Total synthesis of the Kopsia lapidilecta alkaloid (±)-lapidilectine B

Article abstract of DOI:10.1021/jo048917u

The total synthesis of Kopsia lapidilecta alkaloid (±)-lapidilectine B is described. Notable elements of this synthesis include the first natural products application of the Smalley azido-enolate cyclization to form the 1,2-dihydro-3H-indol-3-one (indoxyl

Full text of DOI:10.1021/jo048917u

Total Synthesis of the Kopsia lapidilecta Alkaloid
(()-Lapidilectine B
William H. Pearson,*,† Ill Young Lee,‡ Yuan Mi,§ and Patrick Stoy
Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055
wpearson@berryassoc.com
Received June 27, 2004
The total synthesis of Kopsia lapidilecta alkaloid (()-lapidilectine B is described. Notable elements
of this synthesis include the first natural products application of the Smalley azido-enolate
cyclization to form the 1,2-dihydro-3H-indol-3-one (indoxyl) core and installation of the pyrrolidine
ring by a 2-azaallyllithium [3+2] cycloaddition with the acetylene equivalent phenyl vinyl sulfide.
Closure of the eight-membered perhydroazocine ring is accomplished via the intramolecular SN2
substitution of a mesylate. This constitutes the first synthesis of a member of the 5,6,12,13-
tetrahydro-11a,13a-ethano-3H-pyrrolo[1′,2′:1,8]azocino[5,4-b]indole class of alkaloids.
Introduction
The Kopsia (Apocynaceae, subfamily Plumerioideae)
genus1 of flowering plants grows in South and Southeast
Asia and has been a rich source of alkaloidal natural
products.2-4 Kopsia lapidilecta is one of about 30 species
in this genus and is distinguished by a number of
structurally interesting alkaloids bearing the novel 5,6,-
12,13-tetrahydro-11a,13a-ethano-3H-pyrrolo[1′,2′:1,8]azo-
cino[5,4-b]indole ring system (Figure 1).2-4 Among these
is (+)-lapidilectine B (1), which was isolated by Awang
and co-workers in 1992 from the leaves of Kopsia lapi-
dilecta (Figure 1).3 The structure of (+)-lapidilectine B
was elucidated by two-dimensional NMR experiments
and its absolute configuration was tentatively assigned
as drawn in Figure 1 based on biogenesis and a positive
Cotton effect.2,3 Although no pharmacological effects have
been reported for Kopsia lapidilecta alkaloids, extracts
from other Kopsia species have been used medicinally
for the treatment of rheumatoid arthritis, dropsy (edema),
tonsillitis, and hypertension.1b,4,5 A number of Kopsia
alkaloids have attracted the attention of synthetic chem-
† Current address: Berry & Associates, Inc., 2434 Bishop Circle
East, Dexter, MI 48130.
‡ Current address: Bio-Organic Division, Korea Research Institute
of Chemical Technology, P.O. Box 107, Taejon, Republic of Korea 305-
606.
§ Current address: Genomics Institute of Novartis Research Foun-
dation, 10675 John J. Hopkins Dr., San Diego, CA 92121.
(1) (a) Margraf, F. Blumea 1972, 20, 416-425. (b) Se´venet, T.;
Allorge, L.; David, B.; Awang, K.; Hadi, A.; Hamid, A.; Kan-Fan, C.;
Quirion, J.-C.; Remy, F.; Schaller, H.; Teo, L. E. J. Ethnopharmacol.
1994, 41, 147-183.
FIGURE 1. (+)-Lapidilectine B and related Kopsia alkaloids.
ists,6 but only one synthetic study on Kopsia lapidilecta
alkaloids has recently been reported.7
We have long been interested in the generation and
(2) Awang, K.; Se´venet, T.; Pa¨is, M.; Hadi, A. H. A. J. Nat. Prod.
1993, 56, 1134-1139.
(3) Awang, K.; Se´venet, T.; Hadi, A. H. A.; David, B.; Pa¨is, M.
Tetrahedron Lett. 1992, 33, 2493-2496.
cycloaddition of nonstabilized 2-azaallyllithiums (i.e.,
(4) (a) Kam, T.-S.; Yoganathan, K.; Chuah, C.-H. Tetrahedron Lett.
1995, 36, 759-762. (b) Kam, T.-S.; Yoganathan, K.; Koyano, T.;
Komiyama, K. Tetrahedron Lett. 1996, 37, 5765-5768. (c) Kam, T.-S.;
Yoganathan, K.; Li, H.-Y.; Harada, N. Tetrahedron 1997, 53, 12661-
12670. (d) Rho, M.-C.; Toyoshima, M.; Hayashi. M.; Koyano, T.;
Subramanian, G.; Kam, T.-S.; Komiyama, K. Planta Med. 1999, 307-
310. (e) Kam, T.-S.; Yoganathan, K.; Wei, C. J. Nat. Prod. 1996, 59,
1109-1112.
(5) (a) Burkhill, I. H. A Dictionary of the Economic Products of the
Malay Penisula; Ministry of Agriculture and Cooperatives: Kuala
Lumpur, Malaysia, 1966. (b) Xiao, Z. F.; Kan, C.; Potier, P.; Kan, S.
K.; Lounasmaa, M. Planta Med. 1983, 48, 280-282. (c) Feng, X. Z.;
Kan, C.; Husson, H.-P.; Potier, P.; Kan, S. K.; Lounasmaa, M. J. Nat.
Prod. 1984, 47, 117-122. (d) Mok, S.-L.; Yoganathan, K.; Lim, T.-M.;
Kam, T.-S. J. Nat. Prod. 1998, 61, 328-332.
10.1021/jo048917u CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/13/2004
J. Org. Chem. 2004, 69, 9109-9122
9109

Pearson et al.
SCHEME 1. Initial Retrosynthesis
azaallyl anions) derived from (2-azaallyl)stannanes as a
synthetic method for the formation of pyrrolidine rings.8
The synthetic utility of both inter- and intramolecular
cycloadditions of nonstabilized 2-azaallyllithiums has
been highlighted with the synthesis of several pyrroli-
dine-containing alkaloids of moderate complexity.9 We
embarked on the total synthesis of (()-lapidilectine B to
broaden the use of intermolecular cycloadditions of
nonstabilized 2-azaallyllithiums to a more complex natu-
ral product setting. Specifically, it provided an op-
portunity to employ the anionophile phenyl vinyl sulfide
as an acetylene synthetic equivalent to form the 2,5-
dihydropyrrole ring in the alkaloid.
dihydropyrrole ring with use of a 2-azaallyllithium [3+2]
cycloaddition, the synthesis demonstrates the first ap-
plication of the Smalley azido-enolate cyclization11 to
form the indoxyl core of the alkaloid. The eight-membered
perhydroazocine ring is formed by the intramolecular SN2
displacement of a mesylate by a 2,5-dihydropyrrole.
