
bridgehead quaternary carbon centers, a structural fea-
ture not present in the azabicyclooctanes described above,
Discu ssion
Initially, attention was focused on the synthesis of
3-hydroxymethyl-substituted cyclohex-2-en-1-ones. The
synthesis of 3-substituted cyclohex-2-en-1-ones has been
comprehensively examined by Heathcock et al.10 during
synthetic investigations directed at the antitumor lac-
tone, vernolepin. Recently, multistep syntheses of 3-sub-
stituted cyclohex-2-en-1-ones have been reported sepa-
* Author to whom correspondence should be sent.
† University of Bath.
‡ Zeneca Agrochemicals.
X Abstract published in Advance ACS Abstracts, J une 1, 1996.
(1) For azabicyclo[3.2.1]octanes, see: (a) Lounasmaa, M. The Alka-
loids; Academic Press Inc.: New York, 1988; Vol. 33, pp 1-83. (b)
Focor, G.; Dharanipragada, R. Nat. Prod. Rep. 1990, 7, 539. (c) Turconi,
M.; Nicola, M.; Quintero, M. G.; Maiocchi, L.; Micheletti, R.; Geraldo,
E.; Donetti, A. J . Med. Chem. 1990, 33, 2101. (d) J ung, M. E.; Longmei,
Z.; Tangsheng, P.; Huiyan, Z.; Yan, L.; J ingyu, S. J . Org. Chem. 1992,
57, 3528. (e) Petersen, J . S.; Toteberg-Kaulen, S.; Rapoport, H. J . Org.
Chem. 1984, 49, 2948. (f) Fevig, J . M.; Marquis, R. W.; Overman, L.
E. J . Am. Chem. Soc. 1991, 113, 5085.
(6) For a previous synthesis of a 1,5-dicyano-substituted azabicyclo-
[3.2.1]octane see: Betts, B. E.; Davey, W. J . Chem. Soc. 1961, 1683.
(7) (a) J ennings, K. R.; Brown, D. G.; Wright, D. P. Experientia 1986,
42, 611. (b) Kukel, C. F.; J ennings, K. R. Can. J . Physiol. Pharmacol.
1994, 72, 104.
(8) (a) Blagbrough, I. S.; Coates, P. A.; Hardick, D. J .; Lewis, T.;
Rowan, M. G.; Wonnacott, S.; Potter, B. V. L. Tetrahedron Lett. 1994,
35, 8705. (b) Coates, P. A.; Blagbrough, I. S.; Rowan, M. G.; Pearson,
D. P. J .; Lewis, T.; Potter, B. V. L. Tetrahedron Lett. 1994, 35, 8709.
(9) Ward, J . M.; Cockcroft, V. B.; Lunt, G. G.; Smillie, F. S.;
Wonnacott, S. FEBS Lett. 1990, 270, 45-48.
(2) Klaver, W. J .; Hiemstra, H.; Nico Speckamp, W. J . Am. Chem.
Soc. 1989, 111, 2588.
(3) Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. J . Chem.
Soc., Chem. Commun. 1990, 1412.
(4) Phillip, A.; Pitner, J . B.; J oo, Y. J .; Triggle, D. J .; Carroll, F. I.
J . Chem. Soc., Chem. Commun. 1990, 984.
(5) Shibanuma, Y.; Okamoto, T. Chem. Pharm. Bull. 1985, 33, 3187.
(10) Wege P. M.; Clark, R. D.; Heathcock, C. H. J . Org. Chem. 1976,
41, 3144.
S0022-3263(95)01967-0 CCC: $12.00 © 1996 American Chemical Society

Tandem Horner-Emmons Olefination-Conjugate Addition
J . Org. Chem., Vol. 61, No. 14, 1996 4635
Sch em e 2
Sch em e 3a
F igu r e 1.
a
Reagents and Conditions: (i) KCN, NH4Cl, DMF; (ii) PTSA,
ethylene glycol; (iii) LiAlH4, diglyme; (iv) AcCl, Et3N; (v) H2SO4,
H2O, H2O/THF.
F igu r e 2.
Sch em e 1
Ta ble 1
yield (%) and compound no.
i
ii
iii
iv
v
R ) Me (12)
55 (13) 90 (14) 75 (15) 91 (16) 90 (17)
R ) 1,3-dithian- 40 (18) 92 (19) 79 (20) 93 (21) 87 (1:1(22)/(23))
2-yl (11)
R ) CH2SPh (6) 46 (24) 95 (5) 78 (25) 88 (26) 91 (4)
55% yield. Ketalization (ethylene glycol, PTSA) and
lithium aluminum hydride reduction in diglyme at 85
°C15 proceeded smoothly in yields of 90% and 75%,
respectively. The key intermediate, keto acetamide 17,
was prepared from 16 by treatment with Et3N and acetyl
chloride in 91% yield, followed by deketalization in 90%
yield (Scheme 3 and Table 1).
For the synthesis of key intermediates 6 and 11, the
commercially available 3-ethoxycyclohex-2-en-1-one (7)
was used as a convenient starting material. Treatment
of 7 with dithiane anion10 in THF followed by acidic
hydrolysis gave rise to dithianyl enone 1116 in 62% overall
yield (Scheme 2). The corresponding â-cyano ketone 18
was prepared in yields ranging from 32-40% by reaction
of 11 with KCN, DMF/15% H2O and NH4Cl at 105 °C for
6 h. The moderate yields of this reaction compared to
that of 12 are attributed to the steric influence of the
dithianyl substituent on the â-carbon of the cyclohex-
enone ring. The use of alternative reagents such as
diethylaluminum cyanide17 and trimethylsilyl cyanide18
produced only unchanged starting material. Formation
of acetal 21 from â-cyano ketone 18 was unproblematic
(Scheme 3 and Table 1).
rately by Knochel et al.11a and Gleiter et al.11b The one-
pot “reductive cyclization” (i.e. Birch reduction/hydrolysis)
of 2,6-disubstituted pyridines to produce C-3 alkyl-
substituted cyclohexenones as described by Danishefsky
et al.12 looked attractive, but attempts to apply this
chemistry to the problem were not successful.13 We
therefore decided to utilize 11 and 6, which incorporate
dithianyl and (phenylthio)methyl groups, respectively,
capable of later modification (Scheme 2).
Model reactions for our synthetic route were carried
out on the readily available 3-methylcyclohex-2-en-1-one
(12). Treatment of 12 with KCN, NH4Cl, and DMF/15%
H2O14 gave rise to the conjugate addition product 13 in
(11) (a) Knochel, P.; Chou, T.; J ubert, C.; Rajagopal, D. J . Org. Chem.
1993, 58, 588. (b) Gleiter, R.; Fischer, E. Chem. Ber. 1992, 125, 1899.
(12) (a) Danishefsky, S.; Cain, P.; Nagel, A. J Am. Chem. Soc. 1975,
380. (b) Danishefsky, S.; Cain, P. J . Org. Chem. 1975, 40, 3606. (c)
Danishefsky, S.; Zimmer, A. J . Org. Chem. 1976, 41, 4059.
(13) At a concentration of 16 mmol, Birch reduction of pyridine 8
with lithium and water, formed the required trisubstituted cyclohex-
2-en-1-one 10 and the unrequired tetrasubstituted cyclohex-2-en-1-
one (9) in 27% and 20% yields, respectively. With higher concentra-
tions, diminished yields of 9 and 10 were obtained.
Interestingly, deprotection of ketal 21 gave rise to
azabicyclooctanol (22)19 and the ketoacetamide 23 in 87%
combined yield in an approximate ratio of 1:1 by NMR.
The NMR spectrum of the mixture of 22 and 23 showed
(15) Nagata, W.; Sugusawa, T.; Narisada, M.; Wakabayashi, T.;
Hayase, Y. J . Am. Chem. Soc. 1967, 89, 1483.
(16) Lipshutz, B. H.; Ung, C. S.; Sengupta, S. Synth. Lett. 1989, 64.
(17) Nagata, W.; Yoshioka, M. Tetrahedron Lett. 1966, 18, 1913.
