Formation of highly substituted chiral cyclohexanone derivatives using a tandem conjugate addition/cyclisation

Article abstract of DOI:10.1016/j.tetlet.2004.09.150

A tandem conjugate addition/cyclisation approach, that allows the synthesis of chiral highly substituted cyclohexanones and cyclohexenones, which is applicable to natural product syntheses has been developed. A tandem conjugate addition/cyclisation approa

Full text of DOI:10.1016/j.tetlet.2004.09.150

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8667–8671
Formation of highly substituted chiral cyclohexanone
derivatives using a tandem conjugate addition/cyclisation
David W. Jeffery and Michael V. Perkins*
School of Chemistry, Physics and Earth Sciences, Flinders University, GPO Box 2100, SA 5001, Australia
Received 26 August 2004;revised 17 September 2004;accepted 21 September 2004
Abstract—A tandem conjugate addition/cyclisation approach, that allows the synthesis of chiral highly substituted cyclohexanones
and cyclohexenones, which is applicable to natural product syntheses has been developed.
Ó 2004 Elsevier Ltd. All rights reserved.
Elysioidea sacoglossan molluscs are interesting marine
organisms with the ability to sequester active chloro-
plasts from siphonaceous marine algae and retain these
organelles in their tissues where they carry out photo-
synthesis.1 These organisms have been the source of a
O
O
MeO
O
number of novel polypropionate natural products
(Fig. 1).1–6
MeO
O
tridachiahydropyrone 1
9,10-deoxytridachione 2
Tridachiahydropyrone 1,2 9,10-deoxytridachione 23 and
tridachiapyrone-A 34 all possess a highly substituted
cyclohexadiene ring. 9,10-Deoxytridachione 2 has been
photochemically converted in vivo1 and in vitro3 into
photodeoxytridachione 4, whilst tridachiahydropyrone-
B 55 and –C 65 appear to be photooxygenation products
from tridachiahydropyrone 1.
O
O
H
O
O
MeO
O
MeO
photodeoxytridachione
4
tridachiapyrone-A 3
The function of these polypropionate metabolites in the
organism is unclear, but it has been postulated that they
may act as chemical defence agents against predation or
exposure to UV light.2,7 Tridachiapyrone-A 3 has been
shown to be active against lymphocytic leukemia cells4
but extraction from the natural source is not a viable op-
tion due to its low abundance.
O
O
O
MeO
O
tridachiahydropyrone-B 5, –C
6
Figure 1.
Natural products of this type are yet to attract much
attention from the synthetic community and only during
the development of our synthetic approach was the first
total synthesis of a member of this group of natural
products reported by Miller and Trauner.8 This elegant
approach to ( )-photodeoxytridachione 4 involved a
Lewis acid catalysed cyclisation of the tetraene interme-
diate 7. Thermal cyclisation of the same tetraene 7 gave
the cyclohexadiene ring system present in 9,10-deoxy-
tridachione 2 (Scheme 1).
Keywords: Tridachiones;Conjugate addition;Tridachiahydropyrone.
*
Our approach relies on the formation of the highly sub-
stituted six-membered ring 8 as a single enantiomer by a
Corresponding author. Tel.: +61 8 8201 2496;fax: +61 8 8201
2905;e-mail: mike.perkins@flinders.edu.au
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.150

8668
D. W. Jeffery, M. V. Perkins / Tetrahedron Letters 45(2004) 8667–8671
unsaturated ketone 12. These two compounds were
available from the same alcohol 13 by oxidation and
reaction with the appropriate ylide (Scheme 3).
benzene
80 ˚C
COOEt
7
COOEt
The alcohol 13 was prepared by the sequence shown in
Scheme 3. Commercially available methyl (S)-(+)-3-hy-
droxy-2-methylpropionate was protected as the known
PMB ether12 14 (83%) in multi-gram quantities using
catalytic triflic acid (0.3mol%) and PMB trichloroace-
timidate13 in ether. Small-scale reactions require signifi-
cantly more acid catalyst. The product was distilled
under reduced pressure14 for larger scale reactions.
