Studies on the synthesis of acanthodoral and nanaimoal: Evaluation of cationic cyclization routes

Article abstract of DOI:10.1021/jo9610568

Intramolecular Lewis acid-promoted reactions of α,β-unsaturated ketone 6 and aldehydes 7 and 8 were examined as potential routes to acanthodoral (1), a structurally interesting natural product. Ketone 6 afforded ene product 22 exclusively, and both 7 and 8 gave mixtures of bicyclic aldehydes 3 and 26 and tricyclic aldehyde 25. The latter most likely results from 7 by intramolecular cyclization of the alkene onto the Lewis acid-activated carbonyl moiety affording carbocation 31 followed by a 1,2-hydride shift and ring closure. Starting from 8, tricyclic aldehyde 25 apparently forms by cyclization to cation 35 and ring closure to cyclobutane 36, followed by ring opening to 31, the same cation as formed in reactions of 7. Nanaimoal (3) results from loss of H⁺ from 31, and bicyclic aldehyde 26 may be formed in a similar manner or by a concerted ene reaction. The configuration of 25 establishes that the stereochemistry of the initial cyclization to 31 precludes the possible use of this strategy for the synthesis of acanthodoral. However, acid-promoted cyclization of allylic alcohol 23 efficiently gives diene 29 which undergoes selective hydroboration/oxidation to afford nanaimoal.

Full text of DOI:10.1021/jo9610568

8456
J . Org. Chem. 1996, 61, 8456-8463
Stu d ies on th e Syn th esis of Aca n th od or a l a n d Na n a im oa l:
Eva lu a tion of Ca tion ic Cycliza tion Rou tes
Thomas A. Engler,* Mohammed Hashmat Ali, and Fusao Takusagawa
Department of Chemistry, University of Kansas, Lawrence, Kansas 66045
Received J une 5, 1996X
Intramolecular Lewis acid-promoted reactions of R,â-unsaturated ketone 6 and aldehydes 7 and 8
were examined as potential routes to acanthodoral (1), a structurally interesting natural product.
Ketone 6 afforded ene product 22 exclusively, and both 7 and 8 gave mixtures of bicyclic aldehydes
3 and 26 and tricyclic aldehyde 25. The latter most likely results from 7 by intramolecular
cyclization of the alkene onto the Lewis acid-activated carbonyl moiety affording carbocation 31
followed by a 1,2-hydride shift and ring closure. Starting from 8, tricyclic aldehyde 25 apparently
forms by cyclization to cation 35 and ring closure to cyclobutane 36, followed by ring opening to
31, the same cation as formed in reactions of 7. Nanaimoal (3) results from loss of H+ from 31,
and bicyclic aldehyde 26 may be formed in a similar manner or by a concerted ene reaction. The
configuration of 25 establishes that the stereochemistry of the initial cyclization to 31 precludes
the possible use of this strategy for the synthesis of acanthodoral. However, acid-promoted
cyclization of allylic alcohol 23 efficiently gives diene 29 which undergoes selective hydroboration/
oxidation to afford nanaimoal.
Sch em e 1
In tr od u ction
Acanthodoral (1), isoacanthodoral (2), and nanaimoal
(3) are structurally interesting isomeric sesquiterpenoid
aldehydes isolated from the nudibranch Acanthodoris
nanaimoensis.1a A mixture of 1-3 isolated from the
natural source exhibited antibacterial and antifungal
activities.1b Our attention was drawn to 1 because of its
unusual structure coupled with our interest in Lewis
acid-promoted 2 + 2 cycloadditions as routes to function-
alized cyclobutanes.2 Indeed, a proposed biosynthesis
suggests that aldehydes 2/3 may arise from 1, formed
presumably via some type of formal 2 + 2 process.1
Herein we report our studies directed toward the prepa-
ration of 1 using a biogenetic approach exploring in-
tramolecular Lewis or protic acid-promoted cycloaddi-
tions of alkenes with R,â-unsaturated aldehydes or R,â-
benzoyloxyenones. In the course of these studies, a short
synthesis of nanaimoal was also developed.2,3
enones with simple unactivated alkenes further sug-
gested that treatment of aldehydes 7 and/or 8 with Lewis
or protic acids may generate cations 4 or 5 which may
then proceed on to 1. The latter studies built on earlier
work of Snider and others.6,7 Ionic 2 + 2 cycloadditions
of this type complement photochemical 2 + 2 processes
which are usually not efficient due to rotational deactiva-
tion of the excited state of acyclic enones or enals.8
Our synthetic plan is shown in Scheme 1. Studies on
Ti(IV)-mediated 2 + 2 cycloadditions of R′-alkoxy R,â-
enones with alkenes2,4 suggested that similar reactions
of ketone 6 may produce a 2 + 2 product that could be
converted to 1. In addition, studies by Gassman and
Lottes5a and Majetich5c on Lewis acid-promoted 2 + 2
cycloadditions of acrolein acetals and R,â-unsaturated
Resu lts
A brief examination of intermolecular Lewis acid-
promoted reactions of enones 9a -c with methylenecy-
clohexane was undertaken as a feasibility study (Scheme
2). Promotion of reactions of methoxymethyl vinyl ketone
X Abstract published in Advance ACS Abstracts, November 1, 1996.
(1) (a) Ayer, S. W.; Andersen, R. J .; Cun-heng, H.; Clardy, J . J . Org.
Chem. 1984, 49, 2653-2654. (b) Ayer, S. W. Ph.D. Thesis, the
University of British Columbia, B.C., Canada, 1985. (c) Graziani, E.
I.; Andersen, R. J . J . Am. Chem. Soc. 1996, 118, 4701-4702.
(2) (a) Engler, T. A.; Ali, M. H.; Vander Velde, D. Tetrahedron Lett.
1989, 30, 1761-1764.
(3) (a) For a previous synthesis of 2, see: Liu, H.-J .; Ul´ıbarri, G.;
Nelson, L. A. K. J . Chem. Soc., Chem. Commun. 1990, 1419-1421. (b)
For a previous synthesis of 3, see: Ayer, S. W.; Hellou, J .; Tischler,
M.; Andersen, R. J . Tetrahedron Lett. 1984, 25, 141-144.
(4) (a) Engler, T. A.; Combrink, K. D.; Letavic, M. A.; Lynch, K. O.,
J r.; Ray, J . E. J . Org. Chem. 1994, 59, 6567-6587. (b) Engler, T. A.;
Wei, D.; Letavic, M. A.; Combrink, K. D.; Reddy, J . P. J . Org. Chem.
1994, 59, 6588-6599. (c) Engler, T. A.; Letavic, M. A.; Reddy, J . P. J .
Am. Chem. Soc. 1991, 113, 5068-5070.
(5) (a) Gassman, P. G.; Lottes, A. C. Tetrahedron Lett. 1992, 33,
157-160. See also: (b) Gassman, P. G.; Chavan, S. P.; Fertel, L. B.
Tetrahedron Lett. 1990, 31, 6489-6492. (c) Majetich, G.; Khetani, V.
Tetrahedron Lett. 1990, 31, 2243-2246. For a previous report of 2 +
2 cycloadditions of allyl cations with alkenes, see: (d) Klein, H.;
Freyberger, G.; Mayr, H. Angew. Chem., Int. Ed. Engl. 1983, 22, 49.