(18) (a) Utimoto, K.; Wakabayashi, Y.; Horrie, T.; Inoue, M.;
Shishiyama, Y.; Obayashi, M.; Norzaki, H. Tetrahedron 1983, 39, 967.
(b) Samson, M.; Vandewalle, M. Synth. Commun. 1978, 8, 231.
(14) Nagata, W.; Hirai, S.; Itazaki, H.; Takeda, K. J . Org. Chem.
1961, 26, 2413.

4636 J . Org. Chem., Vol. 61, No. 14, 1996
Callis et al.
Sch em e 4
Sch em e 6
Sch em e 5
Sch em e 7
of 50%, 65%, and 55%, respectively). For the formation
of 29 we assume the deprotonated alcohol 33 is first
converted to ketone (34) (Scheme 6) which can then take
part in the reaction cycle (Scheme 5).
The intramolecular Michael reaction has been the
subject of a recent and detailed review.22 Our Horner-
Emmons olefination conjugate addition approach to
azabicycles from amides appears to have little precedent,
although a few related examples not involving amides
are known in the carbohydrate field.23
a sharp singlet at δ 5.8 which disappears on deuteriation.
The 13C spectrum shows a peak at δ 93 indicating a
quaternary carbon, the C-5 bridgehead chiral center.
These data are consistent with the structure 22 (Scheme
4).
In order to find appropriate conditions for the dif-
ferential protection of the diol 40, reduction of both the
amide and ester groups of 28 was achieved by heating
with LiAlH4 in THF for 0.5 h to produce amino-alcohol
35. Discrete chemical shifts and coupling constants for
the protons H1, H2, H3, and H4 reveals a conformationally
restricted hydroxyethyl side chain, the probable result
of intramolecular H-bonding. Surprisingly, we were
unable to O-alkylate amino alcohol 35 with benzyl
bromide or methyl iodide and sodium hydride under
standard conditions.24 In stark contrast, the conversion
of 35 to the corresponding silyl ether 36 was accom-
plished by utilizing the strong silylating agent TBDM-
The preparation of acetamide 4 closely parallels that
of 17 and 23 (Scheme 3 and Table 1). Ketone 620 was
prepared in 67% yield by treatment of 7 with thioani-
sole,21 DABCO, BuLi, and THF, followed by acid hydroly-
sis10 (Scheme 2). Interestingly, during the transforma-
tion of 16 to 17 and 26 to 4, the (phenythio)methyl or
methyl analogues of 22 were not observed. We assume
that during the acid hydrolysis of the ketal the acetamide
group is held closer to the ketone in 23 than in 17 or 4
as a consequence of the greater steric bulk of the
dithianyl substituent favoring ring closure under acidic
conditions to azabicyclo[3.2.1]octanol (22) (Scheme 4).
Optimum conditions for the ring closure of ketones 4,
17, and a mixture of 22 and 23 to esters 27, 28, and 29,
respectively, were found to be potassium tert-butoxide
(1.1 equiv) and triethyl phosphonoacetate (1.1 equiv) in
DMF or THF (Scheme 5). Clearly, 1 equiv of the base
and the phosphonoacetate is consumed in the formation
of the protonated form of 30, which was not isolated. The
residual 0.1 equiv of base effects deprotonation and hence
the conjugate addition. The enolate 31 formed during
ring closure is responsible for the deprotonation of more
of the acetamide NH in 32, en route to the bicyclic
materials 27, 28, and 29, respectively (formed in yields
25
SOTf and Et3N in CH2Cl2 (Scheme 7).
A Pummerer rearrangement/desulfurization strategy26
was proposed as a means of unmasking the (phenylthio)-
methyl group to an hydroxymethyl group present in the
target molecule 3. Treatment of 28 with sodium perio-
date in MeOH at reflux produced a diastereoisomeric
mixture of sulfoxides 37 in 76% yield. The rearrange-
(22) Little, D.; Masjedizadeh, M. R.; Waldquist, O.; McLoughlin, J .
I. Org. React. 1995, 47, 315.
(23) Olefination conjugate additions with phosphonate sulfones to
optically active tetrahydropyrans have been described: (a) Davidson,
A. H.; Hughes, L. R.; Qureshi, S. S.; Wright, B. Tetrahedron Lett. 1988,
29, 693. (b) Keck, G. E.; Kachensky, D. F.; Enholm, E. J . J . Org. Chem.
1985, 50, 4317. (c) Bloch, R.; Seck, M. Tetrahedron 1989, 45, 3731. (d)
Ali, M. H.; Hough, L.; Richardson, A. C. J . Chem. Soc., Chem. Commun.
1984, 447. (e) Georges, M.; Fraser-Reid, B. J . Org. Chem. 1985, 50,
5754.
(19) 5-Exo-trigonal ring closure of an amide NH group onto a ketone
culminating in the formation of 6-methoxy-7-azabicyclo[4.2.1]nona-8-
one has been reported, see: Newman, H.; Fields, T. L. Tetrahedron
1972, 28, 4051.
(24) Czernecki, S.; Georgoulis, C.; Provelenghiou, C. Tetrahedron
Lett. 1976, 3535.
(20) For previous syntheses of (6) see: (a) Cohen, T.; Yu, L. C. J .
Am. Chem. Soc. 1983, 105, 2811. (b) Luzzio, F. A.; Moore, W. J . J .
Org. Chem. 1993, 58, 2966.
(25) Corey, E. J .; Cho, H.; Rucker, C.; Hua, D. H. Tetrahedron Lett.
1981, 22, 3455.
(26) (a) Delucchi, O.; Miotti, U.; Modena, G. Org. React. 1991, 40,
157. (b) Parham, W. E.; Edwards, L. D. J . Org. Chem. 1968, 33, 4150.
(21) Corey, E. J .; Seebach, D. J . Org. Chem. 1966, 31, 4097.

Tandem Horner-Emmons Olefination-Conjugate Addition
J . Org. Chem., Vol. 61, No. 14, 1996 4637
producing a dark blue solution. After approximately 20 min
the dark blue coloration disappeared and the NH3 was
evaporated off under a stream of nitrogen. H2O (20 mL) was
added dropwise (cautiously!), and the resulting aqueous
mixture were extracted with EtOAc (3 × 20 mL). The
combined organic layers were dried (MgSO4) and evaporated
in vacuo to produce a dark red oil. The crude product was
purified by flash column chromatography (EtOAc) to yield 9
as a light brown solid (0.41 g, 20% Rf 0.71, mp 58-60 °C: lit.
mp 60-61 °C27) and 10 as an orange oil (0.55 g, 27%, Rf 0.40).
Sch em e 8
For 9: 1H NMR (CDCl3), δ 1.92 (3 H, s), 1.96 (2 H, quint, J
) 6.4 Hz), 2.36 (2 H, tq, J ) 6.4 and 1.1 Hz), 2.49 (2 H, t, J )
6.4 Hz), 6.08 (1 H, s); 13C NMR (CDCl3) δ 16.8, 22.2, 30.4, 35.7,
130.7, 143.7, 194.1; IR ν 3450, 1670 cm-1; mass spectrum
m/z(%) 126(100), 111(10), 97(20), 84(20), 70(30), 55(24), 43(33),
27(20); HRMS: calcd for C7H10O2 m/z 126.0680, found 126.0678.
Anal. Calcd for C7H10O2: C, 66.65, H, 7.99. Found: C, 66.80,
H, 8.10.
For 10: 1H NMR (CDCl3), δ 2.18-1.98 (2 H, m), 2.26 (2 H,
q, J ) 6.0 Hz), 2.31 (1 H, s(br)), 2.42 (2 H, t, J ) 7.0 Hz), 4.26
(2 H, d, J ) 1.6 Hz), 6.15 (1 H, s); 13C NMR (CDCl3) δ 22.4,
26.1, 37.7, 64.7, 122.9, 167.4, 200.2; IR ν 3300-3400, 1710,
1646 cm-1; mass spectrum m/z(%) 127(M + H)+(100), 107(10),
91(10), 81(20). Anal. Calcd for C7H10O2: C, 66.65; H, 7.99.
Found: C, 66.40; H, 8.29.