Me2AlCl
( )-photodeoxytridachione 4
COOEt
H
Scheme 1.
tandem conjugate addition–Dieckmann condensation.9
In this approach we employ an EvansÕ chiral auxiliary10
as the leaving group in the capture of the enolate formed
by the conjugate addition to an a,b-unsaturated ketone
or ester 9. The chiral auxiliary also controls the aldol
reaction, generating two of the stereocentres present in
the acyclic precursor 9. The stereocentres of 9 have the
dual role of controlling the facial addition of the nucleo-
phile in the Michael addition and of assisting in the
cyclisation (by virtue of their equatorial orientation in
the six-membered ring 8 that is formed). There are a lim-
ited number of reports of displacement of an EvansÕ chi-
ral auxiliary by carbon nucleophiles in cyclisations.11
Subsequent axial methylation and b-elimination leads
to compound 10, which could be further functionalised
(Scheme 2).
The ester 14 was reduced with LiAlH4 (93%) and the
crude product was subsequently oxidised under Swern
conditions15 with modified product isolation16 to afford
known aldehyde12 15 (99%, crude), which was suffi-
ciently pure for the aldol reaction (Scheme 4). Treatment
of the N-propionyl EvansÕ chiral auxiliary10 16 with di-
butylboron triflate and Et3N generated a Z-enolate,
which underwent a syn aldol10,17 coupling with crude
aldehyde 15 to afford aldol adduct 17 (83%) with high
diastereoselectivity (>95% ds by 1H NMR). TBS protec-
tion18 of 17 with TBSOTf/2,6-lutidine in CH2Cl2 yielded
the diprotected product (97%), which was selectively
deprotected with DDQ in CH2Cl2/pH7 buffer19 to give
primary alcohol 13 (96%). Attempted purification by
flash chromatography of 13 on silica led to complete
conversion to known lactone 18.20 This showed the abi-
lity of the EvansÕ auxiliary to act as a leaving group in
our system, even though it was an undesired side reac-
tion at this stage. This problem was avoided by careful
chromatography on buffered silica,21 allowing purifica-
tion of alcohol 13.
We now report the stereoselective synthesis of some
highly substituted cyclohexanone and cyclohexenone
derivatives using this strategy, that could be incorpo-
rated as the cyclohexadiene moiety found in members
1–3 of the tridachione family of marine natural
products.
Alcohol 13 was cleanly oxidised (99%, crude) under
Swern conditions15,16 to aldehyde 19, which has been
produced on a multi-gram scale and is common to both
The model systems in which we chose to investigate this
approach were the a,b-unsaturated ester 11 and the a,b-
R22CuX
O
O
O
O
a
b,c
O
groups all
R2
R2
equatorial
MeO
OPMB
O
MeO
OH
OPMB
15
O
O
O
O
R1
(83%)
(90%,
14
2 steps)
R1
R1
O
OTBS
O
O
O
N
OTBS
Bn
N
O
10
8
9
O
OTBS
18
(ca. 100%)
16
(83%,
>95% ds)
d
Bn
Scheme 2.
SiO2
O
OTBS
O
OH
17
O
O
e,f
(93%,
N
OH
N
OPMB
O
O
13
O
OTBS
O
O
Bn
2 steps)
Bn
O
O
N
N
OEt
Scheme 4. Reagents and conditions: (a) PMB imidate (1.5equiv),
TfOH (0.3mol%), Et2O, rt, 45min;( b) LiAlH4 (1.1equiv), THF,
0°C!rt, 30min;( c) (i) DMSO (3equiv), C2O2Cl2 (1.5equiv), CH2Cl2,
À78°C, 30min;(ii) product from b, CH2Cl2, À78°C, 45min;(iii) Et 3N
(6equiv), À78°C, 30min!0 °C;( d) (i) 16, Bu2BOTf (1.2equiv),
CH2Cl2, 0°C, 30min;(ii) Et 3N (1.3equiv), 0°C, 30min;(iii) 15
(0.67equiv), À78°C, 30min!0°C, 3–4h;( e) 2,6-Lutidine (3equiv),
TBSOTf (1.5equiv), CH2Cl2, 78°C, 3–4h;( f) DDQ (1.3equiv),
CH2Cl2, pH7 buffer, 0°C, 3.5h.
