Total synthesis of (+)-isolaurepinnacin. Use of acetal-alkene cyclizations to prepare highly functionalized seven-membered cyclic ethers

Article abstract of DOI:10.1021/ja964080b

The first synthesis of the title compound is described. The synthesis features an acetal-vinylsilane cyclization to stereoselectively form the cis-2,7-disubstituted oxepene ring and introduce Δ⁴ unsaturation. Starting with (2R,3S)-2,3-epoxypentan-1-ol (16), mixed acetal 10 is formed in five steps and 72% overall yield. Treatment of 10 with excess BC1₃ in CH₂Cl₂ at -78 → 0°C promotes cyclization to afford Δ⁴-oxepene 39 in 90% yield after deprotection of the silyl ether. Elaboration of the (E)-enyne functionality of the six-carbon side chain completes the synthesis of (±)-isolaurepinnacin.

Full text of DOI:10.1021/ja964080b

2446
J. Am. Chem. Soc. 1997, 119, 2446-2452
Total Synthesis of (+)-Isolaurepinnacin. Use of Acetal-Alkene
Cyclizations To Prepare Highly Functionalized
Seven-Membered Cyclic Ethers
Daniel Berger,1a Larry E. Overman,* and Paul A. Renhowe1b
Contribution from the Department of Chemistry, UniVersity of California,
516 Physical Sciences 1, IrVine, California 92697-2025
ReceiVed NoVember 25, 1996X
Abstract: The first synthesis of the title compound is described. The synthesis features an acetal-vinylsilane cyclization
to stereoselectively form the cis-2,7-disubstituted oxepene ring and introduce ∆4 unsaturation. Starting with (2R,3S)-
2,3-epoxypentan-1-ol (16), mixed acetal 10 is formed in five steps and 72% overall yield. Treatment of 10 with
excess BCl3 in CH2Cl2 at -78 f 0 °C promotes cyclization to afford ∆4-oxepene 39 in 90% yield after deprotection
of the silyl ether. Elaboration of the (E)-enyne functionality of the six-carbon side chain completes the synthesis of
(+)-isolaurepinnacin.
Red algae of the genus Laurencia produce a multitude of
Isolaurepinnacin (3), the second member of the oxepane class
of Laurencia acetogenins to be discovered, was isolated in 1981
by Fukuzawa and Masamune from L. pinnata Yamada.5
Through chemical correlations with degradation products of
laurencin, a metabolite whose structure had been defined
crystallographically,3 these authors established that 3 had the
6R,7R stereochemistry. That the relative configuration of 3 at
C(12) and C(13) differed from laurencin was suggested by
isolation of a small amount of a cis ∆12 alkene upon reductive
cleavage of octahydroisolaurepinnacin with zinc and acetic acid.
The large NOE observed between the H(7) and H(12) methine
hydrogens signaled a cis relationship of the two side chains and
led Fukuzawa and Masamune to propound the 6R,7R,12S,13S
configuration for 3.5 The S configuration at C(12) was
rigorously established in 1989 by Kotsuki’s synthesis of
debromodechlorooctahydroisolaurepinnacin from D-mannitol.8
unique compounds.2 While the majority of these secondary
metabolites are terpenes, a number of structurally novel noniso-
prenoid C15 acetogenins have also been isolated. The majority
of these acetogenins are cyclic ethers adorned with distinctive
enyne or allene side chains and containing at least one bromine
or chlorine substituent.2 Five- and eight-membered cyclic ethers
occur particularly widely, with laurencin (1)3 and trans-
kumausyne (2)4 being representative. Isolaurepinnacin (3)5 and
trans-isoprelaurefucin (4)6 are examples of the rarer class of
C15 Laurencia acetogenins that contain seven-membered oxa-
cyclic (oxepane) rings. Laurencia metabolites have been
popular targets for synthetic investigations and have spurred
the development of a number of new methods for constructing
cyclic ethers.7
In recent years, a number of new methods have been
developed for preparing seven-membered cyclic ethers.9 Our
own investigations in this area have focused on the direct
construction of cyclic ethers through C-C bond-forming
cyclization reactions.10 In 1989, we reported that cis-2,7-
disubstituted ∆4-oxepenes could be prepared in high yield by
Prins cyclizations of mixed acetals of 1-substituted-4-(trimeth-
ylsilyl)-4-penten-1-ol (Scheme 1).11 Three subtle effects are
responsible for the high-yielding formation of ∆4-oxepene 6
from mixed acetal precursor 5: (a) initial Prins cyclization
occurs in an endocyclic sense as a result of the greater stability
of a tertiary R-silyl cation than a primary â-silyl cation,12 (b)
cyclization of the more stable (E)-oxocarbenium ion13 occurs
preferentially in conformation 7 which minimizes destabilizing
X Abstract published in AdVance ACS Abstracts, February 15, 1997.
(1) Current addresses: (a) Wyeth-Ayerst Research, Middletown Road,
Pearl River, NY 10965. (b) Chiron Corporation, 4560 Horton Street,
Emeryville, CA 94608.
(2) (a) Moore, R. E. In Marine Natural Products; Scheuer, P. J., Ed.;
Academic: New York, 1978; Vol. 1, pp 43-121. (b) Erickson, K. L. In
Marine Natural Products; Scheuer, P. J., Ed.; Academic: New York, 1983;
Vol. 5, pp 131-257. (c) Faulkner, D. J. Nat. Prod. Rep. 1996, 13, 75, and
earlier reviews in this series.
(7) For a review of synthetic investigations in this area, see: Albizati,
K.; Martin, V. A.; Agharahimi, M. R.; Stolze, D. A. In Bioorganic Marine
Chemistry; Scheuer, P. J. , Ed.; Springer-Verlag: Berlin, 1992; Vol. 6, pp
69-84.
(8) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem. 1989,
54, 5153.
(3) (a) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193.
(b) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Monteath Robertson, J.
J. Chem. Soc., Chem. Commun. 1965, 638.
(4) Suzuki, T.; Koizumi, K.; Suzuki, M.; Kurosawa, E. Chem. Lett. 1983,
1643.
(9) (a) Elliott, M. C. Contemp. Org. Synth. 1994, 457. (b) Burns, C. J.
Contemp. Org. Synth. 1995, 2, 189. (c) Burns, C. J.; Middleton, D. S.
Contemp. Org. Synth. 1996, 3, 229.
(10) For a brief review, see: Overman, L. E. Aldrichim. Acta 1995, 28,
107.
(5) Fukuzawa, A.; Masamune, T. Tetrahedron Lett. 1981, 41, 4081.
(6) Kurosawa, A.; Irie, T. Tetrahedron Lett. 1973, 4135.
(11) (a) Castan˜eda, A.; Kucera, D. J.; Overman, L. E. J. Org. Chem.
1989, 54, 5695. (b) Berger, D.; Overman, L. E. Synlett 1992, 8117.