3-Cya n o-3-m eth ylcycloh exa n -1-on e (13). 3-Methylcy-
clohex-2-en-1-one (12) (10 g, 90 mmol) was dissolved in 15%
H2O/DMF (100 mL). KCN (11.84 g, 180 mmol) and NH4Cl
(17.29 g, 135 mmol) were added, and the mixture was heated
at 100 °C for 1 h. The solution was cooled to room temperature
and evaporated in vacuo, and H2O (100 mL) was added. The
aqueous phase was extracted with CHCl3 (3 × 75 mL), and
the combined extracts were washed with H2O (2 × 70 mL),
dried (MgSO4), and evaporated in vacuo to form a dark brown
oil. Column chromatography (50% EtOAc/hexane) produced
13 (6.85 g, 55%) as an orange oil: 1H NMR (CDCl3), δ 1.50 (3
H, s), 1.80-2.30 (5 H, m), 2.35 (1 H, dd, J ) 14.5, 1.1 Hz),
2.46 (d(br), J ) 14.5 Hz), 2.70 (1 H, ddd, J ) 14.5, 2.0, 16.0
Hz); 13C NMR (CDCl3) δ 22.1, 26.1, 35.3, 36.6, 39.9, 50.8, 122.5,
205.8; IR ν 2250, 1725 cm-1; mass spectrum m/z(%) 137(25),
94(25), 55(100); HRMS: calcd for C8H11NO m/z 137.0841,
found 137.0834. Anal. Calcd for C8H11NO: C, 70.04; H, 8.08;
N, 10.21. Found: C, 70.10; H, 8.05; N, 10.45.
ment product 38 was obtained as a mixture of diastereo-
isomers in 66% yield by treatment of 37 with acetic
anhydride at reflux for 24 h. The downfield shift in the
NMR spectrum for the PhSCHOAc proton (δ 6.20)
confirmed that 38 had been formed.26b Raney nickel
desulfurization produced 39 in 57% yield after chroma-
tography, together surprisingly with 27 in a yield of 13%.
Reduction of diester 39 produced diol 40, which reacted
under the same conditions as alcohol 35 to form silyl
ether 3 in 83% yield (Scheme 8). The addition of the C-18
anthranoyl succinimide side chain of our intended ana-
logues of MLA can be achieved on silyl ether (3) by
established methodology.8
Con clu sion s
7-Cya n o-7-m eth yl-1,4-d ioxa sp ir o[4.5]d eca n e (14). Ke-
tone 13 (6 g, 33 mmol) was dissolved in toluene (125 mL).
Ethylene glycol (12.2 mL, 218 mmol) and PTSA (0.83 g, 4.3
mmol) were added. The mixture was heated at reflux in a
Dean-Stark trap for 15 h. The solution was cooled to 25 °C
and evaporated in vacuo, and H2O (100 mL) was added. The
mixture was neutralized with 2 M Na2CO3 solution, extracted
with CHCl3 (3 × 70 mL), dried (MgSO4), and evaporated in
vacuo to provide a dark red oil. Column chromatography (50%
EtOAc/hexane) produced acetal 14 (7.13 g, 90%) as a red oil:
1H NMR (CDCl3) δ 1.20-2.10 (8 H, m), 1.40 (3 H, s), 3.80-
4.00 (4 H, m); 13C NMR (CDCl3) δ 20.7, 27.8, 33.7, 34.3, 36.4,
43.8, 64.3, 64.6, 107.0, 124.3; IR ν 2215, 1725 cm-1; mass
spectrum m/z(%) 181(30), 113(75), 99(100); HRMS: calcd for
C10H15NO2 m/z 181.1103, found 181.1097. Anal. Calcd for
C10H15NO2: C, 66.27, N, 7.73, H, 8.34. Found: C, 66.40; N,
7.60; H, 8.49.
We have demonstrated that the tactical combination
of intermolecular Horner-Emmons olefination and in-
tramolecular conjugate addition is an effective method
for the generation of the bridgehead substituted 6-
azabicyclo[3.2.1]octane skeleton. This versatile and gen-
eral methodology described above has produced a range
of heterocycles. One of these heterocycles 28 has been
shown to be capable of further elaboration to precursors
for small ring analogues of the Delphinium alkaloid MLA,
and the (phenylthio)methyl moiety has been shown to be
a suitable masked hydroxymethyl group for the prepara-
tion of the C-18 ester side chain based on MLA (1).
Exp er im en ta l Section
7-(Am in om et h yl)-7-m et h yl-1,4-d ioxa sp ir o[4.5]d eca n e
(15). To a suspension of LiAlH4 (3.14 g, 83 mmol) in diglyme
(50 mL) was added dropwise acetal (14) (6 g, 33 mmol) in
diglyme (150 mL) at 25 °C under nitrogen. The solution was
heated to 85 °C for 5 min and cooled to 0 °C. H2O (100 mL)
was added very cautiously over a period of 0.75 h. The reaction
mixture was extracted with Et2O (3 × 70 mL). The combined
ethereal extracts were dried (MgSO4) and evaporated in vacuo
to yield the amine 15 (4.59 g, 75%) as a green oil, which was
used in the next stage without further purification: 1H NMR
(CDCl3) 0.90 (3 H, s), 1.20-1.70 (10 H, m) 2.44 (1 H, d, J )
13.0 Hz), 2.60 (1 H, d, J ) 13.0 Hz), 3.90 (4 H, m); 13C NMR
(CDCl3) δ 19.5, 24.3, 34.4, 34.76, 36.2, 42.4, 52.3, 64.0, 71.8,
Melting points are uncorrected. Infrared spectra were
recorded either neat or in Nujol as indicated. 1H and 13C NMR
spectra were recorded in CDCl3 solvent and are reported in
ppm downfield from TMS. Elemental analyses were per-
formed at the University of Bath. Mass spectra were recorded
at an ionizing voltage of 70 eV. THF was distilled from sodium
benzophenone ketyl; toluene was distilled from P2O5 under
nitrogen. All chiral compounds in this study were racemic
mixtures unless indicated otherwise, and the names of struc-
tures describe only the relative stereochemistry of substitu-
ents.
2-Hyd r oxy-3-m eth ylcycloh ex-2-en -1-on e (9) a n d 3-(Hy-
d r oxym eth yl)cycloh ex-2-en -1-on e (10). To a vigorously
stirred solution of 2-(hydroxymethyl)-6-methylpyridine (8) (2
g, 16 mmol) in H2O (1.7 mL, 94 mmol) and NH3 (20 mL) at
-78 °C was added lithium (0.33 g, 48 mmol) in small pieces
(27) Ohashi, M.; Takashashi, T.; Inoue, S.; Sato, K. Bull. Chem. Soc.
J pn. 1975, 48, 1892.

4638 J . Org. Chem., Vol. 61, No. 14, 1996
Callis et al.
109.3; IR ν 3300, 1450 cm-1; mass spectrum m/z(%) 185(15),
155(60), 141(50), 113(40), 99(100).
(1 H, s); 13C NMR (CDCl3) δ 22.4, 24.9, 28.0, 30.3, 37.1, 51.6,
127.3, 160.3, 199.0; IR ν (Nujol) 1650, 1440 cm-1; mass
spectrum m/z(%) 214(100), 106(20), 73(52); HRMS: calcd for
C10H14OS2 m/z 214.0486, found 214.0492. Anal. Calcd for
C10H14OS2: C, 56.04; H, 6.58. Found: C, 56.00; H, 6.69.
3-Cya n o-3-(1,3-d ith ia n -2-yl)cycloh exa n -1-on e (18). The
ketone 11 (9 g, 42 mmol), KCN (5.47 g, 84 mmol), and NH4Cl
(3.37 g, 63 mmol) were heated in 15% H2O/DMF (100 mL) for
6 h at 105 °C. The solvent was evaporated in vacuo, and the
resulting residue partitioned between H2O and CHCl3 as for
12, evaporated in vacuo, and dried (MgSO4). Pure product was
obtained by flash chromatography (5% EtOAc/CHCl3) to yield
compound 18 (4.05 g, 40%) as a light brown solid: mp 112-
113 °C; 1H NMR (CDCl3) δ 1.80-2.50 (8 H, m), 2.66 (1 H, d, J
) 14.8 Hz) 2.85 (2 H, ddd, J ) 14.5, 8.2, 2.9 Hz), 3.04 (2 H,
ddd, J ) 14.3, 3.6, 3.6 Hz), 4.10 (1 H, s); 13C NMR (CDCl3) δ
17.2, 21.8, 24.9, 29.8, 31.8, 40.0, 46.7, 47.6, 52.7, 119.6, 205.2;
IR ν (Nujol) 2250, 1650 cm-1; mass spectrum m/z(%) 242(M +
H)+(100), 119(97), 85(26), 69(55); HRMS: calcd for C11H15NOS2
m/z 241.0595, found 241.0594. Anal. Calcd for C11H15NOS2:
C, 54.74; H, 6.26; N, 5.80. Found: C, 54.80; H, 6.30; N, 6.18.