O
O
OTBS
Bn
O
N
OH
11
O
OTBS
O
O
Bn
13
CH3
12
Bn
Scheme 3.

D. W. Jeffery, M. V. Perkins / Tetrahedron Letters 45(2004) 8667–8671
8669
fication, the product 23 in 44% yield as a single isomer.
In this case the enol OH peaks occurred at
d = 16.43ppm and its presence in the crude reaction
mixture was again indicative of a successful cyclisation.
A minor epimeric product was separated that arose
from the minor epimeric enone 12b.
13
(ca. 100%)
O
OTBS
O
O
a
b
N
N
OEt
O
(89%)
O
OTBS
O
11
OTBS
Bn
O
N
O
O
O
O
19
Bn
c
CH3
O
epimeric centre
2:1 syn:anti
(83%)
With success in the reactions involving dimethylcopper-
lithium we turned our attention to the addition of a cup-
rate derived from isopropenylmagnesium bromide, to
emulate more closely the natural product vinyl side
chains. The use of this cuprate proved to be problematic
but we were able to add the cuprate to 12 and effect cy-
clisation using similar conditions to Boring and Sinde-
lar23 (Scheme 6). Addition of enone 12 to the cuprate
at À78°C, followed by warming to room temperature
yielded a black insoluble mixture, but stirring overnight
gave a pale yellow homogeneous solution. Quenching
and purification afforded cyclic product 24 in 60% yield.
As above, a minor epimeric product (from enone 12b)
was separated.
Bn
12a
12b epimer
CO2Et
COCH3
21
Ph3P
Ph3P
20
Scheme 5. Reagents and conditions: (a) (i) DMSO (3equiv), C2O2Cl2
(1.5equiv), CH2Cl2, À78°C, 30min;(ii) 13, CH2Cl2, À78°C, 45min;
(iii) Et3N (6equiv), À78°C, 30min!0°C;( b) 20 (1.2equiv), CH2Cl2,
rt, 4d;( c) 21 (1.2equiv), toluene, 80°C, 4d.
our model studies (Scheme 5). Wittig coupling of alde-
hyde 19 with ylide 20 proceeded slowly at room temper-
ature in CH2Cl2 to give 11 (89%) with high E-selectivity.
The reaction of the aldehyde with ylide 21 was even
more sluggish and required heating in toluene (Scheme
4). While this reaction gave 12 (83%) with high E-selec-
tivity, unfortunately there were varying degrees of epi-
merisation of the stereocentre a to the aldehyde,
leading to an inseparable epimeric mixture (2:1) of 12.
This mixture was used in subsequent reactions.
The stereochemistry of the new stereocentres formed in
the addition/cyclisation was assigned by application of
the experimental findings of Chounan et al.24 on cuprate
addition to unsaturated monoesters/ketones. These find-
ings postulate a modified Felkin–Anh attack of the
nucleophile (cuprate) to give an anti (or in our cyclic
case, syn) relationship between the c methyl and the
newly formed stereocentre (Scheme 7).
We proceeded to test the novel addition–cyclisation ap-
proach for the synthesis of the substituted cyclohexan-
ones using dimethylcopperlithium. The enoate 11 was
added dropwise at room temperature to dimethylcop-
perlithium22 in a 1:1 mixture of ether and dimethylsul-
fide (Scheme 6). The reaction was complete within 1h
as determined by TLC analysis. Quenching (90%
NH4Cl/10% NH4OH) and purification by chromatogra-
phy yielded cyclic product 22 (68%), which contained
varying mixtures of keto:enol tautomers. The presence
of 1H NMR signals for free EvansÕ auxiliary at
d = 5.86, 4.43 and 2.88ppm and the presence of the enol
OH at d = 12.34ppm (from the enol form of the pro-
duct) in the crude reaction mixture were evidence for
successful cyclisation.