S0002-7863(96)04080-2 CCC: $14.00 © 1997 American Chemical Society

Total Synthesis of (+)-Isolaurepinnacin
J. Am. Chem. Soc., Vol. 119, No. 10, 1997 2447
Scheme 3. Synthesis of Vinylsilane Alcohol 14
Scheme 1
R-bromoepoxide 15.15 Key to the implementation of this
approach would be our success in fashioning a mixed acetal of
the complexity of 12 as well as our ability to selectively activate
the methoxy group of 12 to generate a single R-alkoxycarbenium
ion 11.
Scheme 2. Synthesis Plan
Preparation of Vinylsilane Alcohol 14. The synthesis of
bromoepoxide 15 began with enantioenriched epoxyalcohol 16
(Scheme 3). This intermediate was prepared as described16 with
the exception that we employed a modified workup for the
Sharpless epoxidation step.17 The enantiomeric purity of 16
was determined to be >98% ee by 1H NMR analysis of Mosher
ester derivatives.18 Conversion of 16 to the phenylsulfonate
derivative, followed by regioselective opening of the epoxide
according to the procedure of Murai,19 provided a single
bromohydrin 17 in 94% yield. Acquisition of bromoepoxide
15 in synthetically useful amounts from 17 proved difficult due
to the volatility of this epoxide. Several base-solvent pairs
were screened, and it was found that the conversion of 17 f
15 was best accomplished in Et2O by exposing 17 to an excess
of MeLi at low temperature. Careful concentration of the
reaction mixture and distillation of the residue provided 15 in
57% yield (91% based on consumed 17). No improvement in
the yield of 15 was realized by further increasing the amount
of MeLi.
The reaction of 15 with a 2-(trimethylsilyl)allyl nucleophile
should deliver 14. Realizing this objective proved difficult and
necessitated a detailed investigation of the condensation of
terminal epoxides with 2-(trialkylsilyl)allyl organometallics. This
study showed that allylstannane nucleophiles were optimal.15
In the present case, treatment of 15 with a slight excess of
allylstannane 18 in the presence of EtAlCl2 at -78 °C provided
14 in 88% yield.15
Preparation of r-Chloroacetal 27. With quantities of 14
in hand, our attention turned to the synthesis of (R)-R-
chloroacetal 27 (Scheme 4). Although many racemic R-halo-
acetals are found in the literature, we were unable to uncover
examples of the preparation of these intermediates in high
enantiomeric purity. Formation of an R-chloroacetal from an
alcohol precursor was an obvious choice, and the synthesis of
the requisite propargylic alcohol (S)-21 is summarized in
Scheme 4. Glyoxal dimethylacetal was generated in situ from
19 and quenched with an excess of lithium acetylide 20 to
provide (()-21 in 88% yield.20 Jones oxidation of this
intermediate delivered propargylic ketone 22 in high yield.21
allylic interactions, and (c) electron withdrawal by the ring
oxygen controls regioselectivity of the hydride migration (8 f
9).
To pursue the applicability of mixed acetal cyclizations for
the construction of highly functionalized seven-membered cyclic
ethers, we chose isolaurepinnacin (3) as an appropriate total
synthesis target. Herein, we describe, with full experimental
details, these investigations which culminated in an efficient
total synthesis of (+)-(3).14
Results and Discussion
Synthesis Plan. Our approach to 3 is shown antithetically
in Scheme 2. Simplification of the enyne side chain gives cis-
2,7-disubstituted ∆4-oxepene 10, which was projected to arise
from acetal-vinylsilane cyclization of 12. Mixed acetal 12
would arise from coupling of dimethyl acetal 13 and vinylsilane
alcohol 14. This latter fragment, in turn, could originate from
(15) Overman, L. E.; Renhowe, P. A. J. Org. Chem. 1994, 59, 4138.
(16) (a) Chong, J. M. Tetrahedron 1989, 45, 623. (b) Rossiter, B. E.;
Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1981, 103, 464.
(17) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem. Soc. 1988,
110, 2506.
(18) Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543.
(19) Gao, L.; Saitoh, H.; Feng, F.; Murai, A. Chem. Lett. 1991, 1787.
(20) Bernard, D.; Doutheau, A.; Gore, J. Synth. Commun. 1987, 17, 1807.
(21) Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem.
Soc. 1953, 2548.
(12) For reviews of vinylsilane-terminated cyclization reactions, see: (a)
Fleming, I.; Dunogues, I.; Smithers, R. Org. React. 1989, 37, 57. (b)
Blumenkopf, T. A.; Overman, L. E. Chem. ReV. 1986, 86, 857. (c) Overman,
L. E. Lect. Heterocycl. Chem. 1985, 8, 59.
(13) Inversion and rotation barriers of oxocarbenium ions are sufficiently
low that reaction Via only the more stable E stereoisomer is expected:
Cremer, D.; Gauss, J.; Childs, R. F.; Blackburn, C. J. Am. Chem. Soc. 1985,
107, 2435.
(14) For a preliminary report, see: Berger, D.; Overman, L. E.; Renhowe,
P. A. J. Am. Chem. Soc. 1993, 115, 9305.

2448 J. Am. Chem. Soc., Vol. 119, No. 10, 1997
Scheme 4. Synthesis of Chloroacetal 27
Berger et al.
Scheme 5. Determination of the Absolute Configuration of
26
provided (S)-21, [R]23D -3.7 (>98% ee).18 Identical formation
of the R alcohol from 25, inversion of this intermediate by
Mitsunobu reaction with benzoic acid,28 and hydrolysis of the
derived benzoate also provided (S)-21 in >98% ee. Using this
resolution sequence, enantiopure (S)-21 was available in 30%
overall yield from the racemate. Catalytic hydrogenation of
(S)-21 then provided R-hydroxy acetal 26 in essentially quan-
titative yield.
The absolute configuration of 26 was established by chemical
correlation with (2R)-1-methoxy-5-(triisopropylsiloxy)-2-pen-
tanol (Scheme 5). Benzylation of 26 provided 28 in 78% yield.
Attempted reduction of this intermediate to yield methyl ether
29 with TiCl4 and Et3SiH, unexpectedly, delivered the corre-
sponding aldehyde in high yield. Reduction of this latter
intermediate with NaBH4, followed by methylation of the
Attempted enantioselective reduction of 22 with several standard
reagents (LiAlH4-Darvon alcohol,22 Alpine-Borane,23 or ox-
azaborolidine catalyzed borane reductions)24 provided (S)-22 in
low enantiomeric purity (<50% ee). The best reagent found
was (R)-BINAL-H, which provided (S)-21 in a somewhat
disappointing 80% ee and 72% yield from 22.25 Although we
were able to prepare gram quantities of (S)-21 in this way, the
cost of (R)-1,1′-bi-2-naphthol (which is employed in excess)
and the moderate enantioselectivity of the reduction made this
sequence less than ideal.
resulting primary alcohol, yielded 29, [R]23 -6.6. Hydro-
D
genolysis of 29 provided the required sample of (2S)-1-methoxy-
5-(triisopropylsiloxy)-2-pentanol (S-30, [R]23 -0.8).