S0022-3263(96)01056-0 CCC: $12.00 © 1996 American Chemical Society

Synthetic Studies on Acanthodoral and Nanaimoal
J . Org. Chem., Vol. 61, No. 24, 1996 8457
Sch em e 2
F igu r e 1. 1H-1H couplings from a COSY Experiment on 12a
(chemical shifts are in ppm).
methyl vinyl ketone (9b ) under the similar conditions
were difficult to reproduce, however, and cyclobutane 11b
and ene product 12b were found in very low yields
(<10%), if at all. Reactions of acetoxymethyl vinyl ketone
(9c) were more encouraging. With 2.5 equiv of Ti(IV),
as a 1.9:1 mixture of TiCl4:Ti(OiPr)4, as promoter, cy-
clobutane 11c was formed in 34% yield along with ene
product 12c in 45% yield. With TiCl4 as promoter, small
amounts of the desired cyclobutane 11c (8%) were found,
accompanied by chloroenone 13c (62%) as the major
product.
The structure of cyclobutane 11c was assigned from
IR, NMR, and mass spectral data. The molecular ion
indicated a 1:1 adduct, and lack of signals in the NMR
attributable to an olefinic moiety is consistent with the
structural assignment. The position of the CdC in ene
product 12a was established by a COSY experiment, the
results of which are summarized in Figure 1; the struc-
ture of 12c was assigned by spectral comparison to 12a .
The structures shown for chloro ketones 13a /c are
supported by MS and 1H/13C NMR data and by the
conversion of 13c to 12c on treatment with AgNO3/
MeOH.
(9a ) with 2 equiv of Ti(IV), as a 1:1 mixture of TiCl4:Ti-
(OiPr)4,4 at -78 °C followed by warming to -20 °C
afforded ene product 12a and chloro ketone 13a ,9 in low
yields (11-12% and 11-18%, respectively). Reactions of
(6) (a) Snider, B. B.; Rodini, D. J .; van Straten, J . J . Am. Chem.
Soc. 1980, 102, 5872-5880. (b) Snider, B. B.; Deutsch, E. A. J . Org.
Chem. 1983, 48, 1822-1829. (c) Snider, B. B.; Phillips, G. B. J . Org.
Chem. 1981, 46, 2563-2566. For an early example, see: (d) Bu¨chi,
G.; Koller, E.; Perry, C. W. J . Am. Chem. Soc. 1964, 86, 5646-5654.
For early reports of intramolecular addition of alkenes to Lewis acid-
activated carbonyl compounds, see: (e) Stork, G.; Burgstahler, A. J .
Am. Chem. Soc. 1951 73, 3544-3546. (f) Stork, G.; Marx, M. J . Am.
Chem. Soc. 1969, 91, 2371-2373. (g) Corey, E. J .; Balanson, R. D.
Tetrahedron Lett. 1973, 3153-3156. (h) Naegeli, P. Tetrahedron Lett.
1978, 24, 2127-2130. (i) Cookson, R. C.; Smith, S. A. J . Chem. Soc.,
Chem. Commun. 1979, 145-146. (j) Naegeli, P.; Wetli, M. Tetrahedron
1981, 37, Supplement No. 1, 247-255. (k) Baldwin, J . E.; Lusch, M.
J . J . Org. Chem. 1979, 44, 1923-1927.
Formation of products 11/13 likely occurs via alkyla-
tion of the Ti(IV)-activated enone by the alkene6 to give
cation 10 followed by ring closure or reaction with
chloride ion. Whether or not the ene products 12
originate directly from a concerted process, from cation
10 formed directly from the alkene and the enone, or from
ring opening of initially formed cyclobutanes 11 to give
10 is not clear. The formation of ene product 12c from
13c on treatment with AgNO3 indicates the possibility
that cation 10 may be an intermediate to the ene
products.
Although the yields of cyclobutane products from the
model experiments described above were modest, we
reasoned that intramolecular variants might be more
successful and our attention turned to a study of reac-
tions of 6-8. Lewis acid-promoted reactions of (benzoyl-
oxy)methyl enone 6 were examined initially. Enone 6
was prepared as shown in Scheme 3. Preparation of
R-(phenylsulfoxy) keto esters 14a /15a , as mixtures of
diastereomers, was accomplished by the method of Ley-
endecker [treatment of 3-methyl-2-cyclohexenone with
LiCu(CH3)2 and reaction of the resulting enolate with
methyl or ethyl R-(phenylsulfinyl)acrylate]10 and reduc-
tion with Raney nickel or aluminum amalgam gave keto
esters 14b/15b, respectively. Chemoselective methyl-
(7) Lewis acid-promoted 2 + 2 cycloaddition reactions of allenes and
alkynes with alkenes have been more extensively explored. (a) Snider,
B. B. J . Org. Chem. 1976, 41, 3061-3062. (b) Lukas, J . H.; Baardman,
F.; Kouwenhoven, A. P. Angew. Chem., Int. Ed. Engl. 1976, 15, 369-
370. (c) Snider, B. B.; Brown, L. A.; Conn, R. S. E.; Killinger, T. A.
Tetrahedron Lett. 1977, 2831-2834. (d) Snider, B. B.; Rodini, D. J .;
Conn, R. S. E.; Sealfon, S. J . Am. Chem. Soc. 1979, 101, 5283-5293.
(e) Fienemann, H.; Hoffmann, H. M. R. J . Org. Chem. 1979, 44, 2802-
2803. (f) Snider, B. B.; Roush, D. M. J . Am. Chem. Soc. 1979, 101,
1906-1907. (g) Snider, B. B.; Roush, D. M.; Rodini, D. J .; Gonzalez,
D.; Spindell, D. J . Org. Chem. 1980, 45, 2773-2785. (h) Snider, B. B.;
Kirk, T. C.; Roush, D. M.; Gonzalez, D. J . Org. Chem. 1980, 45, 5015-
5017. (i) Snider, B. B.; Spindell, D. K. J . Org. Chem. 1980, 45, 5017-
5020. (j) J ung, M. E.; Halweg, K. M. Tetrahedron Lett. 1981, 22, 2735-
2738. (k) Hoffmann, H. M. R.; Ismail, Z. M.; Weber, A. Tetrahedron
Lett. 1981, 22, 1953-1956. (l) Rosenblum, M.; Scheck, D. Organome-
tallics 1982, 1, 397-400. (m) Fadel, A.; Salau¨n, J .; Conia, J . M.
Tetrahedron 1983, 39, 1567-1573. (n) Snider, B. B.; Ron, E. J . Org.
Chem. 1986, 51, 3643-3652. (o) J enner, G.; Papadopoulos, M. Tetra-
hedron Lett. 1996, 37, 1417-1420. Lewis acid-promoted cycloaddition
reactions of electron-rich alkenes with electron-deficient alkenes have
been well-documented; for selected examples, see: (p) Clark, R. D.;
Untch, K. G. J . Org. Chem. 1979, 44, 248-255. (q) McCulloch, A. W.;
McInnes, A. G. Tetrahedron Lett. 1979, 1963-1966. (r) Semmelhack,
M. F.; Tomoda, S.; Nagaoka, H.; Boettger, S. D.; Hurst, K. M. J . Am.
Chem. Soc. 1982, 104, 747-759. (s) Takeda, T.; Fujii, T.; Morita, K.;
Fujiwara, T. Chem. Lett. 1986, 1311-1314. (t) Quendo, A.; Rousseau,
G. Tetrahedron Lett. 1988, 29, 6443-6446. (u) Fe´tizon, M.; Goulaouic,
P.; Hanna, I.; Prange, T. J . Org. Chem. 1988, 53, 5672-5679. (v)
Nicolaou, K. C.; Hwang, C.-K.; Duggan, M. E.; Bal Reddy, K. Tetra-
hedron Lett. 1987, 28, 1501-1504. (w) Ichikawa, Y.-i.; Narita, A.;
Shiozawa, A.; Hayashi, Y.; Narasaka, K. J . Chem. Soc., Chem.