7-Cya n o-(1,3-d it h ia n -2-yl)-1,4-d ioxa sp ir o[4.5]d eca n e
(19). Ketone 18 (6.6 g, 27 mmol) was dissolved in toluene (125
mL). Ethylene glycol (7.6 mL, 136 mmol) and PTSA (0.52 g,
2.7 mmol) were added. The mixture was heated at reflux with
a Dean-Stark trap for 15 h. The solution was cooled to 25 °C
and evaporated in vacuo, and H2O (100 mL) was added. The
aqueous mixture was neutralized with 2 M Na2CO3 solution
and extracted with CHCl3 (3 × 70 mL), dried (MgSO4), and
evaporated to yield 19 (7.19 g, 92%) as a dark red oil: 1H NMR
(CDCl3), δ 1.50-2.20 (5 H, m), 2.22 (2 H, d, J ) 14.4 Hz) 2.86
(2 H, ddd, J ) 11.3, 4.6, 4.6 Hz), 3.08 (2 H, ddd, J ) 14.3, 5.4,
5.4 Hz), 3.90 (2 H, m), 4.00 (2 H, m), 4.20 (1 H, m); 13C NMR
(CDCl3) δ 20.0, 24.9, 29.3, 29.4, 32.9, 34.4, 39.9, 43.6, 52.8,
64.3, 64.5, 106.8, 121.3; IR ν 2250 cm-1; mass spectrum m/z(%)
7-(Aceta m id om eth yl)-7-m eth yl-1,4-d ioxa sp ir o[4.5]d e-
ca n e (16). Crude amine 15 (5.55 g, 19 mmol) was dissolved
in CH2Cl2 (100 mL) and cooled to 0 °C. Et3N (2.11 g, 20 mmol)
and acetyl chloride (1.64 g, 20 mmol) were added dropwise over
a period of 0.5 h. The reaction mixture was warmed to 25 °C
and stirred for 3 h. H2O (100 mL) was added, and the mixture
was extracted with CHCl3 (3 × 60 mL). The combined extracts
were washed with H2O (4 × 50 mL), dried (MgSO4), and
evaporated in vacuo to yield 16 (5.76 g, 91%) as a green oil
after flash chromatography (10% MeOH/CHCl3): 1H NMR
(CDCl3) δ 1.30-1.90 (10 H, m), 2.10 (3 H, s), 3.10 (1 H, dd, J
) 14.3, 4.8 Hz), 3.73 (1 H, dd, J ) 14.3, 8.2 Hz), 4.77 (1 H, s),
6.20 (1 H, s(br)); 13C NMR (CDCl3) δ 19.4, 23.1, 24.8, 34.2, 34.3,
35.9, 43.0, 48.5, 63.8, 63.9, 108.9, 170.1; IR ν 3250, 1720, 1650,
1550 cm-1; mass spectrum m/z(%) 227(5), 155(30), 99(50),
43(100); HRMS: calcd for C12H21NO3 m/z 227.1521, found
227.1529. Anal. Calcd for C12H21NO3: C, 63.41; N, 6.16; H,
9.31. Found: C, 63.10; N, 6.22; H, 9.30.
3-(Aceta m id om eth yl)-3-m eth ylcycloh exa n -1-on e (17).
The acetamide 16 (4.33 g, 19 mmol) was dissolved in 10% H2O/
THF to which had been added concd H2SO4 (5 drops). The
solution was refluxed for 3 h and then cooled to room
temperature followed by evaporation in vacuo. H2O (100 mL)
was added, and the solution was neutralized with aqueous
saturated NaHCO3 solution followed by extraction with CHCl3
(3 × 70 mL). The CHCl3 extracts were combined and dried
(MgSO4) and evaporated in vacuo to give an orange oil. Flash
chromatography (10% MeOH/CHCl3) provided the ketone 17
(3.14 g, 90%) as a yellow oil: 1H NMR (CDCl3) δ 0.90 (3 H, s),
1.50-1.90 (8 H, m), 2.00 (3 H, s), 3.10 (2 H, dd, J ) 14.3, 6.4
Hz), 3.22 (2 H, dd, J ) 14.3, 6.4 Hz), 5.68 (1 H, s(br)); 13C NMR
(CDCl3) δ 21.6, 22.7, 22.9, 33.5, 40.0, 40.7, 48.9, 50.9, 170.5,
211.4; mass spectrum m/z(%) 184(M + H)+(100), 166(69),
124(28), 111(46); HRMS: calcd for C10H17NO2 m/z 183.1259,
found 183.1260. Anal. Calcd for C10H17NO2: C, 65.54; N, 7.64;
H, 9.35. Found: C, 65.50; N, 7.50; H, 9.70.
286(M + H)+(100), 268(10), 242(10); HRMS: calcd for C13H19
-
NO2S2 m/z 285.0857, found 285.0888. Anal. Calcd for
C13H19NO2S2: C, 54.71; H, 6.71; N, 4.91. Found: C, 54.60; H,
6.90; N, 4.85.
1-Met h yl-5-[(et h oxyca r b on yl)m et h yl]-6-a cet yl-6-a za -
bicyclo[3.2.1]octa n e (28). Triethyl phosphonoacetate (1.35
g, 6 mmol) was dissolved in THF (20 mL) under nitrogen.
Potassium tert-butoxide (1 M, 6 mmol) was added dropwise
at 25 °C. The mixture was stirred at 25 °C for 1 h. Ketone
17 (1 g, 5 mmol) in THF (30 mL) was added dropwise at 25
°C. The solution was heated at reflux for 13 h, cooled to 25
°C, and evaporated in vacuo. H2O (70 mL) was added, and
the mixture was extracted with EtOAc (3 × 60 mL). The
combined extracts were dried (MgSO4) and evaporated in
vacuo to from a clear gum. Column chromatography (EtOAc)
provided 28 (0.68 g, 50%) as a clear gum: 1H NMR (CDCl3) δ
1.05 (3 H, s), 1.21 (3 H, t, J ) 7.1 Hz), 1.40-1.80 (8 H, m),
2.01 (3 H, s), 3.10 (2 H, d, J ) 15.3 Hz), 3.25 (2 H, d, J ) 15.3
Hz), 4.06 (2 H, q, J ) 7.0 Hz); 13C NMR (CDCl3) δ 14.0, 20.1,
23.4, 24.0, 32.0, 37.0, 37.2, 41.1, 48.9, 59.7, 60.5, 64.4, 169.0,
171.0; IR ν 1750, 1725, 1650 cm-1; mass spectrum m/z(%)
253(16), 210(32), 168(100), 122(10), 94(35), 43(15); HRMS:
calcd for C14H23NO3 m/z 253.1678, found 253.1681. Anal.
Calcd for C14H23NO3: C, 66.37; N, 5.53; H, 9.15. Found: C,
66.20; N, 5.49; H, 9.35.