D
Preparation of an authentic sample of (R)-29 began with the
Sharpless asymmetric dihydroxylation of 1-(triisopropylsiloxy)-
4-pentene (31) with (DHQD)2-PHAL29 to give diol 32 in 70%
yield (70% ee).18 Based on ample precedent, this intermediate
is assigned the R configuration.29 Methylation of 32 then
provided a mixture of ethers from which (R)-30, [R]23 +0.6,
D
could be isolated in 36% yield. Since the rotation of this
(S)-Alcohol 21 could be obtained more conveniently in
multigram quantities and high enantiopurity from (()-21 by
chromatographic separation of diastereomeric carbamates 23
obtained from the reaction of (()-21 with (S)-(-)-R-methyl-
intermediate was low, (R)-30 was benzylated to give (R)-29,
[R]23 +5.4. Based on this correlation, the absolute configu-
D
ration of 21 obtained from (R)-BINAL-H reduction of propar-
gylic ketone 22 is S. Since reduction of ynones with (R)-
BINAL-H typically yields (R)-alcohols,25 the reversal in this
case (originally unanticipated) is abscribed to modification of
the transition state assembly by the neighboring acetal group.
27
benzyl isocyanate.26 Cleavage of diastereomer 24 with HSiCl3
(22) Cohen, N.; Lopresti, R. J.; Neukon, C.; Saucy, G. J. Org. Chem.
1980, 45, 582.
(23) Midland, M. M.; McDowell, D. C.; Hatch, R. L.; Tramontano, A.
J. Am. Chem. Soc. 1980, 102, 867.
(24) (a) Parker, K. A.; Ledeboer, M. W. J. Org. Chem. 1996, 61, 3214.
(b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109,
5551; (c) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Org. Chem. 1984,
49, 555.
Conversion of 26 (>98% ee) into the corresponding R-chlo-
roacetal 27, not unexpectedly, proved difficult (Scheme 4).
Several standard methods for introducing the chlorine func-
(25) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709.
(26) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 1839.
(27) Pirkle, W. H.; Hauske, J. R. J. Org. Chem. 1977, 42, 2781.
(28) For a review, see: Mitsunobu, O. Synthesis 1981, 1.
(29) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.; Kwong, H.; Morikawa, K.; Wang, Z.; Xu, D.; Zhang,
X. J. Org. Chem. 1992, 57, 2768.

Total Synthesis of (+)-Isolaurepinnacin
J. Am. Chem. Soc., Vol. 119, No. 10, 1997 2449
Scheme 6. Synthesis of (+)-Isolaurepinnacin (3)
tionality were initially screened and found to be unsatisfactory.30
Success was finally realized by activating 26 as the triflate
derivative, which subsequently was allowed to react with an
excess of anhydrous n-Bu4NCl in CH2Cl2 at room temperature
to yield R-chloroacetal 27 in 71% yield. We are unaware of a
precedent for neighboring group participation by a â-acetal
group in displacement reactions, and, therefore, assume that the
conversion of 26 f 27 occurred with inversion of configura-
tion.31 Since there was no simple way to confirm or refute this
conclusion, evaluation of the correctness of this assumption was
deferred until completion of the total synthesis of 3. The
enantiopurity of 27 also could not be directly assessed; however,
it was later established to be high based on the exquisite
diastereoselection observed in the pivotal cyclization step (Vide
infra).
Formation of Mixed Acetal 34 and Cyclization to Oxepene
36. The synthesis of mixed acetal 34 was readily accomplished
by treating dimethyl acetal 27 at -78 °C with 1 equiv of Me2-
BBr, followed by removal of Me2BOMe under reduced pressure,
to provide R-bromo ether 33 (Scheme 6).32 A 2.5-fold excess
of this crude intermediate was then coupled with alcohol 14 in
the presence of AgOTf and diisopropylethylamine to afford
mixed acetal 34 in quantitative crude yield and a purity of
approximately 90%.33
selectively cleaves the methoxy group of 34 to afford R,â-
dichloro ether 35, an intermediate that can be isolated if the
reaction is carefully quenched at low temperature.34 Upon
warming in the presence of BCl3, 35 is cleanly transformed to
the TIPS ether precursor of 36. Use of the robust TIPS
protecting group was also key to the success of this conversion;
tert-butyldimethylsilyl and benzoyl protecting groups in con-
geners of 34 were cleaved under these cyclization conditions.
To the limits of detection by 500 MHz 1H NMR analysis, only
a single stereoisomer is produced upon cyclization. That the
C(6) epimer of 36 would have been detected was confirmed by
cyclization of the mixed acetal formed from 14 and racemic 27
to provide ∼1:1 mixture of 36 and 6-epi-36.
Conversion of Oxepene 36 to (+)-Isolaurepinnacin. The
(E)-enyne side chain was developed by initial oxidation of 36
with Dess-Martin periodinane,35 followed by reaction of the
resulting crude aldehyde with ethynylmagnesium bromide to
yield propargyl alcohol 37. Dehydration of this intermediate
using a variety of standard conditions was efficient, but not
stereoselective, providing the corresponding (E)- and (Z)-enynes
in comparable amounts.
Based on considerable precedent that formation of the
dicobalthexacarbonyl complex of the alkyne would increase the
stereoselectivity of the dehydration by effectively bulking up
the alkyne group,36 37 was allowed to react with 1.1 equiv of
Co2(CO)8 in Et2O to afford hexacarbonyldicobalt complex 38
in 80% yield. Dehydration of this intermediate was best
accomplished by treatment with Tf2O at -78 °C in CH2Cl2.
After decomplexation of the crude enyne product with ceric
ammonium nitrate, (+)-isolaurepinnacin (3) was isolated in 65%
yield as a 24:1 mixture of E:Z stereoisomers.
Successful cyclization of 34 requires selective activation of
only the methoxy group in a substrate containing five distinct
Lewis basic functional groups. Not surprisingly, treatment of
34 with many common Lewis acids led to the formation of
complex product mixtures. Boron trichloride, however, proved
uniquely effective affording oxepene 36 in 86% yield, after
desilylation. This key conversion was most simply accom-
plished by treating 34 with 1.4 equiv of BCl3 at -78 °C and
allowing the reaction to warm slowly to 0 °C. At -78 °C, BCl3
1
Synthetic 3 displayed H and 13C NMR and IR spectra that
were indistinguishable from those of the natural isolate and
(30) (a) Lee, J. B.; Nolan, T. J. Can. J. Chem. 1966, 44, 1331. (b) Hooz,
J.; Gilani, S. S. H. Can. J. Chem. 1968, 46, 86. (c) Bose, A. K.; Lal, B.
Tetrahedron Lett. 1973, 3937. (d) Bringmann, G.; Schneider, S. Synthesis
1983, 139.
(31) Capon, B.; McManus, S. P. Neighboring Group Participation;
Plenum: New York, 1976.
(32) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49,
3912.
(33) Kronzer, F. J.; Schuerch, C. Carbohydr. Res. 1973, 27, 379.
(34) Goff, D. A.; Harris, R. N., III; Bottaro, J. C.; Bedford, C. D. J.
Org. Chem. 1986, 51, 4711.