Commun. 1989, 1919-1921. (x) Narasaka, K.; Kusama, H.; Hayashi,
Y. Bull. Chem. Soc. J pn. 1991, 64, 1471-1478. (y) Narasaka, K.;
Hayashi, Y.; Shimadzu, H.; Niihata, S. J . Am. Chem. Soc. 1992, 114,
8869-8885. (z) Hojo, M.; Tomita, K.; Hirohara, Y.; Hosomi, A.
Tetrahedron Lett. 1993, 34, 8123-8126. (aa) Monti, H.; Audran, G.;
Le´andri, G.; Monti, J .-P. Tetrahedron Lett. 1994, 35, 3073-3076.
(8) For reviews of photochemical 2 + 2 cycloadditions, see: (a)
Crimmins, M. T. Chem. Rev. 1988, 88, 1453-1473. (b) Baldwin, S. W.
In Organic Photochemistry; Padwa, A., Ed.; Dekker: New York, 1981:
Vol. 5, pp 123-225. (c) Wender, P. A. In Photochemistry in Organic
Synthesis; Coyle, J . D., Ed.; The Royal Society of Chemistry: London,
1986; pp 163-188
(9) Initially, compound 13b was mistakenly identified as the desired
cyclobutane product 11b.2 Unfortunately, all attempts to isolate the
latter product have failed despite considerable effort in which the ratio
and equivalents of TiCl4:Ti(OiPr)4 and reaction temperature were
varied.
(10) (a) Leyendecker, F.; Comte, M.-T. Tetrahedron 1986, 42, 1413-
1421. (b) Leyendecker, F.; Comte, M.-T. Tetrahedron 1987, 43, 85-
92. (c) Leyendecker, F.; Comte, M.-T. Tetrahedron Lett. 1982, 23, 5031-
5034.

8458 J . Org. Chem., Vol. 61, No. 24, 1996
Engler et al.
Sch em e 3a
F igu r e 2. Summary of HMBC NMR data on 22.
Sch em e 4a
a
(a) Al(Hg)/H2O, 74%. (b) Al(Hg)/H2O, 75% or RaNi/H2O, 98%.
(c) TiCl4/Zn/CH2Br2, 71%. (d) i. LiAlH4, 98%; ii. DMSO/ClC(O)-
C(O)Cl, Et3N, 96%; iii. MeMgCl, 100%; iv. DMSO/ClC(O)C(O)Cl,
Et3N, 98%. (e) LiCtCCH2OTBDMS, 100%. (f) Red-Al/H3O+, 94%.
(g) Bu4N+F-/PhC(O)Cl, DMAP, 97%. (h) PCC, 67%.
a
(a) CH2dCHMgBr, 100%. (b) PCC, 92%.
any products; other Lewis acids were not examined. The
position of the carbon-carbon double bond in 22 was
established by 1H-1H decoupling, HETCOR, and HMBC
NMR experiments. Thus, the hydrogens attached to C-2′
appeared as two doublets at 2.38 and 2.30 ppm (J ) 15
Hz) in the 1H NMR spectrum, and the C-2′ resonance
was assigned by a HETCOR experiment. An HMBC
experiment (Figure 2) then revealed coupling between
the hydrogens attached to C-2′ and four sp3 carbons.
Similarly, the C-2′′ methyl hydrogens were coupled to
four sp3 carbons. Other notable 2J /3J C-H couplings are
also shown in Figure 2; that the methine carbon is
coupled to the hydrogens of the gem-dimethyl substitu-
ents and the C-1 hydrogens indicated with certainty the
position of the CdC. Unfortunately, we have been unable
to obtain X-ray quality crystals of 22 or a derivative,
which has prevented assignment of the relative stereo-
chemistry of the two stereogenic centers.
enylation of the ketone carbonyl in 15b was effected with
the Nozaki-Lombardo reagent,11 and the product 16 was
converted to ketone 17 in 92% overall yield by the
sequence shown. Enone 6 then resulted from ketone 17
by the following sequence. Addition of lithium [(tert-
butyldimethylsilyloxy)methyl]acetylide gave alcohol 18
as an ca. 1:1 mixture of diastereomers (by 13C NMR), and
hydroalumination of this mixture followed by protonation
of the resultant alkenylaluminum species gave trans
allylic alcohol 19, again as a mixture of diastereomers.
Fluoride-mediated desilylation of 19 and treatment with
benzoyl chloride/DMAP gave benzoates 20. Finally, PCC
oxidation of the mixture produced a 4:1 mixture of enones
6 and 21, respectively, in 67% yield, and the major isomer
was separated by flash chromatography.12
Treatment of 6 with excess amounts (4 equiv) of Ti-
(IV), initially as a 1:1 mixture of TiCl4:Ti(OiPr)4, followed
by additional TiCl4 to complete the reaction, resulted only
in ene product 22 in 90% yield; no other products were
detected by carefully monitoring the reactions by TLC.
Use of lesser amounts of Ti(IV), i.e., 1 equiv of TiCl4 or
1.5 equiv of a 3:1 mixture of TiCl4:Ti(OiPr)4, failed to give
The syntheses of aldehydes 7/8 are shown in Schemes
4 and 5. Addition of vinylmagnesium bromide to ketone
17 followed by PCC oxidation gave an ca.2:1 mixture of
aldehydes 7a /7b, respectively, in 92% yield. In this
sequence, compound 23 was found and used as a mixture
of diastereomers, and the final aldehydes 7a /b were
separated by careful flash chromatography. Aldehydes
8 were prepared from keto ester 14b in 38% overall yield
by a straightforward sequence involving (i) ketalization,
(ii) LiAlH4 reduction, (ii) perruthenate oxidation, (iii)
methyl Grignard addition, (iv) a second perruthenate
oxidation, (v) Wittig methylenylation, (vi) deketalization,
and (vii) addition of vinylmagnesium bromide followed
by (viii) PCC oxidation. Again, in this sequence, com-
pound 24 and intermediates leading to it were handled
as mixtures of diastereomers (ca. 1:1), and aldehydes
(11) Lombardo, L. Org. Synth. 1987, 65, 81-89.
(12) The stereochemistry in
6 was assigned on the basis of a
comparison of its 1H/13C NMR spectra with those of i, a compound
prepared in our lab in connection with a related project (Ali, M. H,
Ph.D. Dissertation, University of Kansas, 1993). The stereochemistry
in i was established by a 1H-1H NOE experiment, the results of which
are shown.