7-(Am in om et h yl)-7-(1,3-d it h ia n -2-yl)-1,4-d ioxa sp ir o-
[4.5]d eca n e (20). The ketal 19 (6.93 g, 24.3 mmol) was
treated with LiAlH4 (2.50 g, 65.9 mmol) in diglyme as for
compound 14. Partitioning between Et2O and H2O and
evaporation in vacuo in the previously described manner gave
rise to amine 20 (5.53 g, 79%) as an orange oil, which was
used in the next stage without further purification: 1H NMR
(CDCl3) δ 1.25-2.20 (14 H, m), 2.90 (2 H, dd, J ) 18.0, 14.0
Hz), 2.92 (4 H, dd, J ) 7.6, 4.9 Hz), 4.00 (4 H, m), 4.50 (1 H,
s); 13C NMR (CDCl3) δ 19.0, 26.3, 30.0, 31.6, 31.8, 34.9, 37.5,
43.7, 46.6, 57.6, 63.9, 64.1, 108.8; IR ν 3,200-3,500 cm-1; mass
spectrum m/z(%) 290(M + H)+(50), 272(10), 230(5), 99(15).
7-(Acetam idom eth yl)-7-(1,3-dith an -2-yl)-1,4-dioxaspir o-
[4.5]d eca n e (21). Crude amine 20 (5.33 g, 18 mmol) was
dissolved in CH2Cl2 (100 mL) and cooled to 0 °C. Et3N (2.05
g, 20 mmol) and acetyl chloride (1.59 g, 20 mmol) were added
dropwise over a period of 0.5 h. The reaction was warmed to
25 °C and stirred for 3 h. H2O (100 mL) was added and
extracted with CHCl3 (3 × 80 mL). The combined extracts
were washed with H2O (4 × 60 mL), dried (MgSO4), and
evaporated in vacuo to form an orange oil. Column chroma-
tography (10% MeOH/CHCl3) produced 21 (5.67 g, 93%) as an
orange gum: 1H NMR (CDCl3) δ 1.30-1.90 (10 H, m), 2.10 (3
H, s), 2.90 (4 H, m), 3.10 (1 H, dd, J ) 14.3, 4.8 Hz), 3.73 (1 H,
dd, J ) 14.3, 8.2 Hz), 4.77 (1 H, s); 13C NMR (CDCl3) δ 14.0,
18.9, 26.2, 30.5, 31.3, 32.0, 35.0, 38.7, 43.5, 45.2, 56.4, 63.8,
64.2, 109.0, 169.8; mass spectrum m/z(%) 332(M + H)+(50),
272(40), 259(27), 212(100), 119(45), 99(90). Anal. Calcd for
C15H25NO3S2: C, 54.35; N, 4.23; H, 7.60. Found: C, 54.0; N,
3.95; H, 7.87.
3-(1,3-Dith ia n -2-yl)cycloh ex-2-en -1-on e (11). To a solu-
tion of 1,3-dithiane (8.57 g, 71 mmol) in THF (125 mL) at -78
°C was added dropwise BuLi (2.5 M, 28.5 mL, 71 mmol), and
the mixture was stirred at -78 °C for 2 h. 3-Ethoxycyclohex-
2-en-1-one (7) (10 g, 71 mmol) in THF (25 mL) was added
dropwise at -78 °C and the mixture stirred for 30 min. The
mixture was warmed to -5 °C and stored overnight. The
mixture was warmed to 25 °C and concentrated in vacuo, and
H2O (100 mL) was added. The resulting mixture was acidified
(pH 3) with concd HCl and stirred at 25 °C for 1 h. The
mixture was neutralized with saturated aqueous NaHCO3
solution and extracted with Et2O (3 × 80 mL). The combined
extracts were washed with H2O (2 × 70 mL), dried (MgSO4),
and evaporated in vacuo to give a dark red oil. Column
chromatography (50% EtOAc/hexane) produced 11 as a light
1-(1,3-Dit h ia n -2-yl)-5-h yd r oxy-6-a cet yl-6-a za b icyclo-
[3.2.1]octan e (22) an d 3-(Acetam idom eth yl)-3-(1,3-dith ian -
2-yl)cycloh exa n on e (23). Acetamide 21 (5.82 g, 17 mmol)
was dissolved in 10% H2O/THF (60 mL). Five drops of
concentrated H2SO4 were added and the solution refluxed for
3 h. The mixture was cooled to 25 °C and evaporated in vacuo.
H2O (100 mL) was added and the solution neutralized with
aqueous saturated NaHCO3 solution and extracted with CHCl3
1
green solid (9.5 g, 62%): mp 107-108 °C; H NMR (CDCl3) δ
1.80-2.20 (4 H, m), 2.40 (2 H, t, J ) 6.4 Hz) 2.54 (2 H, t, J )
5.9 Hz), 2.95 (4 H, ddd, J ) 2.9, 2.9, 2.9 Hz), 4.64 (1H, s), 6.10

Tandem Horner-Emmons Olefination-Conjugate Addition
J . Org. Chem., Vol. 61, No. 14, 1996 4639
(3 × 70 mL). The combined extracts were dried (MgSO4) and
evaporated in vacuo to form an orange gum. Column chro-
matography (10% MeOH/CHCl3) produced an approximate 1:1
mixture of 22 and 23 (4.37 g, 87%) as an orange solid. This
mixture was used in the next stage without further purifica-
tion: 1H NMR (CDCl3) δ 1.40-1.90 (16 H, m), 1.95 (3 H, s),
2.00 (3 H, s), 2.05-2.10 (4 H, m), 2.30-2.40 (4 H, m), 3.00 (8
H, m), 3.25 (1 H, d, J ) 5.5 Hz), 3.30 (1 H, d, J ) 5.3 Hz), 3.40
(1 H, m), 3.55 (1 H, d, J ) 7.9 Hz), 4.10 (1 H, s), 4.20 (1 H, s),
5.95 (1 H, s), 6.25 (1 H, s); 13C NMR (CDCl3) δ 20.2, 20.9, 22.4,
23.1, 25.7, 30.7, 30.9, 31.2, 31.3, 31.5, 35.5, 40.5, 43.9, 44.9,
46.8, 46.8, 47.3, 56.1, 56.7, 92.8, 170.0, 170.7, 209.6; IR ν
(Nujol) 1705, 1650 cm-1; mass spectrum m/z(%) 287(5), 271(45),
119(100), 110(60), 99(45), 83(84).
C14H15NOS: C, 68.54; H, 6.16; N, 5.71. Found: C, 68.60; H,
6.14; N, 5.79.
7-Cya n o-7-[(p h en ylt h io)m et h yl]-1,4-d ioxa sp ir o[4.5]-
d eca n e (5). The ketone 24 (9.20 g, 37.6 mmol) in toluene was
reacted with ethylene glycol (10.5 mL, 188.3 mmol) and PTSA
(0.71 g, 3.7 mmol) as described for compound 19. Ketal 5 was
isolated by flash chromatography (50% EtOAc/hexane) (10.33
g, 95%) as a green oil: 1H NMR (CDCl3) δ 1.40-2.00 (7 H, m),
2.10 (1 H, d, J ) 13.7 Hz), 3.20 (2 H, s), 4.00 (4 H, m), 7.18-
7.42 (5 H, m); 13C NMR (CDCl3) δ 20.2, 34.0, 34.4, 40.0, 41.3,
44.6, 64.4, 64.6, 106.9, 122.4, 127.3, 129.1, 130.9, 135.0; IR ν
2250 cm-1; mass spectrum m/z(%) 289(100), 180(42), 99(64);
HRMS: calcd for C16H19NO2S m/z 289.1136, found 289.1130.
Anal. Calcd for C16H19NO2S: C, 66.41; N, 4.84; H, 6.62.
Found: C, 66.30; N, 4.86; H, 6.67.
7-(Am in om e t h yl)-7-[(p h e n ylt h io)m e t h yl]-1,4-d ioxo-
a sp ir o[4.5]d eca n e (25). To a suspension of LiAlH4 (3.1 g,
81 mmol) in diglyme (50 mL) was added dropwise acetal 5 (9.45
g, 32 mmol) in diglyme (150 mL) at 25 °C under nitrogen. The
solution was heated to 85 °C for 5 min and cooled to 0 °C. H2O
(100 mL) was added very cautiously over a period of 0.75 h.
The resulting aqueous was extracted with Et2O (3 × 100 mL).