(35) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(36) (a) Nicholas, K. M.; Pettit, R. J. Organomet. Chem. 1972, 44, C21.
(b) See also: Saksena, A. K.; Green, M. J.; Mangiaracina, P.; Wong, J. K.;
Kreutner, W.; Gulbenkian, A. R. Tetrahedron Lett. 1985, 26, 6423.
Melikyan, G. C.; Mineif, A.; Vostrowsky, O.; Bestmann, H. J. Synthesis
1991, 633.

2450 J. Am. Chem. Soc., Vol. 119, No. 10, 1997
Berger et al.
showed the following optical properties: [R]23D +0.6, [R]23
extracted twice with Et2O (20 mL), and the combined organic layers
were washed with saturated aqueous NaHCO3 (20 mL) and brine (20
mL) and dried (MgSO4). Filtration followed by concentration of the
filtrate yielded a thick yellow liquid that was placed under vacuum
(0.1 mm) to remove residual solvent. The crude sulfonate residue was
taken up in 25 mL of dry CH2Cl2 and placed under an atmosphere of
N2.
546
+1.2, and [R]23
+3.2 (c 1.4, CHCl3). A small negative
405
rotation, [R]23D -6.2 (CHCl3), was originally reported for 3 that
had been isolated from L. pinnata Yamada.5 This rotation,
however, is believed to be erroneous and derived from
contamination of the natural sample with strongly levorotatory
laurepinnacin, [R]23D -35.3 (c 1.1, CHCl3).37 Co-occurring (Z)-
Following the general procedure of Murai,19 a solution of HNEt2‚HBr
(12 g, 80 mmol) and dry CH2Cl2 (125 mL) was treated at 23 °C with
neat Et2AlCl (5.0 mL, 39 mmol). The resulting solution was maintained
at 23 °C for 15 min and then cooled to -15 °C. The crude solution of
the phenylsulfonate derivative of 16 then was added, the resulting
yellow solution was maintained at -15 °C for 4 h, and the reaction
then was slowly quenched with H2O (50 mL) at -15 °C. After
warming to 23 °C, the layers were separated, the aqueous layer was
extracted with Et2O (2 × 25 mL), and the combined organic layers
were washed with brine (20 mL), dried (Na2SO4), filtered, and
concentrated. The resulting orange oil was purified on silica gel (4:1
pentane-Et2O; 2:1 pentane-Et2O) to yield 5.98 g (94%) of 17 as a
thick orange oil: 1H NMR (500 MHz, CDCl3) δ 7.93 (br d, 2H), 7.69
(br t, 1H), 7.58 (br t, 2H), 4.15-4.11 (m, 1H), 4.08-4.05 (m, 2H),
3.83-3.81 (m, 1H), 2.16 (br d, 1H), 1.92 (app d of quint, J ) 7.3, 2.0
Hz, 2H), 1.04 (dt, J ) 7.3, 2.0 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 135.3, 134.1, 129.4, 128.0, 71.4, 70.7, 60.6, 28.7, 12.4; IR (film)
3525, 2975, 2938, 2881 cm-1; MS (CI, isobutane) m/e calcd for
isolaurepinnacin showed a rotation of [R]23 +2.0 (c 1.0,
D
CHCl3), which is more in line with the rotation we observe for
our synthetic product.37
To further confirm that the absolute configuration of our
synthetic product was the same as natural isolaurepinnacin,
synthetic 3 was reduced by sequential treatment with H2/BaSO4
and Ra-Ni to give debromodechlorooctahydroisolaurepinnacin
39.5 The rotation observed for this product, [R]23D +1.9 (c 0.43,
CHCl3), corresponded closely to the rotation reported, [R]24
D
+1.5 (c 1.0, CHCl3),8 for this well characterized degradation
product of isolaurepinnacin.
In the original report, isolaurepinnacin was claimed to exhibit
insecticidal activity.5 As a result, a sample of synthetic
isolaurepinnacin was screened by the Insect Management
Research Group of DowElanco. No insecticidal activity was
observed in these tests, a result suggesting that an impurity in
the natural isolate, perhaps laurepinnacin, is the active insec-
ticidal component.37,38
25
C11H16BrO4S: 322.9952; found 322.9925 (MH); [R]D -6.9, [R]577
-6.5, [R]546 -7.2 [R]435 -2.6, [R]405 -14.6 (c 1.3, CHCl3). Anal. Calcd
for C11H15BrO4S: C, 40.88; H, 4.68. Found: C, 40.85; H, 4.67.
Conclusion
(2S,3S)-3-Bromo-1,2-epoxypentane (15). To a solution of 17 (21.5
g, 66.4 mmol) and dry Et2O (50 mL) cooled to -78 °C was added
slowly over 25 min MeLi (2.2 M in Et2O, 30 mL, 66 mmol). A white
precipitate formed immediately, and TLC analysis (2:1 pentane-Et2O)
after 3 h showed that some starting material was still present. Over
the next 12 h, a total of 74 mL of MeLi (2.2 M in Et2O, 160 mmol)
was added in portions to the -78 °C mixture. The reaction was then
quenched with H2O (50 mL) at -78 °C and slowly allowed to warm
to 23 °C. The layers were separated, and the aqueous layer was
extracted with Et2O (3 × 25 mL). The combined organic layers were
washed with brine (2 × 20 mL), dried (Na2SO4), filtered, and
concentrated. The resulting yellow oil was purified on silica gel (9:1
pentane-Et2O; 2:1 pentane-Et2O) to give 7.91 g of recovered 17 and
a pentane-Et2O solution of 15. This solution was concentrated by
careful distillation using a 54 cm concentric tube column to yield 6.29
g of pure 15 as a light yellow liquid (57%, 91% based on consumed
17): 1H NMR (500 MHz, CDCl3) δ 3.60 (dt, J ) 8.0, 5.5 Hz, 1H),
3.21 (ddd, J ) 6.5, 3.5, 3.0 Hz, 1H), 2.97 (dd, J ) 4.5, 4.5 Hz, 1H),
2.74 (dd, J ) 5.0, 2.5 Hz, 1H), 2.02-1.97 (m, 1H), 1.95-1.86 (m,
1H), 1.08 (t, J ) 7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 57.8,
55.5, 48.9, 28.4, 12.2; IR (film) 2975, 2938, 2881 cm-1; MS (CI,
isobutane) m/e calcd for C5H10BrO: 164.9916; found 164.9931 (MH);
The first total synthesis of (+)-isolaurepinnacin was achieved
with high stereoselectivity in 12 steps and 15% overall yield
from cis-2-penten-1-ol. This synthesis rigorously establishes
the S configuration of 3 at C(13) and corrects the rotation of
natural 3 to be dextrorotatory. Of particular note is the integrity
of bromine and chlorine functionalities during the Lewis acid-
promoted mixed acetal cyclization (32 f 34), a conversion that
highlights the extraordinary selectivity that can be achieved in
acetal-alkene cyclizations. The formation of a single stereo-
isomer in this key step, moreover, demonstrates that chiral
R-chloro oxocarbenium do not epimerize during a favorable
acetal-alkene cyclization. This observation suggests that other
oxacyclic marine natural products containing common 1-ha-
loalkyl side chains can be accessed in asymmetric fashion by
Prins-type cyclizations of â-haloacetals.