These synthetic studies also serve to confirm the struc-
ture and relative configuration of lapidilectine B.
Initial Retrosynthetic Plan
In our original retrosynthetic analysis for lapidilectine
B (1) (Scheme 1), we envisioned disconnection of the
eight-membered perhydroazocine ring via an intramo-
lecular substitution of a leaving group by a 2,5-dihydro-
pyrrole. The 2,5-dihydropyrrole in 2 would be installed
by the [3+2] cycloaddition of 2-azaallyllithium 3 with the
acetylene equivalent phenyl vinyl sulfide. The (2-azaal-
lyl)stannane 4, necessary for generating 2-azaallyllithium
3 by tin-lithium exchange, would be formed from a
suitably protected cyclohexanone 5. To efficiently form
the fused 2,3-dihydroindole ring system in 5, we initially
opted for a palladium-catalyzed aminocarbonylation strat-
egy12 starting with aniline 6. Aniline 6 would be elabo-
rated from enone 7, which was formed by a carbonylative
Stille coupling from protected 2-iodoaniline 8 and alkenyl
stannane 9.
We describe herein our synthetic studies which cul-
minated in the total synthesis of (()-lapidilectine B (1).10
In addition to the successful installation of the 2,5-
(6) For recent synthetic work on other Kopsia alkaloids, see: (a)
Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.; Rainey, T. J.;
Westlund, N.; Lynch, V. Tetrahedron 2002, 58, 3423-3443. (b) Magnus,
P.; Hobson, L. A.; Westlund, N. Tetrahedron Lett. 2001, 42, 993-997.
(c) Magnus, P.; Westlund, N. Tetrahedon Lett. 2000, 41, 9369-9372.
(d) Kuehne, M. E.; Li, Y.-L.; Wei, C.-Q. J. Org. Chem. 2000, 65, 6434-
6440. (e) Magnus, P.; Payne, A. H.; Hobson, L. Tetrahedron Lett. 2000,
41, 2077-2081. (f) Magnus, P.; Gazzard, L.; Hobson, L.; Payne, A. H.;
Lynch, V. Tetrahedron Lett. 1999, 40, 5135-5138. (g) Kuehne, M. E.;
Li, Y.-L. Org. Lett. 1999, 1, 1749-1750.
(7) Watanabe, T.; Arai, S.; Nishida, A. Synlett 2004, 907-909.
(8) (a) Pearson, W. H.; Szura, D. P.; Harter, W. G. Tetrahedron Lett.
1988, 29, 761-764. (b) Pearson, W. H.; Szura, D. P.; Postich, M. J. J.
Am. Chem. Soc. 1992, 114, 1329-1345. For a review, see: (c) Pearson,
W. H.; Stoy, P. Synlett 2003, 903-921. For recent work, see: Pearson,
W. H.; Mans, D. M.; Kampf, J. W. J. Org. Chem. 2004, 69, 1235-1247.
(9) For reviews of alkaloid synthesis with 2-azaallyllithiums see ref
8c and: Pearson, W. H. Pure Appl. Chem. 2002, 74, 1339-1347.
(10) For an initial communication of this work, see: Pearson, W.
H.; Mi, Y.; Lee, I.-Y.; Stoy, P. J. Am. Chem. Soc. 2001, 123, 6724-
6725.
(11) (a) Ardakani, M. A.; Smalley, R. K. Tetrahedron Lett. 1979, 20,
4769-4772. (b) Azadi-Ardakani, M.; Alkhader, M. A.; Lippiatt, J. H.;
Patel, D. I.; Smalley, R. K.; Higson, S. J. Chem. Soc., Perkin Trans. 1
1986, 1107-1111.
(12) For the most relevant example of such an aminocarbonylation
strategy, see: (a) Tamaru, Y.; Hojo, M.; Yoshida, Z. J. Org. Chem. 1988,
53, 5731-5741. (b) Tamaru, Y.; Hojo, M.; Higashimura, H.; Yoshida,
Z. J. Am. Chem. Soc. 1988, 110, 3994-4002.
9110 J. Org. Chem., Vol. 69, No. 26, 2004

Total Synthesis of (()-Lapidilectine B
palladium-catalyzed stannylation protocol.17 Carbonyla-
tive Stille coupling18,19 of 19 with known triazinone-
protected iodoaniline 2219 provided enone 2310 in excel-
lent yield. Conjugate addition of vinylmagnesium bromide
to 23 in the presence of lithium 2-thienyl cyanocuprate
under the conditions of Lipshutz20 furnished ketone 24
as an inseparable 4.7:1 mixture of diastereomers. The
relative configuration of the vinyl group and benzyloxy
group in 24 could only be determined after the Smalley
cyclization (vide infra). The yield of this reaction was
found to vary depending on the batch used of com-
mercially available vinylmagnesium bromide and lithium
2-thienylcyanocuprate. The triazinone protecting group
in 24 was removed with hydrochloric acid in aqueous
methanol to give aniline 25 in good yield. It was neces-
sary to closely monitor the progress of this reaction since
prolonged reaction times led to erratic isolated yields,
apparently through decomposition of the desired product.
Finally, diazotization of aniline 25 with sodium nitrite
and hydrochloric acid furnished an aryl diazonium salt
(not shown),10 which was converted to the Smalley
cyclization precursor 1610 by treatment with sodium
azide.21
SCHEME 2. Aminocarbonylation Model Studies
Beginning with model compounds 1013 and 11,13 we
attempted aminocarbonylative cyclization of these sub-
strates using the procedure of Tamaru,12 as well as a
number of alternative conditions from the literature
(Scheme 2).19 The desired cyclization products 12 and 13
were not isolated in any of these experiments. Replace-
ment of the methyl carbamate protecting group in 10 and
11 with a p-toluenesulfonamide moiety12 gave similar
results. Since these model studies failed to yield any
aminocarbonylative cyclization products, we abandoned
this approach and reconsidered our retrosynthesis.
Initial cyclization experiments with 16, using Smalley’s
optimized potassium hydroxide-ethanol conditions,11b
gave a 1.9:1 ratio of desired indoxyl 1510 to undesired
diastereomer 2610 in 60% combined yield. After some
experimentation it was found that potassium hydroxide
in 2-propanol constituted the best Smalley cyclization
conditions for our system, giving a 2.2:1 ratio of 15 to 26
in 68% combined yield (Scheme 6).
Revised Retrosynthetic Plan
Structure Elucidation of Intermediates
We decided to make the same retrosynthetic discon-
nections as before, but this time using an umpolung
approach in the construction of the 1,2-dihydro-3H-indol-
3-one (“indoxyl”) substructure by employing the aniline
nitrogen in 17 as an electrophile instead of a nucleophile
(Scheme 3). Such a process for indoxyl synthesis has been
elegantly demonstrated by Smalley11 featuring the in-
tramolecular attack of an enolate on an aryl azide
(Scheme 4). However, the Smalley cyclization has never
before been applied in a natural products setting.