The combined extracts were dried (MgSO4) and evaporated in
vacuo to form crude amine 25 (7.47 g, 78%) as a red oil: 1H
NMR (CDCl3) δ 1.20-1.80 (8 H, m), 2.70 (2 H, dd, J ) 13.4,
13.4 Hz), 3.15 (2 H, dd, J ) 12.3, 12.3 Hz), 3.90 (4 H, m), 7.20-
7.42 (5 H, m); 13C NMR (CDCl3) δ 18.2, 33.6, 35.7, 40.2, 40.7,
49.1, 63.8, 70.8, 71.7, 109.3, 126.8, 129.1, 130.1, 138.4; IR ν
3,200-3,400 cm-1; mass spectrum m/z(%) 294(100), 184(27),
155(28), 99(20).
1-(1,3-Dith ian -2-yl)-5-[(eth oxycar bon yl)m eth yl]-6-acetyl-
6-a za bicylo[3.2.1]octa n e (29). Triethylphosphonoacetate
(13.01 g, 14 mmol) was dissolved in DMF (20 mL) under
nitrogen. Potassium tert-butoxide (1 M, 14 mL, 14 mmol) was
added dropwise at 25 °C. The mixture was stirred at 25 °C
for 1 h. The mixture of keto amide 22 and alcohol 23 (3.74 g,
13 mmol) in DMF (70 mL) was added dropwise at 25 °C. The
solution was heated at 60 °C for 13 h, cooled to 25 °C, and
evaporated in vacuo. H2O (80 mL) was added and the aqueous
layer extracted with EtOAc (3 × 70 mL). The combined
extracts were dried (MgSO4) and evaporated in vacuo to form
an orange gum. Column chromatography (EtOAc) produced
1
29 (2.56 g, 55%) as a white solid: mp 116-117 °C; H NMR
(CDCl3) δ 1.20 (3 H, t, J ) 7.2 Hz), 1.40-1.90 (6 H, m), 2.00 (3
H, s), 2.90 (4 H, m), 3.00 (1 H, d, J ) 15.9 Hz), 3 27 (1 H, d, J
) 15.9 Hz), 3.45 (1 H, d, J ) 9.9 Hz), 3.52 (1 H, d, J ) 9.9 Hz),
4.10 (2 H, q, J ) 7.2 H), 4.20 (1 H, s); 13C NMR (CDCl3) δ
14.1, 19.6, 23.4, 25.7, 30.9, 31.1, 31.4, 32.6, 40.7, 44.9, 46.4,
57.5, 58.5, 59.7, 64.2, 169.1, 170.7; IR ν (Nujol) 1740, 1640
cm-1; mass spectrum m/z(%) 357(17), 312(15), 238(48), 196(100),
118(43), 69(47), HRMS: calcd for C17H27NO3S2 m/z 357.1432,
found 357.1479. Anal. Calcd for C17H27NO3S2: C, 57.11; N,
3.92; H, 7.61. Found: C, 56.80; N, 3.80; H, 7.76.
7-(Acet a m id om et h yl)-7-[(p h en ylt h io)m et h yl]-1,4-d i-
oxoa sp ir o[4.5]d eca n e (26). Crude amine 25 (7.40 g, 25.2
mmol) was dissolved in CH2Cl2 (100 mL) and cooled to 0 °C.
Et3N (2.80 g, 27.7 mmol) and acetyl chloride (2.17 g, 27.7
mmol) were added dropwise over a period of 0.5 h. The
reaction was warmed to 25 °C and stirred for 3 h. H2O (100
mL) was added and the resulting aqueous extracted with
CHCl3 (3 × 70 mL). The combined extracts were washed with
H2O (4 × 60 mL), dried (MgSO4), and evaporated in vacuo to
form a yellow oil. Column chromatography (10% MeOH/
CHCl3) produced amide 26 (7.42 g, 88%) as a yellow gum: 1H
NMR (CDCl3) δ 1.20-1.80 (6 H, m), 1.90 (3 H, s), 2.10 (2 H,
m), 3.00-3.20 (2 H, m), 3.40 (2 H, m), 3.90 (4H, m), 5.40 (1 H,
s), 7.20-7.40 (5 H, m); 13C NMR δ 19.1, 23.1, 32.0, 33.9, 34.5,
40.2, 40.5, 41.9, 45.9, 63.9, 108.6, 125.9, 128.8, 129.5, 137.4,
170.2; IR ν, 3300, 1740 cm-1; mass spectrum m/z(%) 335(5),
212(10), 99(30), 43(100); HRMS: calcd for C18H25NO3S m/z
335.1555, found 335.1557. Anal. Calcd for C18H25NO3S: C,
64.45; N, 4.18; H, 7.51. Found: C, 64.20; N, 4.13; H, 7.51.
3-(Aceta m id om eth yl)-3-[(p h en ylth io)m eth yl]cycloh ex-
a n on e (4). The ketal 26 (5.08 g, 15.2 mmol) was treated with
10% H2O/THF (100 mL) and concd H2SO4 (cat.) in the manner
described for compound 16. Ketone 4 was isolated by flash
chromatography (10% MeOH/CHCl3) as a yellow oil (4.05 g,
91%): 1H NMR (CDCl3) δ 1.60-2.00 (8 H, m), 2.30 (3 H, s),
2.90 (2 H, s), 3.21 (dd, J ) 14.3, 6.4 Hz), 3.35 (1 H, dd, J )
14.3, 7.2 Hz), 5.41 (1 H, s(br)), 7.20-7.40 (5 H, m); 13C NMR
δ 13.8, 21.0, 22.6, 30.3, 40.3, 43.9, 44.8, 48.7, 126.1, 128.7,
3-[(P h en ylth io)m eth yl]cycloh ex-2-en -1-on e (6). To a
solution of thioanisole (17.72 g, 143 mmol) and DABCO (16.00
g, 143 mmol) in THF (100 mL) at 0 °C was added dropwise
BuLi (2.5 M, 57 mL, 143 mmol), and the mixture was stirred
at 0 °C for 0.75 h. 3-Ethoxycyclohex-2-enone (7) (20 g, 143
mmol) in THF (50 mL) was added dropwise at 0 °C, the
mixture stirred at room temperature for 15 h and concentrated
in vacuo, and H2O (150 mL) was added. The resulting mixture
was acidified (pH 3) with concd HCl and stirred at 25 °C for 1
h. The mixture was neutralized with saturated aqueous
NaHCO3 and extracted with Et2O (3 × 125 mL). The combined
extracts were washed with H2O (2 × 100 mL), dried (MgSO4),
and evaporated in vacuo to give a dark red oil. Column
chromatography (25% EtOAc/hexane) produced ketone 6 (20.84
g, 67%) as a light green oil: 1H NMR (CDCl3) δ 2.00 (2 H, dd,
J ) 6.0, 6.2), 2.30 (2 H, t, J ) 6.1 Hz), 2.45 (2 H, t, J ) 6.2
Hz), 3.60 (1 H, s), 5.80 (1 H, s), 7.20-7.40 (5 H, m); IR ν 1675
cm-1 13C NMR (CDCl3) δ 22.6, 28.2, 37.3, 41.9, 127.4, 127.5,
;
129.0, 131.2, 134.4, 159.9; mass spectrum m/z(%) 218(100),
203(20), 124(25), 110(22), 51(33), 39(62), 27(25); HRMS: calcd
for C13H14OS m/z 218.0721, found 218.0729. Anal. Calcd for
C13H14OS: C, 71.52; H, 6.46. Found: C, 71.60; H, 6.60.
129.4, 136.2, 170.5, 210.4; IR ν 3400-3200, 1700, 1660 cm-1
;
mass spectrum m/z(%) 291(20), 219(45), 182(42), 123(64),
59(44), 30(100). Anal. Calcd for C16H21NO2S: C, 65.95; N,
4.81; H, 7.26. Found: C, 65.70; N, 4.70; H, 7.40.