Experimental Section39
(2S,3S)-3-Bromo-1,2-pentanediol, 1-Phenylsulfonate Ester (17).
To a solution of 16 (2.01 g, 19.7 mmol, 98% ee)16a and dry CH2Cl2
(25 mL) cooled to 0 °C were added successively Et3N (3.6 mL, 26
mmol), phenylsulfonyl chloride (3.0 mL, 24 mmol), and DMAP (120
mg, 0.99 mmol). The resulting yellow solution was allowed to warm
to 23 °C over 2.5 h, during which time a colorless precipitate of Et3N‚
HCl formed. The mixture was quenched with aqueous 10% citric acid
(20 mL), and the layers were separated. The aqueous layer was
25
[R]D +24.1, [R]577 +26.5, [R]546 +30.1, [R]435 +52.1, [R]405 +63.2
(c 1.1, CHCl3).
(5S,6S)-6-Bromo-5-hydroxy-2-trimethylsilyl-1-octene (14). To a
solution of 15 (310 mg, 1.9 mmol), 18 (1.13 g, 2.80 mmol),15 and dry
CH2Cl2 (5 mL) cooled to -78 °C was added neat EtAlCl2 (0.22 mL,
2.1 mmol). The resulting solution was maintained at -78 °C for 19
h. The reaction then was quenched at -78 °C with saturated aqueous
NH4Cl (5.0 mL) and allowed to warm to 23 °C over 1 h. The layers
were separated, the aqueous layer was extracted with Et2O (2 × 10
mL), and the combined organic layers were washed with brine (10 mL),
dried (MgSO4), and concentrated. Purification of the residue on silica
gel (9:1 pentane-Et2O) provided 460 mg (88%) of 14: 1H NMR (500
MHz, CDCl3) δ 5.58 (s, 1H), 5.35 (s, 1H), 4.03-3.99 (m, 1H), 3.54-
3.48 (m, 1H), 2.34-2.27 (m, 1H), 2.23-2.17 (m, 1H), 1.95 (app quint,
J ) 7.0 Hz, 2H), 1.86 (d, J ) 8.5 Hz, 1H), 1.75-1.62 (m, 2H), 1.05
(t, J ) 7.0 Hz, 3H), 0.09 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 151.5,
124.4, 73.2, 67.2, 35.0, 31.8, 29.1, 12.6, -1.44; IR (film) 3413 (br),
2956, 2879 cm-1; MS (EI) m/e calcd for C11H24BrOSi: 278.0701; found
278.0696 (M); [R]D25 -12.4, [R]577 -11.3, [R]546 -12.3, [R]435 -21.5,
[R]405 -5.2 (c 1.1, CHCl3). Anal. Calcd for C11H23BrOSi: C, 47.31;
H, 8.30. Found: C, 47.36; H, 8.31.
(37) Fukuzawa, A., personal communication to L.E.O. on June 10, 1993.
(38) Gipson, R. W.; Pechacek, J. T. DowElanco Insect Management
Research Group, personal communication to L.E.O., January 25, 1994.
(39) Unless noted otherwise, new compounds were nearly colorless oils.
Temperatures refer to external bath temperatures unless noted otherwise.
General experimental details have been described: Deng, W.; Overman,
L. E. J. Am. Chem. Soc. 1994, 116, 11241.
(40) The C(6) epimer of 3, which is available by the sequence outlined
in Scheme 6 starting with rac-27, shows the following diagnostic signals
for C(6) and C(13) in the 13C NMR spectrum: δ 63.3 (natural), 63.1 (epi),
61.7 (epi), 61.4 (natural).

Total Synthesis of (+)-Isolaurepinnacin
J. Am. Chem. Soc., Vol. 119, No. 10, 1997 2451
(()-1,1-Dimethoxy-5-(triisopropylsiloxy)pent-3-yn-2-ol (21). Gly-
oxal dimethylacetal was first generated in situ as described.20 To a
solution of oxalyl chloride (2.5 mL, 29 mmol) and dry THF (100 mL)
at -60 °C was added a solution of DMSO (2.3 mL, 32 mmol) and dry
THF (16 mL) over a period of 5 min. The resulting mixture was
warmed to -30 °C for 3 min and then cooled to -60 °C, at which
time a solution of 2,2-dimethoxyethanol (19, 2.75 g, 25.9 mmol) and
dry THF (24 mL) was added dropwise over 5 min. The resulting
mixture was stirred for 1 h at -60 °C and then was treated with Et3N
(18.0 mL, 129 mmol). After warming to 23 °C, the mixture was stirred
for 1 h and then recooled to -78 °C.
3-(Triisopropylsiloxy)propynyllithium (20), prepared by dropwise
addition of n-BuLi (2.3 M in hexane, 56.3 mL, 130 mmol) to a solution
of the corresponding alkyne (27.5 g, 129 mmol) and dry THF (100
mL) at -78 °C to 23 °C, was added Via cannula to the solution of the
crude aldehyde at -78 °C. The resulting mixture was allowed to warm
to 23 °C with stirring for over 3 h. After quenching with H2O (100
mL), the layers were separated, the aqueous layer was extracted with
Et2O (3 × 50 mL), and the combined organic layers were washed with
brine (75 mL), dried (Na2SO4), and concentrated. Purification of the
residue on silica gel (19:1 pentane-Et2O; 2:1 pentane-Et2O) provided
7.19 g (88%) of (()-21: 1H NMR (500 MHz, CDCl3) δ 4.43 (d, J )
1.5 Hz, 2H), 4.40-4.39 (m, 1H), 4.33 (d, J ) 5.4 Hz, 1H), 3.50 (s,
3H), 3.49 (s, 3H), 1.08 (s, 21H); 13C NMR (125 MHz, CDCl3) δ 105.4,
84.7, 81.5, 63.5, 56.0, 55.6, 52.0, 17.9, 11.9; IR (film) 3431 (br), 2950,
2869, 1463, 1369, 1263, 1194, 1125, 1088 cm-1; MS (CI, isobutane)
m/e calcd for C16H33O4Si: 317.2148; found 317.2223 (MH).
3H), 1.49 (d, 3H, J ) 6.8 Hz), 1.06 (br s, 21H); 13C NMR (125 MHz,
CDCl3) δ 154.0, 143.0, 128.6, 127.4, 125.9, 103.4, 85.2, 79.0, 64.0,
55.5, 54.6, 52.0, 50.9, 22.4, 17.9, 11.9; IR (film) 3331, 2944, 2869,
1719, 1506, 1456, 1375, 1244, 1150, 1088 cm-1; MS (CI, isobutane)
m/e calcd for C25H42NO5Si: 464.2832; found 464.2840 (MH); [R]23
D
-14.0, [R]405 -46.7, [R]435 -35.6, [R]546 -20.7, [R]577 -17.9 (c 0.64,
CHCl3).