Formation of the Smalley cyclization precursor 16
began with known 4-benzyloxycyclohexanone 20,15 which
was converted to alkenyl triflate 21 through O-sulfony-
lation of the corresponding enolate with N-phenyltrifla-
mide16 in 72% yield (Scheme 5). Alkenyl triflate 21 was
transformed into alkenyl stannane 19 with use of Wulff’s
1
Analysis of H NMR coupling constants in diastereo-
mers 15 and 26 suggested that in both compounds the
vinyl and benzyloxy groups had a trans relationship.
However, we were not able to distinguish which diaste-
reomer corresponded with the desired structure 15.
Therefore, we undertook a series of chemical transforma-
tions which would leave no doubt as to the identity of
the diastereomers 15 and 26.
Initially, we converted the minor Smalley cyclization
product 26 into 33 by the transformations shown in
Scheme 7. This sequence began with the installation of
a methyl carbamate group onto the indoxyl nitrogen
using tert-butyllithium and methyl chloroformate to give
27 in 37% yield. Dihydroxylation of the vinyl group in
27 with OsO4-NMO to give 28 was accompanied by
spontaneous cyclization to 29 when reaction times where
prolonged or upon treatment with base or silica gel. The
formation of 29 is strong evidence that the vinyl group
and indoxyl nitrogen are cis in the cyclohexane ring of
26. Attempts to add allylmagnesium bromide to the
indoxyl carbonyl of 28 led only to cyclic carbamate 30 in
moderate yield. This cyclization pathway could be cir-
cumvented by protection of the 1,2-diol in 28 as trimeth-
ylsilyl (TMS) ethers to form 31, followed by allylmagne-
(13) See the Supporting Information.
(14) (a) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson,
K. P. J. Org. Chem. 1996, 61, 3584-3585. (b) Hegedus, L. S.; Allen,
G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100,
5800-5807. (c) Kageyama, M.; Tamura, T.; Nantz, M. H.; Roberts, J.
C.; Somfai, P.; Whritenour, D. C.; Masamune, S. J. Am. Chem. Soc.
1990, 112, 7407-7408.
(15) Bloss, A. S.; Brook, P. R.; Ellam, R. M. J. Chem. Soc., Perkin
Trans. 2 1973, 2165-2173.
(16) Carren˜o, M. C.; Garc´ıa-Cerrada, S.; Urbano, A. Chem. Eur. J.
2003, 9, 4118-4131.
(17) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron,
K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J.
Org. Chem. 1986, 51, 277-279.
(20) (a) Lipshutz, B. H.; Koerner, M.; Parker, D. A. Tetrahedron Lett.
1987, 28, 945-948. (b) Lipshutz, B. H.; Parker, D. A.; Kozlowski, J.
A.; Nguyen, S. L. Tetrahedron Lett. 1984, 25, 5959-5962.
(21) (a) Fukuyama, T.; Xu, L.; Goto, S. J. Am. Chem. Soc. 1992, 114,
383-385. (b) Duclos, R. I., Jr.; Tung, J. S.; Rapoport, H. J. Org. Chem.
1984, 49, 5243-5246.
(18) Knight, S. D.; Overman, L. E.; Pairaudeau, G. J. Am. Chem.
Soc. 1995, 117, 5776-5788.
(19) Farina, V.; Baker, S. R.; Benigni, D. A.; Hauck, S. I.; Sapino,
C. J. Org. Chem. 1990, 55, 5833-5847.
J. Org. Chem, Vol. 69, No. 26, 2004 9111

Pearson et al.
SCHEME 3. Revised Retrosynthesis
SCHEME 4. The Smalley Indoxyl Synthesis
SCHEME 5. Synthesis of the Smalley Precursorsa
sium bromide addition, which gave 32 in good yield after
in situ TMS deprotection with HF‚pyridine. Oxidative
cleavage of the 1,2-diol in 32 with sodium periodate
formed a hemiacetal, which was immediately treated
with camphorsulfonic acid in methanol to furnish methyl
acetal 33 in 45% yield. Apparently an epimerization of
the aldehyde initially formed from 32 occurs under the
oxidation conditions.
The major Smalley cyclization diastereomer 15 was
converted to 14 via a similar sequence (Scheme 8).
Incorporation of the methyl carbamate with use of tert-
butyllithium and methyl chloroformate gave 34 in 89%
yield. Dihydroxylation of 34 with OsO4-NMO formed 35
in 82% yield as an inseparable 6:1 ratio of diastereomers,
but was never accompanied by any cyclized carbamate
products such as 29. Addition of allylmagnesium bromide
to indoxyl 35 proceeded in an excellent 90% yield to give
36, although the diastereoselectivity of this addition could
not immedately be determined. Oxidative cleavage of the
1,2-diol 36 with sodium periodate followed by treatment
with methanolic camphorsulfonic acid led to the desired
methyl acetal 14 in 59% yield. As in 33, formation of the
cyclic acetal confirmed the facial selectivity of the allyl
Grignard addition, which presumably results from steric
shielding of one face of the carbonyl group by the diol
moiety. All doubts about the stereostructure of 14 and
33 were dispelled by an X-ray crystallographic structure
determination of 14.10
a Reagents and conditions: (a) (1) LDA, -78 °C, (2) PhNTf2
(72%); (b) Me3SnSnMe3, Pd(PPh3)4, LiCl, THF (91%); (c) 22,
Pd2dba3‚CHCl3, Ph3As, LiCl, NMP, CO (70 psi), 75 °C (98%); (d)
CH2dCHMgBr, Li-2-thienylcyanocuprate, BF3‚Et2O, THF, -78 °C
(82%); (e) HCl (conc), MeOH, rt (83%); (f) (1) HCl (conc), NaNO2,
H2O, 0 °C, (2) NaN3 (aq), 0 °C (not isolated).
SCHEME 6. Smalley Cyclization
Although the structure of 14 was now confirmed, and
33 was thought to be a diastereomer of 14, it was not
entirely clear what were the relative configurations of
the acetal and benzyloxy carbons in 33. From the 1H
NMR spectra, it appeared that 14 and 33 had the same
relative configuration at the acetal carbon, but were
epimeric at the benzyloxy carbon. To confirm this hy-
pothesis, both 14 and 33 were converted to the γ-lactones
9112 J. Org. Chem., Vol. 69, No. 26, 2004

Total Synthesis of (()-Lapidilectine B
SCHEME 7. Elaboration of Indoxyl 26 to 33a
SCHEME 9. Elucidating the Stereostructure of 14
and 33a
a Reagents and conditions: (a) Me2BBr, CH2Cl2; (b) Ag2CO3-
Celite, C6H6, 80 °C; (c) PCC, silica gel, CH2Cl2; (d) Pd(OH)2-C,
H2, EtOH-THF; (e) PCC, silica gel, CH2Cl2.