Synthetic Studies on Acanthodoral and Nanaimoal
J . Org. Chem., Vol. 61, No. 24, 1996 8459
Sch em e 5a
Ta ble 1. Lew is Acid -P r om oted Rea ction s of 7a /7b
% yields
aldehyde
(ratio)
Lewis acid
temp
(°C)
3/26c
(equiv/ratio)a
25b (ratio)d
7a /7b (2:3) B(OMe)3:BCl3 (1:1)
-78
-78
B(OMe)3:BCl3 (1.5:0.5) -78
-78
44 47 (1:2)
28 39 (1:3)
44 46 (1:2)
no reaction
7a
7b
BCl3 (1)
7a or 7a /b B(OMe)3 (1)
7a
7a
7a
7a
TiCl4:Ti(OiPr)4 (1:0.5) -78 f 0
18 28 (1:2)
SnCl4 (0.8)
-78 f -20 21 41 (1:2)
-78 f -20 56 (1:2)
-78 f -20 18 43 (2:3)
BF3‚Et2O (0.5)
BF3‚Et2O (2)
8
a
b
With respect to aldehyde 7. Isolated yield. c Combined yield,
see text. By 1H NMR.
d
a
Sch em e 6
(a) i. HOCH2CH2OH/[pTsOH], 86%; ii. LiAlH4, 90%; iii.
(Pr4N)RuO4, 100%; iv. MeMgI, 100%; v. (Pr4N)RuO4, 100%. (b)
Ph3PCH2, 94%. (c) i. [pTsOH]/H2O, 91%; ii. CH2dCHMgBr, 100%.
(d) PCC, 58%.
Aldehyde 25 was isolated cleanly from the reaction
mixtures. Unfortunately, its 500 MHz 1H NMR spectrum
was not sufficiently resolved to identify key resonances
and multiplicities necessary to distinguish it from acan-
thodoral (1) or other possible isomers; indeed, the avail-
able spectral data (1H/13C NMR, IR, mass) were consis-
tent with those expected for acanthodoral. At first, we
surmised that alkene-aldehyde products 3/26 might
have been produced by subsequent acid-catalyzed ring
opening of initially formed acanthodoral and that the
crude reaction mixture was a combination of the three.
However, attempts to effect conversion of product 25 to
3 or 26 by treatment with protic or Lewis acids failed; it
was inert. The structure of 25 was ultimately deter-
mined with certainty by NaBH4 reduction and conversion
of the resultant alcohol 27 to urethane 28. Single-crystal
X-ray analysis revealed its tricyclic structure,13 which
apparently results from a cyclization/rearrangement
sequence (see below).
Separation of bicyclic aldehyde products 3 and 26
proved difficult. Preparative GC afforded pure 3; how-
ever, 26 could not be obtained free of impurities. NMR
spectral data of aldehyde 3 were identical to those of
nanaimoal14 which was independently synthesized from
allylic alcohol 23 in 67% overall yield via acid-catalyzed
cyclization to bicyclic diene 29 followed by hydroboration/
oxidation (Scheme 7).
1
F igu r e 3. Summary of selected H-1H NMR data on 7/8 and
NOE data on 7a /8b.
8a /b (ca. 3:1) could be separated by careful flash chro-
matography. The double-bond geometry in aldehydes 7
and 8 was determined by data from H-1H NMR experi-
1
ments (Figure 3). NOE experiments clearly established
the (E)-geometry in 7a and 8b. In addition, the â-methyl
group of the enal moiety in 7a and 7b appears at 2.14
1
and 1.92 ppm, respectively, in their H NMR spectra due
to deshielding by the proximal aldehyde carbonyl group.
A similar deshielding effect is evident in the 1H NMR
spectra of aldehydes 8 in which a ddd (J ) 13, 4, 4 Hz;
gem/ax-eq/eq-eq) appears at ca. 2.94 ppm in the spectrum
of 8a and a dd (J ) 11, 3 Hz) at ca. 2.89 ppm in that of
8b. These signals are assigned to the equatorial hydro-
gens at positions 6 and 2, respectively. Deshielding of
H-2 in 8b suggests that the major conformer has this
hydrogen in an equatorial position to avoid A(1,3) strain
between the aldehyde and the isopentenyl side chain.
Results of Lewis acid-promoted reactions of 7a /b are
presented in Table 1. Reactions of 7a , 7b, or ca. 1:1
mixtures of the two produced the same three products
25, 26, and 3, accompanied by small amounts other
unidentified olefinic products (Scheme 6). The ratio of
the three products varied somewhat with the Lewis acid
employed; the best material balance was found with a
1:1 mixture of B(OMe)3:BCl3 as promoter (2 equiv of
boron with respect to starting aldehyde). In these
reactions, isomerization of 7a to 7b was found to occur
by quenching reactions of pure 7a before completion and
recovering mixtures of 7a /b along with the products.
Similarly, in reactions starting from pure 7b, the pres-
ence of isomer 7a could be detected by TLC during the
course of the reaction.
Because aldehyde 26 could not be obtained pure, its
structural assignment should be regarded as tentative.
However, the structure shown is consistent with NMR
(13) The authors have deposited coordinates for structure 28 with
the Cambridge Data Centre. The coordinates can be obtained from the
Director, Cambridge Crystallographic Data Centre, University Chemi-
cal Lab, Lensfield Road, Cambridge, CB2 1EZ, U.K.
(14) We thank Professor R. J . Andersen of The University of British
Columbia for copies of 1H NMR spectra of nanaimoal.

8460 J . Org. Chem., Vol. 61, No. 24, 1996
Engler et al.
Sch em e 7
Sch em e 9
Sch em e 8
1
data and is further supported by comparison of its H/
13C NMR spectra to those of the ene product 22, which
show a number of similar features (see Supporting
Information). Although formed as a single diastereomer,
the relative stereochemistry in 26 was not assigned.
Studies of Lewis acid-promoted reactions of aldehydes
8a /b were quite interesting and limited to only a few
examples, for reasons discussed below. Treatment with
BCl3:B(OMe)3 gave nanaimoal as a major product (20%,
Scheme 8) accompanied by recovered starting aldehyde
8a (28%) and its isomer 8b (12%), again indicating that
the former isomerizes under the reaction conditions as
found with aldehydes 7. Remarkably, reaction of 8a with
TiCl4 at -85 °C and treatment of the crude reaction
mixture directly with NaBH4 gave tricyclic alcohol 27 in
55% yield; the same product as found in treatment of
aldehydes 7 with Lewis acids followed by reduction of the
products. Alcohol 27 was also found in 23% yield upon
treatment with 2.5:1 mixture of aldehydes 8a /b with a
mixture of TiCl4:Ti(OiPr)4 followed by NaBH4 reduction.
In the latter reactions, unidentified ene products were
also produced in minor amounts. Because the formation
of 27 in these reactions was surprising, its structure was
again determined by conversion to a p-bromourethane
derivative; single-crystal X-ray analysis once more re-
vealed structure 28.