Following the general procedure of Pirkle,27 a solution of carbamate
24 (1.21 g, 2.62 mmol), Cl3SiH (0.30 mL, 2.88 mmol), Et3N (0.40
mL, 2.88 mmol), and dry toluene (7 mL) was stirred at 23 °C for 12
h. The resulting mixture was quenched with saturated aqueous NH4-
Cl (20 mL), the layers were separated, and the aqueous layer was
extracted with Et2O (3 × 20 mL). The combined organic layers were
washed with brine (2 × 10 mL), dried (Na2SO4), and concentrated.
Purification of the residue on silica gel (2:1 pentane-Et2O) yielded
0.73 g (88%) of (S)-21 as a light yellow oil (>98% ee by Mosher
ester analysis):18 [R]23 -3.7.
D
Carbamate diastereoisomer 25 (4.34 g, 9.38 mmol) was cleaved with
Cl3SiH and Et3N, exactly as described for epimer 24, to give the
corresponding (R)-alcohol (2.62 g, 8.28 mmol, >98% ee).18 A solution
of this sample, Ph3P (3.46 g, 13.2 mmol) and dry THF (100 mL) was
treated dropwise with a solution of DEAD (2.1 mL, 13.2 mmol) and
dry THF (10 mL) over 10 min at -20 °C. After 1 h, a solution of
benzoic acid (0.96 g, 7.9 mmol) and dry THF (10 mL) was added
dropwise over 5 min, and the resulting solution was allowed to warm
to 23 °C. After 3 h, the reaction was concentrated, and the resulting
residue was purified on silica gel to provide 3.3 g of the (2S)-benzoate.
To a solution of this sample of the (2S)-benzoate and dry MeOH
(160 mL) at 23 °C was added K2CO3 (5.43 g, 39.3 mmol) in portions
over 5 min. After 4 h, the reaction was concentrated, and the resulting
residue was dissolved in Et2O (50 mL). The organic layer was washed
with H2O (2 × 10 mL) and brine (2 × 10 mL), dried (MgSO4), filtered,
and concentrated. Purification of the residue on silica gel yielded 1.67
g (64%) of (S)-21 (>98% ee by Mosher ester analysis)18 as a light
yellow oil.
1,1-Dimethoxy-5-(triisopropylsiloxy)pent-3-yn-2-one (22). A so-
lution of (()-21 (1.82 g, 5.75 mmol) and acetone (35 mL) was treated
dropwise at 0 °C with Jones reagent.21 After the disappearance of (()-
21 had been confirmed by TLC analysis (2:1 pentane-Et2O), the
reaction was quenched with i-PrOH (5 mL) and solid NaHCO3 (100
mg). The resulting mixture was filtered through silica gel to remove
chromium salts, and the plug was washed with ∼250 mL of Et2O. The
resulting solution was concentrated, and the oily residue was purified
on silica gel (2:1 pentane-Et2O) to yield 1.58 g (88%) of 22 as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 4.65 (s, 1H), 4.58 (s, 2H),
3.44 (s, 6H), 1.09 (s, 21H); 13C NMR (125 MHz, CDCl3) δ 181.9,
102.8, 94.8, 82.0, 54.3, 52.0, 17.8, 11.9; IR (film) 2944, 2869, 2213,
1694, 1463, 1369, 1250, 1194, 1175, 1119, 1075, 994 cm-1; MS (CI,
isobutane) m/e calcd for C16H31O4Si: 315.1991; found 315.2007 (MH).
(2S)-1,1-Dimethoxy-5-(triisopropylsiloxy)pent-3-yn-2-ol (S-21) from
Reduction of 22 with (R)-BINAL-H. Following the general procedure
of Noyori,25 (R)-(-)-BINAL-H was prepared in dry THF (51 mL) from
(R)-(-)-1,1′-bi-2-naphthol (3.00 g, 10.5 mmol), LiAlH4 (1 M in THF,
10.4 mL, 10.4 mmol), and EtOH (0.61 mL, 11 mmol). This reagent
was cooled to -100 °C in a liquid nitrogen-isooctane bath and a
solution of 22 (1.36 g, 4.33 mmol), and dry THF (7 mL) was added
dropwise (down the side of the cooled flask) over 2 h using a syringe
pump. The resulting mixture was stirred at -100 °C for an additional
3 h and then at -85 °C for 12 h. The reaction was then quenched
with MeOH (4 mL) and poured into a 1 M solution of NaOH (4 mL).
The layers were separated, and the organic layer was washed with 1
M NaOH until TLC analysis of the organic layer indicated that all of
the binaphthol had been removed. The aqueous layer was extracted
with Et2O (2 × 50 mL), and the combined organic layers were washed
with brine (75 mL), dried (Na2SO4) and concentrated. Purification of
the residue on silica gel (2:1 pentane-Et2O) provided 0.96 g (70%) of
(2S)-1,1-Dimethoxy-5-(triisopropylsiloxy)pentan-2-ol (26). A mix-
ture of (S)-21 (2.99 g, 9.46 mmol, >98% ee), 5% Pd/BaSO4 (200 mg)
and dry MeOH (32 mL) was stirred under 1 atm of H2 for 3 h. The
reaction was then filtered through a plug of silica gel, and the plug
was washed with ∼500 mL of Et2O. Concentration, followed by
purification of the residue on silica gel (2:1 pentane-Et2O) provided
2.93 g (97%) of 26 as a clear oil (>98% ee by Mosher ester analysis):
18
1H NMR (500 MHz, CDCl3) δ 4.14 (d, J ) 5.9 Hz, 1H), 3.72 (t, J
) 6.0 Hz, 2H), 3.62 (ddd, J ) 9.1, 6.0, 2.6 Hz, 1H), 3.44 (s, 3H), 3.41
(s, 3H), 1.77-1.64 (m, 3H), 1.50-1.42 (m, 1H), 1.05 (s, 21H); 13C
NMR (125 MHz, CDCl3) δ 107.0, 71.2, 63.5, 55.0, 54.8, 29.0, 28.6,
18.0, 12.0; IR (film) 3463 (br), 2944, 2869, 1463, 1381, 1244, 1194,
1100, 981, 881 cm-1; MS (CI, isobutane) m/e calcd for C16H37O4Si:
321.2461; found 321.2436 (MH); [R]23 -11.7, [R]405 -26.4, [R]435
D
-22.8, [R]546 -13.2, [R]577 -10.5 (c 1.2, CHCl3).
(2R)-2-Chloro-1,1-dimethoxy-5-(triisopropylsiloxy)pentane (27).