SCHEME 10. Preparation of the [3+2]
Cycloaddition Precursora
a Reagents and conditions: (a) (1) t-BuLi, THF, -20 °C, (2)
ClCO2Me (37%); (b) OsO4, NMO, acetone (72%); (c) allylMgBr,
THF, -40 °C (57%); (d) TMS-imidazole, 100 °C (81%); (e) (1)
allylMgBr (3 equiv), THF, -50 °C, (2) HF‚pyr, THF (75%); (f) (1)
NaIO4, 4:1 THF/H2O, (2) CSA, MeOH, rt (45%).
SCHEME 8. Elaboration of Indoxyl 15 to 14a
a Reagents and conditions: (a) (1) O3, Sudan III, CH2Cl2-
MeOH, -78 °C, (2) NaBH4, MeOH (87%); (b) TBDPSCI, DIEA,
CH2Cl2 (91%); (c) Pd(OH)2-C, H2 (1 atm), AcOH (cat.), EtOH-
THF (92%); (d) TPAP, NMO, 4 Å molecular sieves, CH2Cl2 (95%).
carbon. This supposition was confirmed by conversion of
37 and 38 to a common ketone 39 by debenzylation with
Pearlman’s catalyst25 and oxidation with PCC. The
possibility that 14 and 33 were also epimeric at the acetal
carbon was discounted due to a severe steric interaction
between the acetal methoxy group and axial benzyloxy
group in such a hypothetical compound.
Methyl acetal 14 was further converted into the
2-azaallyllithium cycloaddition precursor 43 through the
transformations in Scheme 10. Careful ozonolysis of 14
a Reagents and conditions: (a) t-BuLi, ClCO2Me, -10 °C (89%);
(b) OsO4 (cat.), NMO, acetone, rt (82%); (c) allylMgBr, THF, -40
°C (90%); (d) (1) NaIO4, THF, rt, (2) CSA, MeOH, rt (59%).
37 and 38 through dimethylboron bromide demethyla-
tion22 followed by oxidation with Fe´tizon’s reagent23 or
PCC24 (Scheme 9). Since lactones 37 and 38 were not
equivalent, they must be epimeric at the benzyloxy
(22) Guindon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984,
49, 3912-3920.
(23) McKillop, A.; Young, D. W. Synthesis 1979, 401-422. For recent
examples of oxidation of cyclic hemiacetals to γ-lactones with Fe´tizon’s
reagent, see: (a) Tatsuta, K.; Takahashi, M.; Tanaka, N.; Chikauchi,
K. J. Antibiot. 2000, 53, 1231-1234. (b) Enders, D.; Kroll, M.; Raabe,
G.; Runsink, J. Angew. Chem., Int. Ed. 1998, 37, 1673-1675.
(24) For recent examples of oxidation of cyclic hemiacetals to
γ-lactones with PCC, see: (a) Clayden, J.; Kenworthy, M. N.; Helliwell,
M. Org. Lett. 2003, 5, 831-834. (b) Ho¨lemann, A.; Reissig, H.-U. Org.
Lett. 2003, 5, 1463-1466. (c) Breit, B.; Heckmann, G.; Zahn, S. K.
Chem. Eur. J. 2003, 2, 425-434.
(25) Pearlman, W. M. Tetrahedron Lett. 1967, 8, 1663-1664.
J. Org. Chem, Vol. 69, No. 26, 2004 9113

Pearson et al.
SCHEME 11. 2-Azaallyllithium [3+2]
treated with phenyl vinyl sulfide, THF, and 1 equiv of
n-butyllithium at -78 °C to effect formation of transient
nonstabilized 2-azaallyllithium 45 via tin-lithium ex-
change. 2-Azaallyllithium 45 was trapped in situ with
phenyl vinyl sulfide to initially give N-lithiopyrrolidine
46 and pyrrolidine 4710 after aqueous workup. After
column chromatography an inseparable complex mixture
of three major and at least six minor diastereomers or
rotamers was obtained in 75% yield, and the stereose-
lectivity of the cycloaddition could not be immediately
discerned. It was found that n-butyllithium could be used
in excess (2.5 equiv) with no loss in yield, which facili-
tated conducting the cycloaddition reactions on small
scale. Attempts at conducting the cycloaddition sequence
in the presence of an unprotected lactone moiety instead
of a methyl acetal were met only with decomposition.
Similarly, attempts at installing a phenyl sulfoxide (vide
infra) moiety directly by using phenyl vinyl sulfoxide as
an anionophile also failed.
Cycloadditiona
Since the newly formed quaternary carbon at C-13a
(according to the IUPAC numbering of 1; see ref 10)
needed a specific relative configuration to allow closure
of the eight-membered ring later in the synthesis, the
facial selectivity of the cycloaddition was of particular
interest to us. We felt that the methyl acetal and bulky
TBDPS ether would sterically shield the “upper” face of
the 2-azaallyllithium and prevent formation of the un-
desired pyrrolidine 51 (eq 1). To clarify this issue,
a Reagents and conditions: (a) Teoc-Cl, DIEA, CH2Cl2 (91%);
(b) m-CPBA (1 equiv), NaHCO3, CH2Cl2, -30 °C to rt (88%); (c)
Cl2CdCCl2, pyr, 125 °C (85%).
with Sudan III as an indicator26 of complete reaction
produced primary alcohol 40 in 87% yield after reductive
workup with sodium borohydride. Protection of 40 as the
tert-butyldiphenylsilyl (TBDPS) ether gave 41 in 91%
yield, which was debenzylated with Pearlman’s catalyst25
under hydrogen to give secondary alcohol 42 in 92% yield.
Finally, 42 was oxidized to ketone 43 by tetra-n-propyl-
ammoniumperruthenate/N-morpholine oxide (TPAP-
NMO)27 in 95% yield, setting the stage for the subsequent
[3+2] cycloaddition.
pyrrolidine 47 was transformed to the N-Teoc31 derivative
48 with 2-(trimethylsilyl)ethylchloroformate31 in 91%
yield, also isolated as a complex mixture of diastereomers
(Scheme 11). Direct quenching of the N-lithiopyrrolidine
46 with chloroformates gave inferior yields of the N-
protected pyrrolidines, a phenomenon we have previously
observed.8b Judicious oxidation of phenyl sulfide 48
furnished the sulfoxide 49 (not shown), which underwent
thermal elimination away from the nitrogen32 to give the
2,5-dihydropyrrole 50 in good yield. Although the 1H
NMR spectra of 50 was complicated by two sets of
rotamer resonances with differing coalescence points,
variable-temperature 1H NMR established the presence
of a single diastereomer.33 The all-important relative
configuration of 50 at C-13a could not immediately be
confirmed by NOE experiments and would only be borne
out by completion of the synthesis of lapidilectine B.