Sch em e 10
Discu ssion
However, the stereochemistry of carbocations 31/32
suggests that the initial alkylation proceeds via a con-
formation which is not suitable for the production of
acanthodoral. Likely conformations for this step are
30a -c. Other possible conformations would lead to the
stereoisomeric carbocation 33 (Scheme 10), and it is not
obvious how product 25 would result from such an
intermediate (although a deprotonation-protonation se-
quence is conceivable). Of conformations 30a -c, the
latter can probably be ruled out because of a relatively
highly strained syn-pentane orientation of the enal side
chain with respect to the axial methyl group. It is not
clear which of the other two gives rise to a lower energy
pathway to 31. Conformer 30a suffers from a type of A(1,3)
strain,15 two gauche interactions between the enal side
chain and the gem-dimethyl substituents,17 and a steric
interaction between the â-methyl group of the side chain
and the C-5′ axial hydrogen on the ring. On the other
The formation of tricyclic aldehyde 25 from both enals
7 and 8 was unexpected and indicated a common inter-
mediate, produced presumably through rearrrangement
processes. An analysis of possible routes from 7 is shown
in Scheme 9. A likely first step is an intramolecular
alkylation of the Lewis acid-activated enal moiety in 30
by the carbon-carbon π bond which results in 3° cation
31.6 A subsequent 1,2-hydrogen shift produces a second
3° carbocation 32 which undergoes ring closure to tricyclic
aldehyde 25. Interconversion of carbocations 31 and 32
is reasonable since both are 3° carbocations likely to be
similar in energy, and a faster rate of 5-membered ring
formation than 4-membered ring closure accounts for the
formation of 25. It is conceivable that a cyclobutane
carboxaldehyde product might be formed from 31, but if
so, such an intermediate reverts to 31 under the reaction
conditions.6a

Synthetic Studies on Acanthodoral and Nanaimoal
J . Org. Chem., Vol. 61, No. 24, 1996 8461
Sch em e 11
Finally, formation of aldehyde 26 from 7 may also result
from cation 31, or an intramolecular ene reaction; ene
product 22 may be formed in a similar manner from
ketone 6. Since we have been unable to assign the
relative stereochemistry in 22/26, it is not possible to
determine which of the various pathways lead to them
at this time.
Thus, a stepwise 2 + 2 process is apparently occurring
in reactions of 8 and may also be involved in those of 7,
but the stereochemistry of the initial alkylations to
produce cation intermediates 31/35 suggests that these
approaches are not practical for synthesis of acan-
thodoral, or isoacanthodoral. A new approach is planned.
Exp er im en ta l Section 18
Sch em e 12
Enones 9a /c were prepared by literature methods.19 Be-
cause of their largely routine nature, experimental details for
the preparation of 6, 7a /b, and 8a /b are included in the
Supporting Information.
Tita n iu m (IV)-Ca ta lyzed Rea ction of Meth ylen ecyclo-
h exa n e w it h Met h oxym et h yl Vin yl Ket on e (9a ). TiCl4
(0.24 mL, 2.20 mmol) was added to a solution of Ti(OiPr)4 (0.66
mL, 2.20 mmol) in CH2Cl2 (20 mL) at 0 °C. After 5 min, the
mixture was cooled to -78 °C and ketone 9a (218 mg, 2.18
mmol) was added, producing a bright yellow solution. After
15 min, methylenecyclohexane (215 mg, 2.23 mmol) was added
and the reaction mixture was stirred for 3 h at -78 °C. The
mixture was then warmed to -20 °C and allowed to stand for
16 h. Solid sodium bicarbonate (ca. 1 g) was added followed
by 2-propanol (2 mL). The mixture was poured into saturated
aqueous sodium bicarbonate and the resultant mixture ex-
tracted with CH2Cl2. The combined extracts were washed with
water and brine, dried (K2CO3), and filtered. Concentration
of the filtrate provided a light yellow oil, and flash chroma-
tography with 15% EtOAc/hexane as eluent produced products
12a (57 mg, 13%) and 13a (57 mg, 11%), both as colorless oils.
Physical and spectral data for 12a : Rf 0.41 (20% EtOAc/
hexane); 1H NMR (300 MHz) 1.5-1.6 (m, 4H), 1.71 (dt, J ) 7,
2, 2H), 1.8-1.95 (m, 6H), 2.40 (t, J ) 7.2, 2H), 3.42 (s, 3H),
4.00 (s, 2H), 5.32 (br s, 1H); 13C NMR (75 MHz) 21.15, 22.46,
22.89, 25.19, 27.97, 37.33, 38.14, 59.26, 77.60, 121.77, 136.76,
208.64; HRMS 196.1453 (calcd for C12H20O2, 196.1463).
Physical and spectral data for 13a : Rf 0.31 (20% EtOAc/
hexane); 1H NMR (300 MHz) 1.18-1.20 (m, 1H), 1.5-1.90 (m,
13H), 2.48 (t, J ) 7, 2H), 3.42 (s, 3H), 4.02 (s, 2H); 13C NMR
(75 MHz) 17.69, 22.25, 25.39, 38.67, 39.56, 44.52, 59.27, 75.61,
77.59, 208.30; HRMS 196.1465 [calcd for C12H20O2 (M+ - HCl),
196.1462].
hand, 30b incorporates one less gauche interaction, but
an added axial substituent as well as a steric interaction
between the enal side chain and the axial C-5′ hydrogen.
Both are probably energetically accessible, and the Cur-
tin-Hammett Principle does not allow for a confident
prediction of the relative energies between transition
states emanating from 30a /b.
The rationale for studying reactions of enal 8 was that
should intramolecular alkylation of the Lewis acid-
activated enal moiety by the CdC occur, as apparently
occurs in reactions of 7, then the resultant 3° carbocation
should be less prone to 1,2-hydride shifts since such a
process could only produce a less stable 2° carbocation
intermediate. However, the formation of tricyclic alde-
hyde 25 suggests the route shown in Scheme 11. Alkyl-
ation of the Lewis acid-activated enal moiety in 34 by
the carbon-carbon π bond produces 3° carbocation 35.
Ring closure to cyclobutane 36 followed by Lewis acid-
promoted ring opening6a provides cation 31, the same
cation formed in reactions of 7, which then proceeds on
to 25 as discussed previously. Cation 35 again appar-
ently arises via a conformation (34) unsuitable for the
production of acanthodoral; note that 36 is a stereoisomer
of acanthodoral. Other possible conformations for this
step would lead to diastereomeric carbocation 37 (Scheme
12), from which it is again not apparent how 25 would
be formed.
Tita n iu m (IV)-Ca ta lyzed Rea ction s of Meth ylen ecy-
cloh exa n e w ith Acetoxym eth yl Vin yl Keton e (9c). TiCl4
(0.14 mL, 1.27 mmol) was added to a solution of Ti(OiPr)4 (0.20
(18) All compounds were prepared as racemic mixtures. All experi-
ments were carried out in oven- or flame-dried glassware, under a
positive pressure of dry nitrogen or argon and were magnetically
stirred, unless otherwise noted. All solvents and reagents were distilled
from appropriate drying agents before use. Samples for NMR were
dissolved in CDCl3, and chemical shifts are expressed as ppm (δ)
relative to tetramethylsilane, residual CHCl3, or CDCl3 as internal
standards. Samples for NOE experiments were degassed by freeze-
thaw techniques under a nitrogen atmosphere immediately before the
experiments. Chromatographic separations were carried out either by
flash chromatography using MN-Kieselgel 60 silica gel (0.04-0.063
mm mesh size) or by PCTLC (preparative centrifugal thin-layer
chromatography) with silica gel (Merck no. 7749) on a Chromatotron
Model 7924T. Analytical thin-layer chromatography was done on
precoated silica gel plates with a 254 nm fluorescent indicator (Merck
no. 5715) and developed in the indicated solvent systems. Compounds
were visualized under a UV lamp and/or by staining with either
p-anisaldehyde/sulfuric acid or phosphomolybdic acid solutions. Rf’s
refer to TLC experiments. GC analyses were obtained on a 25 m ×
0.22 mm BP20 capillary column from Scientific Glass Engineering.