A solution of 26 (593 mg, 1.85 mmol) and dry CH2Cl2 (12 mL) was
cooled to 0 °C, and dry pyridine (0.25 mL, 3.2 mmol) and Tf2O (0.47
mL, 2.8 mmol) were sequentially added dropwise. This mixture was
stirred for 1 h at 0 °C, (n-Bu)4NCl (1 M in CH2Cl2, 18.5 mL, 18.5
mmol) was added, and the reaction was stirred at 23 °C for 12 h and
then concentrated. The residue was purified on silica gel (19:1
pentane-Et2O) to afford 445 mg (71%) of 27 as a colorless oil: 1H
NMR (500 MHz, CDCl3) δ 4.33 (d, J ) 6.0 Hz), 3.94 (ddd, J ) 9.3,
6.3, 3.2 Hz, 1H), 3.73-3.70 (m, 2H), 3.44 (s, 3H), 3.43 (s, 3H), 2.07-
2.02 (m, 1H), 1.85-1.73 (m, 1H), 1.73-1.62 (m, 2H), 1.05 (s, 21H);
13C NMR (125 MHz, CDCl3) δ 106.2, 62.7, 61.6, 55.3, 54.7, 29.4,
29.2, 18.0, 11.9; IR (film) 2944, 2869, 1463 cm-1; MS (CI, isobutane)
(S)-21 (80% ee by Mosher ester analysis):18 [R]23 -3.7, [R]405 -7.7,
D
[R]435 -7.4, [R]546 -5.5, [R]577 -5.2 (c 1.1, CHCl3).
Preparation of (2S)-1,1-Dimethoxy-5-(triisopropylsiloxy)pent-3-
yn-2-ol (S-21) by Chromatographic Resolution of (()-21. Following
the general procedure of Pirkle,26 a solution of alcohol (()-21 (16.8 g,
53.0 mmol), N,N-dimethylethanolamine (200 mg, 2.2 mmol), and dry
toluene (11 mL) was treated dropwise with (S)-(-)-R-methylbenzyl
isocyanate (11.4 mL, 79.5 mmol), and the resulting solution was heated
at 110 °C for 6 h. The crude product was concentrated, and the residue
was purified on silica gel (1 kg; 2:1 pentane-Et2O) to afford 4.15 g of
24, 5.45 g of 25, and 11.5 g of mixed fractions (combined yield of
86%). 24: 1H NMR (500 MHz, CDCl3) δ 7.35-7.29 (m, 5H), 5.48
(br d, J ) 4.7 Hz, 1H), 5.09 (br d, J ) 7.0 Hz, 1H), 4.85-4.83 (m,
1H), 4.43 (br d, J ) 4.9 Hz, 1H), 4.40 (s, 2H), 3.47 (s, 3H), 3.43 (s,
25
m/e calcd for C16H36ClO3Si: 339.2122; found 339.2089 (MH); [R]D
+13.4, [R]577 +10.6, [R]546 +11.9, [R]435 +17.6, [R]405 +19.4 (c 1.07,
CHCl3). Anal. Calcd for C16H36ClO3Si: C, 56.69; H, 10.41. Found:
C, 56.76; H, 10.41.
(3S,4S)-3-Bromo-4-[(2R)-2-chloro-1-methoxy-5-(triisopropylsiloxy)-
pentoxy]-7-(trimethylsilyl)-7-octene (34). To a solution of 27 (286
mg, 0.844 mmol) and dry CH2Cl2 (4.5 mL) at -78 °C was added Me2-
BBr (1.02 M in CH2Cl2, 0.83 mL, 0.84 mmol) over a period of 5 min.
The reaction was maintained at -78 °C for 1 h, at 23 °C for an

2452 J. Am. Chem. Soc., Vol. 119, No. 10, 1997
Berger et al.
additional h, and the solvent and Me2BOMe were then removed under
saturated aqueous NH4Cl (1 mL), the layers were separated, and the
aqueous layer was extracted with Et2O (2 × 5 mL). The combined
organic layers were washed with brine (10 mL), dried (Na2SO4), and
concentrated. Purification of the residue on silica gel (2:1 pentane-
Et2O) afforded 31 mg (74%) of the propargylic alcohol 37 as a yellow
oil: 1H NMR (500 MHz, CDCl3) δ 5.80-5.78 (m, 2H), 4.43-4.40
(m, 1H), 3.95-3.89 (m, 2H), 3.60-3.49 (m, 2H), 2.54-2.48 (m, 3H),
2.32-2.29 (m, 2H), 2.11-2.05 (m, 1H), 2.02-1.80 (m, 6H), 1.03 (t,
J ) 7.2 Hz, 3H); IR (film) 3381 (br), 3300, 3019, 2969, 2938, 2900,
2119, 1656, 1456, 1431, 1381, 1325, 1306, 1219, 1113, 1069, 1031
cm-1; MS (CI, NH3) m/e calcd for C15H2679BrClNO2: 366.0835; found
366.0835 (M + NH4).
(+)-Isolaurepinnacin (3). Following the general procedure of
Nicholas and Pettit,36a a solution of Co2(CO)8 (47 mg, 0.14 mmol) and
dry Et2O (1 mL) was added dropwise to a solution of 37 (48 mg, 0.14
mmol) and dry Et2O (1 mL) at -23 °C. The resulting orange-red
solution was warmed to 0 °C and after 2 h was concentrated. This
residue was dissolved in dry CH2Cl2 (2 mL) and cooled to -78 °C,
and freshly distilled Tf2O (69 µL, 0.41 mmol) was added dropwise.
The resulting solution was then allowed to warm to -5 °C, and after
2 h, the reaction was quenched with saturated aqueous NaHCO3 (2
mL), and the layers were separated. The H2O layer was extracted with
Et2O (3 × 5 mL), and the combined organic layers were dried (MgSO4)
and concentrated. The resulting residue was dissolved in acetone (2
mL) and (NH4)2Ce(NO3)6 (0.75 g, 1.4 mmol) was added. After gas
evolution had ceased, the solution was concentrated, and the residue
was purified on silica gel (19:1 pentane-Et2O) to provide 29 mg (65%)
of 3 as a colorless oil, whose NMR data matched those of the natural
isolate: [R]23D +0.6, [R]405 +3.2, [R]435 +2.0, [R]546 +1.2, [R]577 +0.7
(c 1.4, CHCl3).40
Preparation of (2S,7R)-2-Hexyl-7-propyl-2,3,4,5,6,7-hexahydro-
oxepin (39) from Synthetic Isolaurepinnacin. The procedure em-
ployed in the original degradation of natural isolaurepinnacin was
employed.5 A mixture of synthetic (+)-3 (15 mg, 0.05 mmol), Pd/
BaSO4 (10 mg), and dry MeOH (1 mL) was stirred under 1 atm of H2
at 23 °C. After 1.5 h, the reaction was filtered through Florisil, the
plug was washed with ∼20 mL of Et2O, and the eluent was concentrated
to yield octahydroisolaurepinnacin, which was used without further
purification.
A mixture of this sample, Raney Ni (200 mg), and dry EtOH (2
mL) was heated at 150 °C for 24 h in a sealed tube. The reaction was
then cooled to 23 °C, filtered, and concentrated. The resulting residue
was purified on silica gel (9:1 pentane-Et2O) to yield 8 mg (77%) of
37 as a colorless oil. The 1H NMR and 13C NMR spectra of this sample
were identical to that reported for this compound.5,8 The optical rotation
of 37 was [R]23D +1.9 (c 0.43, CHCl3); lit.8 [R]24D +1.6 (c 1.2, CHCl3).
reduced pressure to yield crude R-bromoether 31: diagnostic doublet
1
in the H NMR at δ 4.25 (J ) 5.8 Hz, 1H, OCHBr).