2-Azaallyllithium Cycloaddition
The generation and [3+2] cycloaddition of nonstabi-
lized 2-azaallyllithiums has previously been reported by
our group in both the inter- and intramolecular mode of
cycloaddition.8,9,28-30 In the intermolecular mode, we
found that phenyl vinyl sulfide is a very useful aniono-
phile since it can serve as either an ethylene8b,28,29 or
acetylene8b,29 synthetic equivalent. In the present case,
we required it to serve as an acetylene equivalent.
The necessary (2-azaallyl)stannane precursor 44 was
prepared in situ from ketone 43, using (tri-n-butyl)-
stannylmethylamine30 and trimethylaluminum28,29 in
toluene (Scheme 11). Stannane 44 was then sequentially
(26) Veysoglu, T.; Mitscher, L. A.; Swayze, J. K. Synthesis 1980,
807-810.
(31) Shute, R. E.; Rich, D. H. Synthesis 1987, 346-349.
(32) Sulfoxides and selenoxides are known to prefer thermal elimi-
nation away from heteroatoms, see ref 8b and: (a) Sharpless, K. B.;
Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697. (b) Haraguchi, K.;
Tanaka, H.; Maeda, H.; Itoh, Y.; Saito, S.; Miyasaka, T. J. Org. Chem.
1991, 56, 5401-5408.
(27) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666.
(28) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett.
1997, 38, 3369-3372.
(29) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688-689.
(30) (a) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1992, 57, 6354-
6357. (b) Pearson, W. H.; Stoy, P.; Mi, Y. J. Org. Chem. 2004, 69, 1919-
1939.
(33) In our initial communication (ref 10), we reported in error that
50 was isolated as an inseparable mixture of two diastereomers, which
we have presently shown to be carbamate rotamers. See the Supporting
Information.
9114 J. Org. Chem., Vol. 69, No. 26, 2004

Total Synthesis of (()-Lapidilectine B
SCHEME 12. The Initial Unsuccessful Endgame
Strategy
SCHEME 13. Completion of the Synthesisa
Completion of the Synthesis
a Reagents and conditions: (a) BCl3, CH2Cl2, 0 °C (67%); (b)
PCC, Celite, CH2Cl2 (91%); (c) HF‚pyr, THF (88%); (d) MsCl,
CH2Cl2, -10 °C to rt (92%); (e) TFA-CH2Cl2 (1:2), rt, 30 min
(quant).
Our initial strategy for completing the synthesis of 1
from 47 involved closing the eight-membered ring first,
followed by installation of the lactone and alkene moieties
(Scheme 12). Although we achieved some initial success
closing the eight-membered ring via a triphenylphos-
phine/carbon tetrachloride-promoted dehydrative cycliza-
tion, we were unable to hydrolyze the methyl acetal to a
lactol or oxidize the sulfide to a sulfoxide due to the
presence of the basic tertiary nitrogen. We decided to
circumvent this problem by proceeding from compound
50 in which the nitrogen is protected as an N-Teoc
carbamate and the alkene is already installed.
With 2,5-dihydropyrrole 50 in hand, completion of the
synthesis required only the transformation of a methyl
acetal into a γ-lactone followed by closure of the eight-
membered perhydroazocine ring. We accessed lactone 53
through a sequence of demethylation to form the hemi-
acetal 52, followed by oxidation (Scheme 13). Conversion
of methyl acetal 50 to the hemiacetal 52 with use of
aqueous Brønsted acids failed, but after some experi-
mentation, boron trichloride34 emerged as the most
reliable reagent for this transformation, giving 52 in 67%
yield. Although a variety of oxidative conditions were
examined including Swern, Dess-Martin, TPAP-NMO,27
and PDC, only PCC24 reliably provided lactone 53 in 91%
yield.
reactive fluoride reagents such as TBAF, TASF,35 or CsF
proved to be sluggish or accompanied by partial elimina-
tion of the mesylate leaving group. However, brief treat-
ment of 55 with trifluoroacetic acid (TFA) in dichlo-
romethane followed by evaporation of solvent cleanly
gave the 2,5-dihydropyrrole‚TFA salt 56, setting the
stage for the intramolecular SN2 displacement of the
mesylate.36 The penultimate compound 56 was not
isolated, but treated with diisopropylethylamine (DIEA)
for 2 h at room temperature, then heated to 60 °C in
acetonitrile for 10 h to give (()-lapidilectine B (1) in
excellent yield (76%). Although no natural (+)-lapidilec-
tine B remains from the original isolation work for direct
comparison, the NMR, IR, UV, and mass spectra of
synthetic (()-1 match those reported for natural (+)-1.37
Conclusion
We have completed the total synthesis of (()-lapidi-
lectine 1 in 23 linear steps and 0.10% overall yield from
4-benzyloxycyclohexanone. This represents the first syn-
thesis of a 5,6,12,13-tetrahydro-11a,13a-ethano-3H-pyr-
rolo[1′,2′:1,8]azocino[5,4-b]indole alkaloid from Kopsia
lapidilecta, and demonstrates the utility of a nonstabi-
lized 2-azaallyllithium [3+2] cycloaddition in a complex
We found that once the lactone moiety was present,
the dehydrative cyclization shown in Scheme 12 no longer
worked well. Instead, we resorted to the displacement of
a mesylate leaving group to close the eight-membered
ring. Transformation of the TBDPS silyl ether to a
mesylate was uneventfully accomplished by treatment
of 53 with HF‚pyridine to give alcohol 54, followed by
O-sulfonylation with methanesulfonyl chloride to furnish
55. Deprotection of the N-Teoc protecting group with
(35) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-6437.
(36) For recent examples of formation of perhydroazocine rings by
intramolecular SN2 reactions, see: (a) Pauly, R.; Sasaki, N. A.; Potier,
P. Tetrahedron Lett. 1994, 35, 237-240. (b) Monterde, M. I.; Nazaba-
dioko, S.; Rebolledo, F.; Brieva, R.; Gotor, V. Tetrahedron: Asymmetry
1999, 10, 3449-3455. (c) Winkler, J. D.; Stelmach, J. E.; Axten, J.
Tetrahedron Lett. 1996, 37, 4317-4318.
(34) For a related process involving demethylation of a methyl
tetrahydrofuryl ether with BBr3, see: Crimmins, M. T.; Pace, J. M.;
Nantermet, P. G.; Kim-Meade, A. S.; Thomas, J. B.; Watterson, S. H.;
Wagman, A. S. J. Am. Chem. Soc. 2000, 122, 8453-8463.