The marine natural products 1–3 and others bear a trans
relationship between the unsaturated side chain and an
adjacent quaternary methyl group. The cyclic products
22–24 were methylated by treatment with NaH and
MeI in THF at room temperature and under these con-
ditions, with two or more equivalents of NaH there was
also full elimination of the OTBS group to yield enones
25–2725 (Scheme 6). Elimination appears to occur both
prior to and after methylation, as a range of products
(methylated/saturated, methylated/unsaturated, not
methylated/unsaturated) could be isolated depending
on reaction time. Notably, trans (axial) methylation26
was virtually exclusive for these simple enone/enoate
systems with only a single isomeric product apparent
The addition of dimethylcopperlithium to the enone 12
was carried out in an identical fashion giving, after puri-
O
O
R22CuLi
EtO
EtO
O
a
c
–
11
12
O TBSO
R2
O
O
H
Me
R1
(68%)
(64%)
O
O
OTBS
O
O
R1
22
25
N
O
H
R
R
TBSO
Anti
Bn
a (R = Me)
(44%)
Bn
c
R1 = –CH3, –OEt
R2 = –CH3,
O
N
or
(60%)
O
OTBS
O
b (R = C(CH3)=CH2
Syn
O
(60%)
O
R2
23 (R = Me)
24 (R = C(CH3)=CH2)
26 (R = Me)
27 (R = C(CH3)=CH2)
R1
O
R2
O
N
R1
O
Scheme 6. Reagents and conditions: (a) (i) CuI (5equiv), MeLi
(10equiv), Me2S, Et2O, rt;(ii) 11 (or 12), Et2O, rt, 1h;( b) (i) CuI
OTBS
O
OTBS
O
Bn
(2equiv),
isopropenylmagnesium
bromide
(4equiv),
THF,
À78!À20°C, 20min;(ii) 12, THF, À78°C!rt, 16h;( c) (i) NaH
(2equiv), THF, rt, 10min;(ii) MeI (10equiv), rt, 1–3d.
Scheme 7. Modified Felkin–Anh attack of cuprate.

8670
D. W. Jeffery, M. V. Perkins / Tetrahedron Letters 45(2004) 8667–8671
in the 1H NMR spectrum of the crude reaction mixture.
The entire ring stereochemistry has been confirmed by
NOE experiments on related analogues27 and supports
trans (axial) methylation and is in accordance with the
findings of Chounan et al.24
2004, 69, 991–992;(f) Kozhinov, D. V.;Behar, V. J. Org.
Chem. 2004, 69, 1378–1379.
10. Evans, D. A.;Gage, J. R. Org. Synth. 1990, 68, 77–91.
11. (a) Trova, M. P.;Wang, Y. Tetrahedron 1993, 49, 4147–
4158;(b) Sieburth, S. McN;Chen, C.-A. Synlett 1995,
928–930;(c) Vanderwal, C. D.;Vosburg, D. A.;Weiler, S.;
Sorensen, E. J. Org. Lett. 1999, 1, 645–648;(d) Hinterding,
K.;Singhanat, S.;Oberer, L. Tetrahedron Lett. 2001, 42,
8463–8465;(e) Vanderwal, C. D.;Vosburg, D. A.;Weiler,
S.;Sorensen, E. J. J. Am. Chem. Soc. 2003, 125, 5393–
5407.
12. Walkup, R. D.;Kane, R. J.;Boatman, P. D., Jr.;
Cunningham, R. T. Tetrahedron Lett. 1990, 31, 7587–
7590.
13. Nakajima, N.;Horita, K.;Abe, R.;Yonemitsu, O.
Tetrahedron Lett. 1988, 29, 4139–4142.
In conclusion, we have developed a viable strategy for
the formation of chiral, highly substituted cyclohexan-
one and cyclohexenone derivatives using a tandem
conjugate addition/Dieckmann condensation approach
where an EvansÕ chiral auxiliary acts as a leaving group.
We are investigating this strategy for the formation of
the cyclohexadiene moieties as found in some marine
polypropionate metabolites from the Tridachia family
of molluscs.
14. Walkup, R. D.;Kahl, J. D.;Kane, R. R. J. Org. Chem.
1998, 63, 9113–9116.