A solution of this sample, dry CH2Cl2 (2.3 mL) and i-Pr2NEt (0.96
mL, 5.5 mmol) was cooled to 0 °C. A solution of 14 (94 mg, 0.34
mmol) and dry CH2Cl2 (1 mL) was then added, followed by AgOTf
(220 mg, 0.84 mmol). The resulting brown mixture was stirred for 3
h and then allowed to warm to 23 °C. The crude reaction was flushed
through a plug of silica gel to remove the silver salts, and the plug
was washed with ∼150 mL of Et2O. Concentration of the eluent,
followed by purification of the residue on silica gel (50:1 pentane-
Et2O, 25:1 pentane-Et2O) provided 203 mg (103%) of mixed acetal
34, which was contaminated with ∼10% of an inseparable impurity
(1H NMR analysis): 1H NMR (500 MHz, CDCl3) δ 5.61-5.60 (m,
1H), 5.36-5.34 (m, 1H), 4.55-4.53 (m, 1H), 4.16-4.01 (m, 1H), 3.97-
3.92 (m, 1H), 3.85-3.77 (m, 1H), 3.76-3.67 (m, 2H), 3.46 and 3.44
(s, 3H), 2.47-2.40 (m, 1H), 2.39-2.26 (m, 1H), 2.24-1.93 (m, 4H),
1.91-1.77 (m, 1H), 1.76-1.58 (m, 3H), 1.10-1.02 (s, 24H), 0.10 (s,
9H); IR (film) 2956, 2869, 1463, 1381, 1250, 1200, 1106, 1069, 925
cm-1; MS (CI, isobutane) m/e calcd for C25H5179BrClO2Si2: 553.2299;
found 553.2311 (MH-MeOH).
(2S,7R)-2-[(1S)-1-Bromopropyl]-7-[(1R)-chloro-4-hydroxybutyl]-
2,3,6,7-tetrahydrooxepin (36). To a solution of mixed acetal 34 (64
mg) and dry CH2Cl2 (2.5 mL) at -78 °C was added BCl3 (1 M in
CH2Cl2, 40 µL, 0.04 mmol) over a period of 10 min. The resulting
solution was allowed to warm to 23 °C over 20 min and then was
concentrated. This residue was dissolved in dry CH2Cl2 (2.5 mL) and
cooled to 0 °C, and BCl3 (1 M in CH2Cl2, 0.11 mL, 0.11 mmol) was
then added dropwise. The resulting solution was maintained at 0 °C
for 15 min, and the reaction was then quenched with 1 M NaOH (2.2
mL). The layers were separated, the aqueous layer was extracted with
Et2O (2 × 10 mL), and the combined organic layers were washed with
brine (20 mL), dried (Na2SO4), and concentrated.
The resulting residue was dissolved in dry THF (1 mL), and TBAF
(1 M in THF, 260 µL, 0.26 mmol) was added at 0 °C. The reaction
was then allowed to warm to 23 °C over 4 h. Concentration, followed
by purification of the residue on silica gel (1:1 pentane-Et2O) provided
30 mg (86% from 14) of 36 as a light yellow oil: 1H NMR (500 MHz,
CDCl3) δ 5.80-5.77 (m, 2H), 3.93-3.87 (m, 2H), 3.67 (t, J ) 6.1 Hz,
2H), 3.57-3.50 (m, 2H), 2.53-2.47 (m, 2H), 2.33-2.29 (m, 2H), 2.01-
1.95 (m, 2H), 1.86-1.74 (m, 3H), 1.67-1.63 (m, 1H), 1.03 (t, J ) 7.2
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 129.0, 128.9, 82.0, 81.8, 64.9,
62.1, 61.6, 33.9, 32.4, 30.2, 29.8, 28.0, 12.6; IR (film) 3363 (br), 3025,
2938, 2875, 1700, 1656, 1456, 1381, 1325, 1219, 1113, 1063 cm-1
;
MS (CI, isobutane) m/e calcd for C13H2379BrClO2: 325.0570; found
325.0558 (MH); [R]23D +10.2, [R]405 +25.8, [R]435 +21.4, [R]546 +12.0,
[R]577 +10.1 (c 1.0, CHCl3).
Acknowledgment. This paper is dedicated to Professor
Dieter Seebach on the occasion of his 60th birthday. Financial
support for this investigation was provided by NSF (CHE-90-
03812 and CHE-9412266), while NMR and mass spectra were
determined at UCI with spectrometers purchased with the
assistance of NSF and NIH Shared Instrumentation Grants. We
particularly thank Professor Akio Fukuzawa (Department of
Engineering, Hokkaido Tokai University) for copies of spectra
for natural isolaurepinnacin and for providing us with, and
allowing us to report, unpublished information on the rotation
of isolaurepinnacin and (3Z)-isolaurepinnacin isolated from
Laurencia pinnata Yamada.
At shorter reaction times, the intermediate R-chloroether 35 could
1
be observed by H NMR analysis: diagnostic doublet at δ 4.45 (J )
5.9 Hz, 1H, OCHCl).
The cyclization of 34 prepared from 14 and (()-27 provided 36
and a diastereomer in a 1:1 ratio (GLC analysis): 13C NMR (125 MHz,
CDCl3) diagnostic signals at δ 82.7 (epi), 82.0, 81.8, 81.2 (epi), 65.0
(epi), 64.9, 62.2 (epi), 62.1, 61.6, 61.4 (epi).
(2S,7R)-2-[(1S)-1-Bromopropyl]-7-[(1R)-chloro-(4RS)-hydroxy-
5-hexynyl]-2,3,6,7-tetrahydrooxepin (37). Dess-Martin periodinane35
(101 mg, 0.12 mmol) was added to a solution of alcohol 36 (39 mg,
0.12 mmol) and dry CH2Cl2 (1 mL), and the resulting mixture was
stirred at 23 °C for 25 min. The reaction was then quenched with 1 M
NaOH (1 mL), and the resulting mixture was stirred until the aqueous
layer was homogeneous. The layers were separated, the aqueous layer
was extracted with Et2O (2 × 5 mL), and the combined organic layers
were washed with brine (5 mL), dried (Na2SO4), and concentrated to
give the corresponding aldehyde: 1H NMR (300 MHz, CDCl3)
diagnostic singlet at δ 9.82 (1H).
Supporting Information Available: Experimental proce-
dures and characterization data for the preparation of 16,
1-(triisopropyl)-2-propyne, and compounds reported in Scheme
5 and copies of 1H NMR (500 MHz) and 13C NMR (125 MHz)
spectra of synthetic (+)-3 (7 pages). See any current masthead
page for ordering and Internet access instructions.
A solution of this crude aldehyde and dry THF (1 mL) at -78 °C
was immediately treated dropwise with ethynylmagnesium bromide (0.5
M in THF, 1.1 mL, 0.5 mmol), and the resulting solution was allowed
to warm to 23 °C over 1 h. The reaction was then quenched with
JA964080B