3-Cya n o-3-[(p h en ylt h io)m et h yl]-1-cycloh exa n -1-on e
(24). Ketone 6 (10 g, 46 mmol) was dissolved in 15% H2O/
DMF (100 mL). KCN (5.97 g, 92 mmol) and NH4Cl (3.68 g,
68 mmol) were added, and the mixture was heated at 100 °C
for 3 h. The solution was cooled to room temperature and
evaporated in vacuo and H2O (100 mL) added. The mixture
was extracted with CHCl3 (3 × 90 mL), and the combined
extracts were washed with H2O (80 mL), dried (MgSO4), and
evaporated in vacuo to form a dark brown oil. Column
chromatography (5% EtOAc/CHCl3) produced cyano ketone 24
(5.17 g, 46%) as an orange oil: 1H NMR (CDCl3) δ 1.80-2.40
(5 H, m), 2.50 (2 H, d(br), J ) 18.0 Hz), 2.70 (1 H, d(br), J )
5-[(Eth oxyca r bon yl)m eth yl]-1-[(p h en ylth io)m eth yl]-6-
acetam ido-6-azabicyclo[3.2.1]octan e (28). Triethyl phospho-
noacetate (1.33 g, 6 mmol) was dissolved in THF (20 mL) under
nitrogen. Potassium tert-butoxide (1 M, 6 mL, 6 mmol) was
added dropwise at 25 °C for 1 h. Ketone 4 (1.57 g, 5 mmol) in
THF (30 mL) was added dropwise at 25 °C. The solution was
heated at reflux for 13 h, cooled to 25 °C, and evaporated in
vacuo. H2O (70 mL) was added and the mixture extracted with
EtOAc (3 × 60 mL). The combined extracts were dried
(MgSO4) and evaporated in vacuo to form a yellow gum.
Column chromatography (EtOAc) produced a yellow gum 28
(1.26 g, 65%): 1H NMR (CDCl3) 1.20 (3 H, t, J ) 7.2 Hz), 1.40-
1.80 (6 H, m), 2.00 (3 H, s), 3.00 (2 H, s), 3.06 (1 H, d, J ) 15.6
Hz), 3.20 (1 H, d, J ) 15.6 Hz), 3.30 (1 H, d, J ) 9.9 Hz), 3.40
(1 H, d, J ) 9.9 Hz), 4.10 (2 H, quart, J ) 15.6 Hz), 7.08-7.40
14.5 Hz), 3.23 (2 H, dd, J ) 13.7 Hz), 7.20-7.43 (5 H, m); 13
C
NMR (CDCl3) δ 22.0, 32.9, 40.1, 43.0, 43.9, 48.6, 120.7, 127.6,
129.3, 131.1, 134.9, 205.1; IR ν (Nujol) 2250, 1725 cm-1; mass
spectrum m/z(%) 245(5), 123(23), 43(100); HRMS: calcd for
C14H15NOS m/z 245.0874, found 245.0956. Anal. Calcd for

4640 J . Org. Chem., Vol. 61, No. 14, 1996
Callis et al.
(5 H, m); 13C NMR (CDCl3) δ 14.1, 19.9, 23.4, 32.4, 34.6, 41.0,
41.9, 43.0, 47.2, 58.3, 59.8, 64.1, 126.1, 128.8, 129.4, 136.8,
169.1, 170.9; IR ν 1745, 1650 cm-1; mass spectrum m/z(%)
combined extracts were evaporated in vacuo, washed with
saturated NaHCO3 solution (20 mL) and H2O (20 mL), dried
(MgSO4), and evaporated in vacuo to produce an orange gum.
Column chromatography (Et2O) produced an approximate 1;1
diastereoisomeric mixture of diesters 38 (0.29 g, 66%) as an
orange gum: 1H NMR (CDCl3) δ 1.20 (6 H, t, J ) 7.8 Hz),
1.40-1.80 (16 H, m), 1.95 (3 H, s), 2.00 (3 H, s), 3.15 (2 H, d,
J ) 14.1 Hz), 3.40 (1 H, d, J ) 10.9 Hz), 3.45-3.50 (4 H, m),
4.10 (4 H, q, J ) 7.9 Hz), 6.20 (2 H, s), 7.20-7.70 (10 H, m);
13C NMR (CDCl3) δ 14.1, 19.5, 20.7, 23.5, 31.1, 32.3, 32.5, 40.9,
45.2, 46.1, 46.2, 55.9, 56.7, 59.9, 63.9, 64.3, 85.6, 86.4, 128.4,
129.0, 133.6, 169.3, 170.8; IR ν 1750, 1650 cm-1; mass
spectrum m/z(%) 420(M + H)+(100), 360(25), 268(20), 222(15);
HRMS: calcd for C22H29NO5S m/z 419.1766, found 419.1762.
Anal. Calcd for C22H29NO5S: C, 62.98; N, 3.34; H, 6.97.
Found: C, 62.70; N, 3.30; H, 7.01.
362(M + H)+(100), 316(10), 196(10); HRMS: calcd for C20H27
NO3S m/z 361.1712, found 361.1710. Anal. Calcd for C20H27
-
-
NO3S: C, 66.45; N, 3.87; H, 7.53. Found: C, 66.20; N, 3.90;
H, 7.64.
1-[(P h e n ylt h io)m e t h yl]-5-(h yd r oxye t h yl)-6-e t h yl-6-
a za bicyclo[3.2.1]octa n e (35). To a suspension of LiAlH4
(0.38 g, 10 mmol) in THF (10 mL) was added dropwise ester
28 (1.43 g, 4 mmol) in THF (30 mL) at 25 °C under nitrogen.
The solution was heated at reflux for 0.5 h and cooled to 0 °C.
H2O (50 mL) was added very cautiously over a period of 0.5 h.
The aqueous was extracted with Et2O (3 × 50 mL). The
combined extracts were dried (MgSO4) and evaporated in
vacuo to form ester 35 (0.88 g, 73%) as a yellow gum: 1H NMR
(CDCl3) δ 1.02 (3 H, s), 1.20 (1 H, ddd, J ) 17.6, 2.5, 2.5 Hz),
1.40-1.70 (7 H, m), 1.95 (1 H, ddd, J ) 17.6, 12.4, 2.5 Hz),
2.18 (1 H, dd, J ) 17.6, 2.5, 2.5 Hz), 2.45 (1 H, d, J ) 8.9 Hz),
2.80 (1 H, dd, J ) 7.5, 7.5 Hz), 3.10 (2 H, s), 3.15 (1 H, d, J )
8.9 Hz), 3.65 (1 H, ddd, J ) 14.2, 2.5, 2.5 Hz), 3.97 (1 H, ddd,
J ) 14.2, 12.4, 2.5 Hz), 6.00 (1 H, s(br)), 7.20-7.40 (5 H, m);
13C NMR (CDCl3) δ 14.3, 20.0, 32.1, 35.7, 36.5, 40.2, 41.1, 43.7,
44.0, 49.9, 50.7, 64.1, 126.4, 130.1, 130.7, 147.3; IR ν 3,100-
3,500 cm-1; mass spectrum m/z(%) 306(M + H)+(100), 182(73);
HRMS: calcd for C18H27NOS m/z 305.1813, found 305.1820.
Anal. Calcd for C18H27NOS: C, 70.77; N, 4.59; H, 8.91.
Found: C, 70.50; N, 4.35; H, 8.78.
1-(Acetoxym eth yl)-5-[(eth oxycar bon yl)m eth yl]-6-acetyl-
6-a za bicyclo[3.2.1]octa n e (39). Phenylthio diester 38 (0.19
g, 0.4 mmol) was dissolved in EtOH (10 mL). Raney nickel
(3.71 g, 63 mmol) was added and the solution heated at reflux
for 0.5 h and cooled to 25 °C. The mixture was filtered and
evaporated in vacuo to form an orange gum. Column chro-
matography (40% hexane/acetone) produced diester 39 (0.08
g, 57%) and ester 27 (0.015 g, 13%).
For 39: 1H NMR (CDCl3) δ 1.20 (3 H, s), 1.40-1.80 (6 H,
m), 2.03 (3 H, s), 2.05 (3 H, s), 3.10 (1 H, d, J ) 15.6 Hz), 3.20
(1 H, d, J ) 15.6 Hz), 3.30 (1 H, d, J ) 9.7 Hz), 3.45 (1 H, d,
J ) 9.7 Hz), 3.95 (1 H, d, J ) 11.2 Hz), 4.00 (1 H, d, J ) 11.2
Hz), 4.10 (2 H, q, J ) 7.2 Hz); 13C NMR (CDCl3) δ 14.4, 19.8,
20.9, 23.8, 29.8, 32.6, 32.8, 41.2, 41.4, 44.6, 57.0, 60.2, 64.2,
68.9, 169.6, 171.1,171.3; IR ν 1745, 1650 cm-1; mass spectrum
m/z(%) 311(15), 238(55), 196(100), 168(72), 122(50), 105(40);
HRMS: calcd for C16H25NO5 m/z 311.1733, found 311.1695.