15. Mancuso, A. J.;Swern, D. Synthesis 1981, 165–185.
16. Smith, A. B., III;Beauchamp, T. J.;LaMarche, M. J.;
Kaufman, M. D.;Qiu, Y.;Arimoto, H.;Jones, D. R.;
Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654–8664.
17. (a) Evans, D. A.;Bartroli, J.;Shih, T. L. J. Am. Chem.
Soc. 1981, 103, 2127–2129;(b) Evans, D. A. Aldrichim.
Acta 1982, 15, 23.
18. (a) Corey, E. J.;Venkateswarlu, A. J. Am. Chem. Soc.
1972, 94, 6190–6191;(b) Corey, E. J.;Cho, H.;Rucker, C.;
Hua, D. H. Tetrahedron Lett. 1981, 22, 3455–3458.
19. Paterson, I.;Florence, G. J.;Gerlach, K.;Scott, J. P.;
Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535–9544.
20. Stork, G.;Paterson, I.;Lee, F. K. C. J. Am. Chem. Soc.
1982, 104, 4686–4688.
Acknowledgements
We wish to thank the Australian Research Council for
funding and Flinders University for its support and
facilities. We are grateful for the correspondence with
R. D. Walkup, and also C. Adams from the A. B. Smith
III research group, for their helpful insights with the
manipulations of 14 and 15.
Supplementary data
21. Prepared by slowly turning a round bottom flask con-
taining 100g of flash silica with 10mL of pH7 phosphate
buffer on a rotary evaporator without vacuum overnight
at room temperature.
22. House, H. O.;Chu, C.-Y.;Wilkins, J. M.;Umen, M. J. J.
Org. Chem. 1975, 40, 1460–1469.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet-
let.2004.09.150. Supporting information available. Cop-
ies of NMR spectra, experimental procedures and data
for compounds 22–27.
23. Boring, D. L.;Sindelar, R. D. J. Org. Chem. 1988, 53,
3617–3621.
References and notes
24. Chounan, Y.;Ono, Y.;Nishii, S.;Kitahara, H.;Ito, S.;
Yamamoto, Y. Tetrahedron 2000, 56, 2821–2831.
25. All new compounds gave spectroscopic data in agreement
1. Ireland, C. M.;Scheuer, P. J. Science 1979, 205, 922–
923.
2. Gavagnin, M.;Mollo, E.;Cimino, G.;Ortea, J. Tetrahe-
dron Lett. 1996, 37, 4259–4262.
3. Ireland, C. M.;Faulkner, D. J.
37(Suppl. No. 1), 223–240.
4. Ksebati, M. B.;Schmitz, F. J. J. Org. Chem. 1985, 50,
5637–5642.
20
with the assigned structures. Compound 25 had ½aŠ
D
À131.9 (c 0.46, CHCl3); 1H NMR (300MHz, CDCl3)
d 6.50–6.46 (m, 1H, CH@C), 4.11 (q, 2H, J = 7.1Hz,
OCH2CH3), 2.64–2.56 (m, 1H, CH(CH3)CH@C), 2.17
(qd, 1H, J = 7.0, 5.3Hz, C(CH3)CH(CH3)), 1.82–1.79 (m,
3H, C(CH3)@CH), 1.42 (s, 3H, C(CH3)), 1.22 (t, 3H,
7.1Hz, OCH2CH3), 1.09 (d, 3H, J = 7.0Hz, C(CH3)CH-
(CH3)), 1.03 (d, 3H, J = 7.2Hz, CH(CH3)CH@C); 13C
NMR (75.5MHz, CDCl3) d 197.4, 173.4, 147.6, 133.5,
60.8, 55.6, 41.8, 33.6, 20.3, 16.4, 14.7, 13.9, 13.0;HRMS
Tetrahedron 1981,
5. Fu, X.;Hong, E. P.;Schmitz, F. J. Tetrahedron 2000, 56,
8989–8993.