(37) In the original isolation work, several impurities in the 1H NMR
spectrum were observed. We also noted these peaks but were able to
show they were due to carbamate rotamers by variable-temperature
1H NMR spectroscopy, see ref 10.
J. Org. Chem, Vol. 69, No. 26, 2004 9115

Pearson et al.
Rf 0.20 (60:30:10 hexanes/ethyl acetate/MeOH); IR (CHCl3)
setting. Other notable features include the first applica-
tion of the Smalley azido-enolate cyclization in total
synthesis as well as an intramolecular SN2 displacement
to close the eight-membered perhydroazocine ring.
1
1685 (s), 1636 (s), 1596 (w), 1520 (s), 1305 (s) cm-1; H NMR
(360 MHz, CDCl3) δ 7.80-7.10 (m, 9 H), 5.94-5.80 (m, 1 H ×
0.17), 5.72-5.56 (m, 1 H × 0.83), 5.20-4.80 (m, 2 H), 4.62-
4.38 (m, 6 H), 3.80-3.35 (m, 2 H), 3.10-2.65 (m, 7 H), 2.25-
1.10 (m, 6 H); 13C NMR (90 MHz, CDCl3) δ 208.5, 208.2, 156.1,
146.7, 146.5, 141.4, 138.9, 138.8, 138.1, 137.2, 136.5, 131.5,
131.2, 128.6, 128.2, 127.5, 127.4, 127.3, 125.1, 125.0, 123.0,
122.9, 122.6, 115.8, 114.8, 114.6, 72.8, 71.8, 70.0, 69.7, 69.0,
68.8, 54.8, 51.2, 42.3, 39.7, 37.5, 36.3, 34.9, 32.0, 31.7, 29.8,
29.1, 28.4, 24.1, 27.8; MS (EI, 70 eV) m/z (rel intensity) 447
(M+, 54), 356 (7), 302 (22), 272 (16), 259 (22), 231 (17), 146
(23), 132 (87), 113 (52), 91 (100); HRMS (EI, 70 eV) calcd for
C27H33N3O3 (M+) 447.2522, found 447.2515. The trans rela-
tionship between the vinyl and the benzyloxy group was
determined based on the stereochemistry of the subsequent
compounds, 15 and 26. However, the relative configuration of
the major diastereomer with respect to the third chiral center
could not be determined.
(1R*,2R*,4R*)- and (1S*,2R*,4R*)-1-[2-(Amino)benzoyl]-
4-benzyloxy-2-vinylcyclohexanes (25). Concentrated HCl
(37%, 1.06 g, 10.8 mmol) was added to a solution of 24 (121
mg, 0.270 mmol) in MeOH (4 mL) at room temperature. The
reaction was closely monitored by TLC and after 50 min the
reaction was basified with 20% aqueous NaOH at 0 °C (pH
>10). The mixture was extracted with ether (3×) and the
etheral solution was washed with brine (1×), dried (MgSO4),
and concentrated. Chromatography (15% ethyl acetate/hex-
anes, 2 drops of concentrated NH4OH per 100 mL of eluting
solvent) provided 75 mg (83%) of 25 as a green-yellow oil that
contained two inseparable diastereomers (1:5.4 by 1H NMR
integration). The relative configuration of the major diastereo-
mer could not be determined. Rf 0.37 (20% ethyl acetate/
hexanes); IR (CHCl3) 3499 (m), 3352 (m), 1641 (s), 1613 (s),
1579 (s), 1548 (s), 1450 (s), 1161 (s) cm-1; 1H NMR (360 MHz,
CDCl3) δ 7.75 (app d, J ) 8.0 Hz, 1 H × 0.84), 7.70 (app d, J
) 8.0 Hz, 1 H × 0.16), 7.50-7.10 (m, 6 H), 6.70-6.55 (m, 2
H), 6.40-6.10 (m, 2 H), 5.83 (ddd, J ) 17.9, 10.4, 8.0 Hz, 1 H
× 0.16), 5.68 (ddd, J ) 17.5, 10.4, 7.1 Hz, 1 H × 0.84), 5.05-
4.70 (m, 2 H), 4.60-4.50 (m, 2 H), 3.85-3.50 (m, 1 H), 3.26
(td, J ) 11.1, 3.6 Hz, 1 H), 3.10-2.94 (m, 1 H), 2.30-2.00 (m,
2 H), 2.00-1.60 (m, 2 H), 1.58-1.35 (m, 2 H); 13C NMR (90
MHz, CDCl3) δ 205.8, 205.2, 150.8, 150.0, 141.5, 141.3, 139.1,
139.0, 134.7, 134.0, 133.9, 131.3, 130.7, 130.6, 128.32, 128.27,
128.26, 127.5, 127.4, 127.3, 127.2, 117.9, 117.4, 115.5, 114.0,
73.0, 72.0, 70.0, 69.7, 49.5, 37.1, 35.0, 31.5, 29.2, 25.0, 22.6,
22.2, 14.1, 14.0; MS (CI, NH3) m/z (rel intensity) 336 ([M +
H]+, 100), 320 (4), 308 (1), 244 (39), 228 (25), 151 (12), 135
(12), 120 (94), 91 (49); HRMS (CI, NH3) calcd for C22H26NO2
([M + H]+) 336.1963, found 336.1961.
(1′R*,3′R*,4′R*)-1-Methoxycarbonyl-1,2-dihydroindol-
3-one-2-spiro-4′-(1′-benzyloxy-3′-vinylcyclohexane) (27).
tert-Butyllithium (0.15 mL of a 1.7 M solution in pentane, 0.26
mmol) was added in a dropwise fashion to a solution of the
indoxyl 26 (42 mg, 0.13 mmol) in THF (3.5 mL) at -20 °C.
After 15 min, a solution of methyl chloroformate (54 mg, 0.58
mmol) in THF (0.5 mL) was added at -20 °C dropwise and
the reaction was allowed to warm to room temperature. After
30 min, the reaction was quenched with aqueous saturated
NH4Cl. The aqueous layer was extracted with ether (3×) and
the combined organic solution was dried (MgSO4) and concen-
trated. Chromatography (15% to 20% ethyl acetate/hexanes
gradient) gave 18 mg (37%; 70% based on the recovered
starting material) of 27 as a yellow oil, along with 20 mg of
recovered starting material. Rf 0.43 (30% ethyl acetate/
hexanes); IR (CHCl3) 1713 (s), 1609 (s), 1469 (s) cm-1; 1H NMR
(400 MHz, CDCl3) δ 8.05 (d, J ) 8.1 Hz, 1 H), 7.78-7.72 (m,
1 H), 7.65-7.58 (m, 1 H), 7.48-7.24 (m, 5 H), 7.14 (t, J ) 7.3
Hz, 1 H), 5.43 (ddd, J ) 17.3, 10.3, 7.7 Hz, 1 H), 4.90 (app d,
J ) 17.3 Hz, 1 H), 4.80 (app d, J ) 10.3 Hz, 1 H), 4.60 (s, 2 H),
3.98-3.92 (m, 1 H), 3.90 (s, 3 H), 3.36-3.25 (m, 1 H), 2.44-
2.34 (m, 1 H), 2.30-2.14 (m, 2 H), 2.06-1.92 (m, 2 H), 1.86-
1.78 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 201.7, 153.4, 152.4,
Experimental Section
For general experimental procedures, see the Supporting
Information.