Anal. Calcd for C16H25NO5: C, 61.72; N, 4.50; H, 8.09. Found:
C, 61.60; N, 4.50; H, 8.30.
1-[(P h en ylth io)m eth yl]-5-[(ter t-bu tyld im eth ylsiloxy)-
eth yl]-6-eth yl-6-a za bicyclo[3.2.1]octa n e (36). Alcohol (35)
(0.20 g, 0.66 mmol) was dissolved in CH2Cl2 (8 mL). The
reaction was cooled to 0 °C (ice/salt) and triethylamine (0.07
g, 0.72 mmol) was added. The resulting solution was stirred
for approximately 30 min, and then TBDMSOTf (0.19 g, 0.72
mmol) was added. Stirring was continued for 30 min, and the
solvent was evaporated in vacuo. H2O (10 mL) was added and
the resulting solution extracted with EtOAc (3 × 10 mL). The
combined extracts were washed with H2O (2 × 10 mL), dried
(MgSO4), and evaporated in vacuo to form silyl ether 36 (0.18
g, 65%) as a yellow gum: 1H NMR (CDCl3) δ 0.04 (6 H, s),
0.86 (9H, s), 1.22 (3 H, m), 1.50-1.70 (5 H, m), 1.80 (3 H, m),
1.90-2.10 (2 H, m), 2.30 (1 H, d, J ) 11.9 Hz), 2.80 (2 H, m),
3.20 (2 H, s), 3.60 (1 H, d, J ) 11.5 Hz), 3.70 (1 H, m), 4.0 (1
H, m), 7.20-7.40 (5 H, m); 13C NMR (CDCl3) δ -3.7, 11.9, 19.1,
25.6, 32.3, 33.2, 34.1, 42.4, 42.8, 43.5, 43.9, 57.6, 59.5, 71.6,
126.5, 129.8 132.6 136.1; IR ν 1450, 1050, 850 cm-1; mass
spectrum m/z(%) 420(M + H)+(100), 296(50), 164(50). Anal.
Calcd for C24H41NOSSi: C, 68.68; N, 3.34; H, 9.85. Found: C,
68.40; N, 3.21; H, 9.69.
1-(H yd r oxym e t h yl)-5-(h yd r oxye t h yl)-6-e t h yl-6-a za -
bicyclo[3.2.1]octa n e (40). To a suspension of LiAlH4 (1.05
g, 27.7 mmol) in THF (10 mL) was added dropwise diester 39
(3.32 g, 10.7 mmol) in THF (30 mL) at 25 °C under nitrogen.
The solution was heated and worked up as described for amide
28 to form diol 40 (1.53 g, 67%) as a yellow gum: 1H NMR
(CDCl3) δ 1.05 (3 H, t, J ) 6.8 Hz), 1.10-1.40 (4 H, m), 1.50-
1.70 (2 H, m), 1.75 (1 H, m), 1.95 (1 H, m), 2.00 (1 H, d, J )
10.7 Hz), 2.40 (1 H, d, J ) 9.8 Hz), 2.50 (2 H, s), 2.95 (1 H, m),
3.20 (1 H, m), 3.50 (2 H, s), 3.60 (1 H, m,), 4.00 (1 H, m); 13C
NMR (CDCl3) δ 14.27, 19.82, 32.88, 33.01, 35.00, 40.45, 41.84,
46.63, 57.92, 60.42, 65.47, 69.09; IR (neat) ν 3200-3400, 1470,
1000 cm-1; mass spectrum m/z(%) 213(25), 182(100), 154 (15).
Anal. Calcd for C12H23NO2: C, 67.57; N, 6.57; H, 10.87.
Found: C, 67.30; N, 6.37; H, 10.77.
1-[(P h en ylsu lfin yl)m eth yl]-5-[(eth oxycar bon yl)m eth yl]-
6-a cetyl-6-a za bicyclo[3.2.1]octa n e (37). Ester 28 (0.5 g, 1.4
mmol) was dissolved in MeOH (10 mL). Sodium periodate
(0.62 g, 2.9 mmol) was added and the mixture heated at reflux
for 1 h. The solution was cooled to 25 °C and evaporated in
vacuo. The mixture was diluted with CH2Cl2 (30 mL), washed
with brine (20 mL), dried (MgSO4), and evaporated in vacuo
to form an approximate 1:1 diastereoisomeric mixture of
sulfoxides (37) (0.40 g, 77%) as an orange oil: 1H NMR (CDCl3)
δ 1.20 (6 H, t, J ) 7.1 Hz), 1.40-1.85 (12 H, m), 2.00 (6 H, s),
2.65 (2 H, d, J ) 13.7 Hz), 2.86 (2 H, d, J ) 13.7 Hz), 3.20 (2
H, d, J ) 10.4 Hz), 3.54 (2 H, d, J ) 10.4 Hz), 3.68 (4 H, d, J
1-(Hydr oxym eth yl)-5-[(ter t-bu tyldim eth ylsiloxy)eth yl]-
6-eth yl-6-a za bicyclo[3.2.1]octa n e (3). Diol 40 (1.10 g, 5.2
mmol) was reacted in CH2Cl2 (10 mL) with Et3N (0.55 g, 5.7
mmol) and TBDMSOTf (1.43 g, 5.7 mmol) as described for
alcohol 35 to form silyl ether 3 (1.40 g, 83%, Rf 0.19) as a clear
gum: 1H NMR (CDCl3) δ 0.05 (6 H, s), 0.90 (9H, s), 1.25 (3 H,
t, J ) 7.0 Hz), 1.30-2.00 (10 H, m), 2.80 (2 H, m), 2.90 (2 H,
m), 3.60 (2 H, s), 3.70 (1 H, m), 3.75 (1 H, m); 13C NMR (CDCl3)
δ -5.51, 12.29, 18.16, 19.00, 25.61, 31.40, 32.09, 38.19, 38.76,
42.21, 44.66, 59.57, 66.86, 70.24; IR (neat) ν 3,300-3,400
(br),1450, 1250, 1100, 820, 780 cm-1; mass spectrum m/z(%)
) 5.1 Hz), 4.20 (4 H, q, J ) 7.1 Hz), 7.20-7.50 (10 H, m); 13
C
NMR (CDCl3) δ 14.0, 19.8, 23.5, 32.1, 34.3, 35.4, 40.2, 40.4,
40.7, 40.8, 48.5, 58.1, 58.3, 59.9, 62.7, 67.1, 68.0, 123.5, 127.4,
327(15), 296(100), 182 (15), 164 (67). Anal. Calcd for C18H37
-
129.3, 131.7, 169.4, 170.8, 170.9; IR ν 1750, 1650, 1050 cm-1
;
NO2Si: C, 66.00; H, 11.38; N, 4.28. Found: C, 65.70; H, 11.30;
N, 4.03.
mass spectrum m/z(%) 378(M + H)+(100), 362(20); HRMS:
calcd for C20H27NO4S m/z 360.1633 (M - OH+), found 360.1640.
Anal. Calcd for C20H27NO4S: C, 63.63; N, 3.71; H, 7.21.
Found: C, 63.50; N, 3.65; H, 7.22.
Ack n ow led gm en t. The authors are grateful for
financial support from the EPSRC and Zeneca Agro-
chemicals (CASE award to D.J .C.). B.V.L.P. is a Lister
Institute Research Professor.
1-Acetoxy-1-[(p h en yth io)m eth yl]-5-[(eth oxyca r bon yl)-
m eth yl]-6-a cetyl-6-a za bicyclo[3.2.1]octa n e (38). Sulfox-
ides (37) (0.40 g, 1 mmol) were heated at reflux for 24 h in
Ac2O (8 mL). The solution was cooled to 25 °C, diluted with
H2O (15 mL), and extracted with EtOAc (3 × 30 mL). The
J O9519672