Formation of nanaimoal from aldehydes 7 or 8 may
occur via loss of H+ from cations 31/32 or also possibly
33/37. If the latter are formed, however, they apparently
do not close to acanthodoral (1) or if they do, reversion/
conversion to 33 occurs under the reaction conditions.
(15) The ∆G for interconversion of chair conformers of 2-methyl-
methylenecyclohexane is ca. 1.0 kcal/mol versus 1.7-1.8 kcal/mol for
methylcyclohexane, indicating A(1,3) strain in the former raises the
energy of the equatorial conformer by ca. 0.7 kcal/mol.16 In conformer
30a , however, greater A(1,3) strain is expected because of the way the
enal appendage must fold for reaction with the exo-methylene moiety.
(16) Lessard, J .; Tan, P. V. M.; Martino, R.; Saunders, J . K. Can. J .
Chem. 1977, 55, 1015-1023.
(17) However, the cumulative effect of two gauche interactions of
this type are not additive; it is less than expected, see: Eliel, E. L.;
Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-Inter-
science: New York, 1994; p 705.
1
Preparative GC was done on a 6 ft × /4 in. Carbowax or FFAP column.
(19) (a) Hennion, G. F.; Kupiecki, F. P. J . Org. Chem. 1953, 18,
1601-1609. (b) Wenkert, E.; Golob, N. F.; Sathe, S. S.; Smith, R. A. J .
Synth. Commun. 1973, 3, 205-209.

8462 J . Org. Chem., Vol. 61, No. 24, 1996
Engler et al.
mL, 0.67 mmol) in CH2Cl2 (10 mL) at -35 °C. After 15 min,
the reaction mixture was cooled to -78 °C and ketone 9c (100
mg, 0.78 mmol) was added, producing a bright orange solution.
After 30 min, methylenecyclohexane (100 mg, 1.04 mmol) was
added. The reaction mixture was stirred for 0.5 h at -78 °C,
and solid sodium bicarbonate (about 1 g) followed by 2-pro-
panol (2 mL) was then added. Workup as described in the
previous experiment produced a yellow oil. Flash chromatog-
raphy with 20% EtOAc/hexane as eluent produced compound
11c (60 mg, 34%) and compound 12c (79 mg, 45%).
Spectral and physical data for 11c: Rf(50% ether/hexane)
0.5; 1H NMR (500 MHz) 1.10-1.20 (m, 2H), 1.21-1.35 (m, 2H),
1.50-1.82 (m, 9H), 2.17 (s, 3H), 2.33-2.42 (m, 1H), 2.94 (dd,
J ) 8, 8, 1H), 4.59 (ABq, J ) 17, 2H); 13C NMR (75 MHz) 15.61,
20.54, 21.88, 22.77, 25.74, 28.77, 31.85, 40.34, 45.27, 51.37,
68.76, 170.19, 203.15; HRMS 224.1405 (calcd for C13H20O3,
224.1412).
was added followed by 2-propanol (5 mL). The mixture was
slowly warmed to rt and water was added, and the organic
phase was separated. The aqueous phase was extracted with
CH2Cl2, and the combined organic solutions were washed with
brine, dried (Na2SO4), and filtered. The filtrate was concen-
trated under a flow of nitrogen (to avoid evaporation of volatile
products under vacuum1a), and the residue was flash chro-
matographed using 2% ether/pentane as eluent to produce 25
(59 mg, 44%) as a colorless oil and a (1:2) mixture of ene
products 3 and 26 (63 mg) containing some undetermined
olefinic compounds by 1H NMR. Compounds 3 (tR 9.5 min)
and 26 (tR 11 min) were partially separated by preparative
GC [1/4in. × 6 ft FFAP, column and detector temperature 200
°C, injector temperature 240 °C, 4 µL, 20 mL/min].
Spectral and physical data for 25: Rf(20% ether/hexane)
0.79; 1H NMR (500 MHz) 0.87(s, 3H), 0.98 (s, 3H), 1.09 (s, 3H),
1.20-1.65 (m, 9H), 1.76-1.93 (m, 4H), 2.08 (d, J ) 6, 1H), 10.14
(d, J ) 6, 1H); 13C NMR (125 MHz) 19.61, 21.11, 25.16, 26.55,
33.41, 33.86, 35.18, 37.63, 39.20, 40.75, 44.83, 48.12, 61.83,
67.53, 207.35; HRMS 220.1833 (calcd for C15H24O, 220.1827).
Spectral and physical data for 3: Rf(25% ether/hexane) 0.58;
1H NMR (500 MHz) 0.96 (s, 6H), 1.04 (s, 3H), 1.40-1.65 (m,
6H), 1.74-1.85 (m, 4H), 1.94-2.05 (m, 2H), 2.22 (dd, J ) 3,
14.5, 1H), 2.28 (dd, J ) 3, 14.5, 1H), 9.84 (dd, J ) 3, 1H); 13C
NMR (125 MHz) 19.28, 21.24, 25.91, 27.82, 27.86, 31.52, 32.08,
33.54, 34.70, 39.64, 43.57, 53.58, 125.22, 133.67, 203.93; HRMS
220.1835 (calcd for C15H24O, 220.1827).
Spectral and physical data for compound 12c: Rf(50% ether/
1
hexane) 0.45; H NMR (500 MHz) 1.50-1.65 (m, 4H), 1.68-
1.76 (dt, J ) 11, 2H), 1.85-2.00 (m, 6H), 2.17 (s, 3H), 2.37
(dd, J ) 8, 8, 2H), 4.64 (s, 2H), 5.39 (br s, 1H); 13C NMR (75
MHz) 20.53, 21.07, 22.48, 22.91, 25.22, 27.96, 37.23, 38.08,
67.99, 122.02, 136.62, 171.20, 203.91; HRMS 225.1462 (M+
1) [calcd for C13H21O3, 225.1490].
+
In another experiment, ketone 9c (162 mg, 1.26 mmol) was
added to a solution of TiCl4 (0.125 mL, 1.14 mmol) in CH2Cl2
(20 mL) at -78 °C to produce a bright red solution. After 15
min, methylenecyclohexane (114 mg, 1.19 mmol) was added.
The reaction mixture was stirred for 45 min and worked up
as described above to produce a yellow oil. PCTLC using 10%
EtOAc/hexane as eluent produced compound 11c (20 mg, 8%),
compound 13c (186 mg, 62%), and unreacted enone (14 mg)
as clear liquids.
Spectral data for 26: 1H NMR (500 MHz) 0.84 (s, 3H), 0.91
(s, 3H), 1.07 (s, 3H), 1.20-1.38 (m, 4H), 1.64-1.74 (m, 4H),
1.88-2.02 (m, 2H), 2.08 (dd, J ) 3, 13.5, 1H), 2.23 (dd, J ) 3,
15, 1H), 2.28 (dd, J ) 3, 15, 1H), 5.36 (br s, 1H), 9.81 (dd, J )
3, 1H); 13C NMR (125 MHz) 22.63, 23.80, 28.44, 28.88, 31.24,
35.50, 37.04, 38.22, 44.07, 47.07, 48.93, 49.29, 121.18, 136.57,
204.08.