6. (a) Gavagnin, M.;Mollo, E.;Castelluccio, F.;Montanaro,
D.;Ortea, J.;Cimino, G. Nat. Prod. Lett. 1997, 10, 151–
156;(b) Gavagnin, M.;Spinella, A.;Castelluccio, F.;
Cimino, G. J. Nat. Prod. 1994, 56, 8989–8993;(c) Dawe,
R. D.;Wright, J. L. C. Tetrahedron Lett. 1986, 27, 2559–
2562.
7. (a) Faulkner, D. J.;Ghiselin, M. T. Mar. Ecol. Prog. Ser.
1983, 13, 295–301;(b) Pawlik, J. R. Chem. Rev. 1993, 93,
1911–1922.
8. Miller, A. K.;Trauner, D. Angew. Chem., Int. Ed. 2003,
42, 549–552.
9. (a) Stetter, H.;Marten, K. Liebigs Ann. Chem. 1982, 240–
249;(b) Bunce, R. A.;Harris, C. R. J. Org. Chem. 1992,
(LSI) calculated for C13H19Oþ3 (M+ÀH): 223.1334;
20
found:223.1328. Compound 26 had ½aŠ À96.4 (c 0.14,
D
CHCl3); 1H NMR (300MHz, CDCl3) d 6.37–6.34 (m, 1H,
CH@C), 2.90–2.79 (m, 1H, CH(CH3)CH@C), 2.24, (s, 3H,
CH3CO), 2.21–2.12 (m, 1H, C(CH3)CH(CH3)), 1.81 (dd,
3H, J = 2.6, 1.4Hz, C(CH3)@CH), 1.35 (s, 3H, C(CH3)),
1.08 (d, 3H, J = 7.2Hz, CH(CH3)CH@C), 0.89 (d,
3H, J = 6.9Hz, C(CH3)CH(CH3)); 13C NMR (75.5MHz,
CDCl3) d 210.3, 200.0, 147.4, 133.5, 62.0, 42.5, 31.9, 30.8,
21.0, 16.9, 16.0, 11.3;HRMS (EI) calculated for C 12H18O2
20
D
(M+):194.1307;found:194.1313. Compound 27 had ½aŠ
À69.0 (c 0.33, CHCl3); 1H NMR (300MHz, CDCl3) d
6.41–6.39 (m, 1H, CH@C), 4.86–4.84 (m, 1H,
@CHACHB), 4.72–4.70 (m, 1H, @CHACHB), 3.08–
2.97(m, 1H, CH(CH3)CH@C), 2.70 (dd, 1H, J = 5.7,
1.2Hz, CHC(CH3)@CH2), 2.19 (s, 3H, CH3CO), 1.84–
57, 6981–6985;(c) Bunce, R. A.;Harris, C. R.
Commun. 1996, 26, 1969–1975;(d) Deville, J. P.;Behar, V.
Org. Lett. 2002, 4, 1403–1405;(e) Martinez, A. D.;
Synth.
Deville, J. P.;Stevens, J. L.;Behar, V.
J. Org. Chem.

D. W. Jeffery, M. V. Perkins / Tetrahedron Letters 45(2004) 8667–8671
8671
1.82 (m, 3H, C(CH3)@CH), 1.57–1.56 (m, 3H,
C(CH3)@CH2), 1.42 (s, 3H, C(CH3)), 1.08 (d, 3H, J =
7.5Hz, CH(CH3)CH@C); 13C NMR (75.5MHz, CDCl3) d
209.0, 199.1, 147.4, 143.0, 134.5, 118.4, 61.6, 57.8, 29.7,
29.6, 24.6, 22.6, 17.4, 16.0;HRMS (ESI) calculated for
C14H20O2Na+ (M+Na+): 243.1361;found: 243.1352.
26. (a) Zimmerman, H. E. J. Org. Chem. 1955, 20, 549–557;
(b) Piers, E.;Tse, H. L. A. Tetrahedron Lett. 1984, 25,
3155–3158;(c) Paquette, L. A.;Wiedeman, P. E.;Bulman-
Page, P. C. J. Org. Chem. 1988, 53, 1441–1450;(d) Piers,
E.;Llinas-Brunet, M. J. Org. Chem. 1989, 54, 1483–1484.
27. Perkins, M. V.;Jeffery, D. W. Unpublished results.