4-Benzyloxy-1-[(trifluoromethanesulfonyl)oxy]cy-
clohexene (21). A solution of LDA was made from diisopro-
pylamine (2.08 mg, 20.6 mmol) and n-butyllithium (7.63 mL
of a 2.7 M solution in hexanes, 20.6 mmol) in THF (69 mL) at
-10 °C and then cooled to -78 °C. A solution of the ketone 20
(3.83 g, 18.7 mmol) in THF (3 mL) was then slowly added.
After 2 h at -78 °C, solid N-phenyltrifluoromethanesulfo-
nimide16 (6.68 g, 18.7 mmol) was added in one portion. The
mixture was allowed to warm to 0 °C gradually, and stirred
at 0 °C for an additional 1 h. The reaction was taken up in
20% ethyl acetate/hexanes, washed with water (2×) and brine
(1×), dried (MgSO4), and concentrated. Chromatography (5%
to 7% ethyl acetate/hexanes gradient) afforded 4.55 g (72%)
of 21 as a yellow oil. Rf 0.23 (7% ethyl acetate/hexanes); IR
1
(neat) 1693 (s) cm-1; H NMR (300 MHz, CDCl3) δ 7.40-7.26
(m, 5 H), 5.70-5.60 (m, 1 H), 4.56 (ABq, ∆υ ) 6.4 Hz, JAB
)
11.9 Hz, 2 H), 3.78-3.66 (m, 1 H), 2.60-2.20 (m, 4 H), 2.24-
1.88 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 128.4, 127.6, 127.4,
115.4, 71.1, 70.4, 29.8, 27.4, 25.2; MS (CI, NH3) m/z (rel
intensity) 354 ([M + NH4]+, 100), 299 (15), 281 (8), 203 (4),
148 (5), 108 (18), 91 (18); HRMS (CI, NH3) calcd for C14H19-
NO4F3S ([M + NH4]+) 354.0987, found 354.0991.
4-Benzyloxy-1-trimethylstannylcyclohexene (19). Tet-
rakis(triphenylphosphine)palladium(0) (0.78 g, 0.68 mmol) was
added to a solution of alkenyl triflate 21 (2.27 g, 0.68 mmol)
and hexamethylditin (2.33 g, 7.10 mmol) in THF (14 mL),
followed by addition of anhydrous lithium chloride (1.72 g, 40.6
mmol, flame-dried in air, cooled in vacuo). The mixture was
heated at reflux for 4 h, then cooled to room temperature, and
most of the solvent was removed in vacuo. The resulting
residue was diluted with hexanes and washed with water (3×)
and brine (1×). The combined aqueous phases were extracted
with hexanes (1×) and the combined organic phases were dried
(MgSO4) and concentrated. Chromatography (3% to 7% ethyl
acetate/hexanes gradient) provided 2.16 g (91%) of 19 as a
colorless oil. Rf 0.19 (5% ethyl acetate/hexanes); IR (neat) 1623
(m), 1396 (s), 1188 (s), 1096 (s) cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.40-7.18 (m, 5 H), 5.72-5.66 (m, 1 H), 4.55 (ABq,
∆υ ) 11.7 Hz, JAB ) 12.1 Hz, 2 H), 3.64-3.54 (m, 1 H), 2.50-
2.24 (m, 2 H), 2.24-2.04 (m, 2 H), 2.02-1.92 (m, 1 H), 1.66-
1.54 (m, 1 H), 0.05 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 140.6,
139.1, 135.6, 128.3, 127.5, 127.3, 73.8, 69.7, 34.1, 30.0, 28.8,
-10.4. Anal. Calcd for C16H24OSn: C, 54.74; H, 6.89. Found:
C, 55.06; H, 6.78.
(1R*,2R*,4R*)- and (1S*,2R*,4R*)-4-Benzyloxy-1-[2-(1,3-
dimethylhexahydro-2-oxo-1,3,5-triazin-5-yl)benzoyl]-2-
vinylcyclohexanes (24). At -78 °C, vinylmagnesium bro-
mide (6.80 mL of a 1.0 M solution in THF, 6.80 mmol) was
added to a solution of lithium 2-thienylcyanocuprate (27.2 mL
of a 0.25 M solution in THF, 6.80 mmol) in THF (23 mL). Boron
trifluoride etherate (0.29 mL, 2.29 mmol) was added 10 min
later at -78 °C, followed by the addition of a solution of the
enone 23 (0.952 g, 2.27 mmol) in THF (4 mL). The mixture
was allowed to warm to room temperature slowly and stirred
at room temperature for an additional 2 h. The reaction was
treated with saturated aqueous NH4OH (20 mL) and NH4Cl
(20 mL). The mixture was stirred at room temperature for 15
min and then extracted with ether (3×). The combined etheral
solution was washed with water (1×) and brine (1×), then
dried (MgSO4) and concentrated. Chromatography (60:40
hexanes/ethyl acetate to 60:30:10 hexanes/ethyl acetate/MeOH
gradient) gave 0.83 g (82%) of 24 as a yellow oil that contains
two inseparable diastereomers (1:4.7 by 1H NMR integration).
9116 J. Org. Chem., Vol. 69, No. 26, 2004

Total Synthesis of (()-Lapidilectine B
139.2, 136.9, 136.2, 128.3, 127.4, 127.3, 124.0, 123.2, 122.6,
117.5, 116.5, 77.8, 71.9, 69.6, 52.6, 41.4, 30.8, 28.4, 24.6; MS
(EI, 70 eV) m/z (rel intensity) 392 ([M + H]+, 5), 391 (M+, 4),
285 (35), 246 (51), 203 (34), 178 (13), 146 (13), 129 (35), 111
(24), 91 (100); HRMS (EI, 70 eV) cacld for C24H26NO4 ([M +
H]+) 392.1862, found 392.1854.
117 (64), 100 (100); HRMS (CI, NH3) calcd for C26H30NO5 ([M
+ H]+) 436.2124, found 436.2132.