(2,5,5-Tr im eth ylocta h yd r o-2,4a -m eth a n on a p h th a len -
9-yl)m eth a n ol (27). Sodium borohydride (60 mg, 1.6 mmol)
was added to a solution of 25 (40 mg, 0.18 mmol) in methanol
(10 mL). After 0.5 h at rt, the mixture was treated with
saturated aqueous ammonium chloride. The organic phase
was separated, and the aqueous phase was extracted with CH2-
Cl2. The combined organic solutions were washed with brine,
dried (Na2SO4), and filtered. Concentration of the filtrate and
flash chromatography of the residue using 5% ether/hexane
as eluent yielded 27 (38 mg, 94%) as a white solid: mp 72-73
°C; Rf(25% ether/hexane) 0.23. 1H NMR (500 MHz) 0.85 (s,
3H), 1.00 (s, 3H), 1.10 (s, 3H), 1.20-1.85 (m, 15H), 3.75 (dd, J
) 11, 9, 1H), 4.04 (dd, J ) 11, 2, 1H); 13C NMR (125 MHz)
20.45, 21.25, 26.14, 26.44, 33.07, 33.72, 34.84, 36.32, 39.45,
40.52, 44.56, 45.14, 54.05, 58.81, 61.95; HRMS 222.1981 (calcd
for C15H26O, 222.1984).
p-Br om ou r eth a n e 28. A mixture of 27 (37.8 mg, 0.17
mmol), p-bromophenyl isocyanate (32 mg, 0.16 mmol), and
benzene (4 mL) was refluxed for 8 h and cooled to rt, and the
solvent was removed under vacuum to produce a white solid.
PCTLC using 5% ether/hexane as eluent produced 28 (67 mg,
100%) as a white solid. Recrystallization from 5% ether/
hexane gave long thin needle-shaped crystals: mp 134-136
°C; Rf(25% ether/hexane) 0.54. 1H NMR (500 MHz) 0.87 (s,
3H), 1.04 (s, 6H), 0.90-1.80 (m, 14H), 4.18-4.22 (dd, J ) 11,
11, 1H), 4.60-4.67 (dd, J ) 11, 2, 1H), 6.61 (br s, 1H). 7.30
(d, J ) 8, 2H), 7.4 (d, J ) 8, 2H); 13C NMR (125 MHz) 20.24,
21.13, 26.09, 26.37, 32.99, 33.73, 34.95, 36.25, 39.40, 40.39,
44.38, 45.40, 54.24, 54.37, 64.71, 115.76, 120.13, 131.93,
137.13, 153.43; HRMS 419.1449 (calcd for C22H30O2NBr,
419.1460).
1,1,6-Tr im eth yl-6-vin yl-1,2,3,4,5,6,7,8-octa h yd r on a p h -
th a len e (29). A 48% aqueous hydrogen fluoride solution (0.5
mL) was added to a solution of alcohols 23 (195 mg, 0.87 mmol)
in acetonitrile (4 mL). After 1 h, CHCl3 (5 mL) was added
and the organic phase was separated. The aqueous phase was
extracted with CHCl3, and the combined CHCl3 solutions were
washed with saturated aqueous sodium bicarbonate and brine,
dried (MgSO4), and filtered. PCTLC with pentane as eluent
gave 29 (145 mg, 82%) as a clear oil: Rf(hexane) 0.7. 1H NMR
(500 MHz) 0.96 (s, 3H), 0.97 (s, 3H), 0.99 (s, 3H), 1.36-1.71
(m, 7H), 1.80-2.00 (m, 5H), 4.85-4.86 (dd, J ) 1.5, 10.5, 1H),
Spectral data for 13c: 1H NMR (300 MHz) 1.10-1.22 (m,
1H), 1.40-1.90 (m, 13H), 2.10 (s, 3H), 2.41 (dd, J ) 7, 7, 2H),
4.59 (s, 2H); 13C NMR (75 MHz) 17.47, 20.26, 22.07, 25.23,
38.41, 39.89, 44.23, 67.77, 75.41, 170.00, 203.38; HRMS
261.1265 (M+ + 1) [calcd for C13H22O3Cl, 261.1257].
Rea ction of 13c w ith Silver Nitr a te. Chloro ketone 13c
(55 mg, 0.21 mmol) was dissolved in a concentrated solution
of silver nitrate in methanol (5 mL), and the mixture was
stirred for 3 h at rt. The mixture was filtered to remove a
white solid, and the filtrate was concentrated under vacuum.
Flash chromatography on silica gel with 10% EtOAc/hexane
as eluent gave 12c as a colorless oil (45 mg, 95%).
2-Oxo-3-(2,5,5-tr im eth yl-1,2,3,4,4a,5,6,7-octah ydr on aph -
th a len -2-yl)p r op yl Ben zoa te (22). TiCl4 (0.015 mL, 0.14
mmol) was added to a solution of Ti(OiPr)4 (0.04 mL, 0.14
mmol) in CH2Cl2 (10 mL) at -78 °C. The mixture was warmed
to -10 °C and recooled to -78 °C, and a solution of 6 (50 mg,
0.14 mmol) in CH2Cl2 (5 mL) was added dropwise. After 4 h,
the reaction mixture was warmed to -20 °C and allowed to
stand for 16 h. The reaction mixture was cooled to -78 °C,
and additional TiCl4 (0.015 mL, 0.136 mmol) was added. The
reaction mixture was then warmed to -20 °C, and another
aliquot of TiCl4 (0.015 mL, 0.14 mmol) was added. The
reaction mixture was slowly warmed to 0 °C, and solid sodium
bicarbonate (ca. 1 g) was added followed by 2-propanol (5 mL).
The mixture was extracted with CH2Cl2, and the combined
extracts were washed with brine, dried (MgSO4), and filtered.
Concentration of the filtrate produced a yellow oil, and PCTLC
using 5% ether/hexane as eluent afforded 22 (45 mg, 90%):
1H NMR (500 MHz) 0.83 (s, 3H), 0.91 (s, 3H), 1.08 (s, 3H),
1.17-1.37 (m, 4H), 1.53-1.71 (m, 2H), 1.78-2.00 (m, 4H), 2.12
(dd, J ) 3, 14, 1H), 2.30 (d, J ) 15, 1H), 2.38 (d, J ) 15, 1H),
4.81 (d, J ) 17, 1H), 4.82 (d, J ) 17, 1H), 5.36 (br s, 1H), 7.45
(t, J ) 8, 2H), 7.56 (t, J ) 8, 1H), 8.08 (d, J ) 8, 2H); 13C NMR
(125 MHz) 22.62, 23.97, 24.65, 28.44, 28.56, 31.22, 34.89, 35.79,
37.82, 43.47, 47.14, 48.82, 69.72, 120.99, 128.39, 129.34,
129.86, 133.30, 136.99, 165.82, 203.68; HRMS 354.2197 (calcd
for C23H30O3, 354.2195).
Lew is Acid -P r om oted Rea ction of 7b. Trimethyl borate
(0.11 mL, 0.97 mmol) was added dropwise to a solution of 7b
(136 mg, 0.62 mmol) in CH2Cl2 (5 mL). After 1 h, a 1.0 M
solution of boron trichloride in THF (0.50 mL, 0.5 mmol) was
added and, after 15 min, solid sodium bicarbonate (ca. 1 g)

Synthetic Studies on Acanthodoral and Nanaimoal
J . Org. Chem., Vol. 61, No. 24, 1996 8463
4.90-4.93 (dd, J ) 1.5, 18, 1H), 5.74-5.85 (dd, J ) 10.5, 18,
1H); 13C NMR (75 MHz) 19.45, 21.71, 25.67, 27.89 (2 CH3’s),
31.61, 33.52, 34.48, 35.09, 39.83, 42.34, 110.04, 125.42, 133.58,
147.79; HRMS 204.1870 (calcd for C15H24, 204.1878).
followed by methanol (5 mL, the orange color faded). The
reaction mixture was allowed to warm to -20 °C, and solid
sodium borohydride (125 mg, 3.3 mmol) was added. The
reaction mixture was allowed to warm to rt, and water was
added to destroy the excess borohydride. The solvent was
removed, and the residue was redissolved in CH2Cl2. The
organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic solutions were
washed with brine, dried (MgSO4), filtered, and concentrated
under vacuum. Flash chromatography of this residue with
10% ether/hexanes as eluent gave 27 (22 mg, 55% yield).
(c) P r om otion w ith TiCl4:Ti(OiP r )4. TiCl4 (0.03 mL, 0.27
mmol) was added to a solution of Ti(OiPr)4 (0.07 mL, 0.25
mmol) in CH2Cl2 (10 mL) at -78 °C, followed by the dropwise
addition of a 2.5:1 mixture of 8a and 8b (85 mg, 0.39 mmol)
in CH2Cl2 (5 mL). After 1 h, additional TiCl4 (0.03 mL, 0.27
mmol) was added and the mixture turned dark orange im-
mediately. After 1.5 h, another portion of TiCl4 (0.03 mL, 0.27
mmol) was added, and the reaction mixture was stirred for
an additional 1 h. The reaction mixture was warmed to -40
°C, and solid sodium bicarbonate (1 g) was added followed by
2-propanol (1 mL). The reaction mixture was allowed to warm
to rt and filtered, and the filtrate was concentrated under a
flow of nitrogen. The residue was dissolved in methanol (10
mL) and sodium borohydride (216 mg, 5.5 mmol) added. After
30 min, saturated aqueous ammonium chloride was added and
the reaction mixture was diluted with brine and CH2Cl2. The
organic phase was separated, and the aqueous phase was
extracted with CH2Cl2. Combined organic solutions were
washed with brine, dried (MgSO4), filtered, and concentrated
under vacuum. Flash chromatography of the residue with 10%
ether/hexanes as eluent gave 27 (11 mg, 23% yield).
Hyd r obor a tion -Oxid a tion of 29: 2-(2,5,5-tr im eth yl-
1,2,3,4,5,6,7,8-octa h yd r on a p h th a len -2-yl)eth a n ol. A 0.5 M
solution of 9-BBN-H in THF (0.60 mL, 0.90 mmol) was added
dropwise to a solution of 29 (54 mg, 0.26 mmol) in THF (5
mL). After 4 h, the reaction mixture was treated with water
(5 mL) followed by a 3 M aqueous sodium hydroxide (0.20 mL,
0.60 mmol). A solution of 30% aqueous hydrogen peroxide
(0.20 mL) was added, and the reaction mixture was warmed
to 50 °C using a hot water bath. After 0.5 h, the reaction
mixture was cooled to rt and saturated aqueous sodium
bicarbonate was added. The organic phase was separated, and
the aqueous phase was extracted with ether. The combined
organic solutions were washed with brine, dried (MgSO4), and
filtered. Concentration of the filtrate and flash chromatogra-
phy of the residue with 10% ether/hexane as eluent gave the
title compound (58 mg, 98%) as a clear oil: 1H NMR (500 MHz)
0.87 (s, 3H), 0.96 (s, 3H), 0.97 (s, 3H), 1.20-1.32 (m, 2H), 1.36
(t, J ) 6.5, 2H), 1.38-1.46 (m, 2H), 1.48-1.64 (m, 5H), 1.77-
1.80 (m, 2H), 1.96-2.00 (br s, 1H), 3.69-3.74 (m, 2H); 13C NMR
19.40, 21.34, 24.83, 27.78, 27.99, 30.73, 31.70, 33.49, 34.68,
39.77, 43.83, 43.95, 59.63, 125.46, 133.34; HRMS 222.1975
(calcd for C15H26O, 222.1984).
Na n a im oa l (3). DMSO (0.056 mL, 0.79 mmol) was added
dropwise to a solution of oxalyl chloride (0.035 mL, 0.40 mmol)
in CH2Cl2 (5 mL) at -70 °C over a period of 5 min. After 10
min, a solution of the alcohol prepared in the previous
experiment (53 mg, 0.24 mmol) in CH2Cl2 (3 mL) was added
dropwise followed after 15 min by triethylamine (1.0 mL, 7.17
mmol). The reaction mixture was slowly warmed to 0 °C, and
water was added. The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2. The combined
extracts were washed with brine, dried (Na2SO4), and filtered.
Concentration of the filtrate and PCTLC of the residue with
5% ether/pentane produced 3 (43 mg, 82%) as a colorless liquid.
Lew is Acid -P r om oted Rea ction s of 8a /b. (a ) P r om o-
tion w ith BCl3:B(OMe)3. A solution of 8a (100 mg, 0.45
mmol) in CH2Cl2 (5 mL) was added to a solution of trimethyl
borate (0.56 mL, 0.5 mmol) in CH2Cl2 (10 mL) at -78 °C. After
30 min, a 1.0 M solution of boron trichloride in hexane (0.5
mL, 0.5 mmol) was added dropwise. After 2 h, the reaction
mixture was warmed to -20 °C, saturated aqueous sodium
bicarbonate was added, and the reaction mixture was allowed
to warm to rt. The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2. The combined
organic solutions were washed with brine, dried (MgSO4), and
filtered, and the filtrate was concentrated under vacuum.
Flash chromatography of the residue with ether/hexanes (1:
17) as eluent gave 3 (20 mg, 20%), along with unreacted 8a
(28 mg, 28%) and isomer 8b (12 mg, 12%).
Ack n ow led gm en t. The authors gratefully acknowl-
edge support for this work from the National Science
Foundation (CHE-9116576), the University of Kansas
General Research Fund, and, in part, the National
Institutes of Health. We also thank Mr. Rajesh Iyengar
for obtaining some spectral data. The high-field NMR
and mass spectrometers and X-ray crystallographic
facilities used in this research were made available
through equipment grants from the NSF, NIH, and the
State of Kansas.
Su p p or tin g In for m a tion Ava ila ble: ORTEP drawing of
1
28; H and 13C NMR spectra for all new compounds; experi-
mental procedures for synthesis of 15a (the procedures used
were identical to those used for 14a 10), 6, 7a /b, 8a /b, and
spectral data for all intermediates; IR and mass spectral data
for 3, 11c, 12a /c, 13a /c, 22, 25-29, and 2-(2,5,5-trimethyl-
1,2,3,4,5,6,7,8-octahydronaphthalen-2-yl)ethanol (the hydrobo-
ration/oxidation product of 29 (103 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(b) P r om otion w ith TiCl4. A solution of 8a (40 mg, 0.18
mmol) in CH2Cl2 (2.5 mL) was added to a solution of TiCl4
(0.055 mL, 0.50 mmol) in a mixture of CH2Cl2 (5 mL) and
pentane (1 mL) cooled to -85 °C. After 10 min, solid sodium
bicarbonate (ca. 1 g) was added to the orange reaction mixture
J O9610568