(1′R*,3′S*,4′R*)-1-Methoxycarbonyl-1,2-dihydroindol-
3-one-2-spiro-4′-[1′-benzyloxy-3′-(1,2-bistrimethylsilan-
yloxy)ethylcyclohexane] (31). The diol 28 (29 mg, 0.074
mmol) was dissolved in 1-(trimethylsilyl)imidazole (0.5 mL)
and heated at 100 °C. After 1.5 h, the reaction was diluted in
hexane, washed with water (2×) and brine (1×), dried (Mg-
SO4), and concentrated. Chromatography (10% ethyl acetate/
hexanes) on a short column provided 34 mg (81%) of 31 as a
light yellow oil. Rf 0.30 (10% ethyl acetate/hexanes); IR (CHCl3)
1727 (s), 1706 (s), 1212 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ
8.03 (d, J ) 8.5 Hz, 1 H), 7.76 (dd, J ) 7.1, 0.5 Hz, 1 H), 7.58
(td, J ) 7.0, 1.5 Hz, 1 H), 7.50-7.20 (m, 5 H), 7.14 (t, J ) 7.5
Hz, 1 H), 4.57 (ABq, ∆υ ) 13.3 Hz, JAB ) 12.1 Hz, 2 H), 4.02-
3.88 (m, 4 H), 3.59 (dd, J ) 10.4, 2.2 Hz, 1 H), 3.57-3.50 (m,
1 H), 3.43 (dd, J ) 11.0, 5.1 Hz, 1 H), 3.16-3.08 (m, 1 H), 3.31
(td, J ) 13.6, 4.8 Hz, 1 H), 2.10-1.80 (m, 4 H), 1.70-1.50 (m,
1 H), 0.06 (s, 9 H), -0.40 (s, 9 H); 13C NMR (100 MHz, CDCl3)
δ 200.5, 153.7, 151.1, 139.3, 135.8, 128.3, 127.3, 127.2, 124.9,
123.2, 123.1, 117.8, 75.6, 72.2, 72.0, 69.4, 65.1, 52.6, 39.3, 30.7,
28.5, 24.4, -0.04, -0.60; MS (DCI, NH3) m/z (rel intensity)
570 ([M + H]+, 100), 569 (M+, 1), 512 (12), 480 (13), 466 (14),
372 (5), 282 (4), 163 (6), 91 (7); HRMS (DCI, NH3) calcd for
C30H44NO6Si2 ([M + H]+) 570.2707, found 570.2700.
(1′R*,3′S*,4′R*)-1-Methoxycarbonyl-1,2-dihydroindol-
3-one-2-spiro-4′-[1′-benzyloxy-3′-(1,2-dihydroxyethyl)cy-
clohexane] (28) and Cyclic Carbamate 29. N-Methylmor-
pholine N-oxide (0.010 g, 0.086 mmol) was dissolved in a
solution of the carbamate 27 (0.028 g, 0.072 mmol) in acetone
(4 mL), followed by addition of osmium tetroxide (0.051 g of a
2.5 wt % solution in 2-propanol, 0.005 mmol). The reaction
was stirred at room temperature overnight and quenched with
aqueous 10% Na2SO3. The mixture was stirred for an ad-
ditional 15 min and diluted with chloroform. The organic phase
was dried (MgSO4) and concentrated. Chromatography (60:
40 hexanes/ethyl acetate to 60:30:10 hexanes/ethyl acetate/
MeOH gradient) gave 22 mg (72%) of 28 as a yellow oil. Both
1H and 13C spectra showed a single isomer was formed.
However, the relative configuration of -CH(OH)(CH2OH)
could not be determined. Rf 0.15 (60:30:10 hexane/ethyl
acetate/MeOH); IR (CHCl3) 3404 (w), 1706 (s), 1609 (m), 1352
1
(s) cm-1; H NMR (400 MHz, CDCl3) δ 7.98 (d, J ) 8.5 Hz, 1
H), 7.72-7.50 (m, 2 H), 7.44-7.20 (m, 5 H), 7.14-7.04 (m, 1
H), 4.50 (ABq, ∆υ ) 30.3 Hz, JAB ) 12.1 Hz, 2 H), 3.96-3.80
(m, 1 H), 3.85 (s, 3 H), 3.60-3.10 (m, 3 H), 2.92-2.80 (m, 1
H), 2.40-1.50 (m, 8 H); 13C NMR (100 MHz, CDCl3) δ 200.7,
152.4, 138.8, 136.8, 128.4, 127.5, 123.9, 123.2, 117.4, 76.3, 73.6,
70.2, 64.8, 52.9, 40.9, 30.1, 29.3, 25.5; MS (DCI, NH3) m/z (rel
intensity) 426 ([M + H]+, 26), 425 (M+, 3), 408 (34), 394 (100),
350 (60), 318 (30), 287 (41), 242 (13), 91 (45); HRMS (DCI,
NH3) calcd for C24H28NO6 ([M + H]+) 426.1917, found 426.1925.
(1′R*,3′S*,4′R*,3R*)-3-Hydroxy-1-methoxycarbonyl-3-
(2-propenyl)-2,3-dihydro-1H-indole-2-spiro-4′-[1′-benzyl-
oxy-3′-(1,2-dihydroxy)ethylcyclohexane] (32) Allylmag-
nesium bromide (0.15 mL of a 1.0 M solution in diethyl ether,
0.15 mmol) was added to a solution of ketone 31 (42 mg, 0.074
mmol) in THF (3 mL) at -50 °C and was allowed to warm to
room temperature. After 10 h, the reaction was quenched with
aqueous saturated NH4Cl and diluted with ether. The organic
layer was washed with water (1×) and brine (1×), dried
(MgSO4), and concentrated. Without further purification, the
crude mixture was dissolved in THF (1.5 mL) and treated with
HF‚pyridine (0.050 mL) and the mixture was stirred at room
temperature. After 5 h the reaction was carefully quenched
with aqueous saturated NaHCO3, extracted with CHCl3 (3×),
dried (Na2SO4), and concentrated. Chromatography (60:30:10
hexanes/ethyl acetate/MeOH) gave 26 mg (75% over two steps)
of 32 as a yellow oil. Rf 0.22 (60:30:10 hexane/ethyl acetate/
When the reaction time was prolonged or when 28 was
treated with silica gel or base, the cyclized carbamate 29 was
also observed. 29: Rf 0.21 (60:30:10 ethyl acetate/hexane/
MeOH); IR (CHCl3) 3408 (br s), 1708 (s), 1605 (s), 1469 (s)
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.20 (d, J ) 8.4 Hz, 1 H),
7.75 (d, J ) 7.7 Hz, 1 H), 7.67 (dt, J ) 7.8, 1.1 Hz, 1 H), 4.65-
4.58 (m, 1 H), 4.58 (ABq, ∆υ ) 23.0 Hz, JAB ) 12.1 Hz, 2 H),
3.94 (dd, J ) 12.9, 2.6 Hz, 1 H), 3.91 (s, 1 H), 3.74-3.64 (m, 1
H), 3.67 (dd, J ) 12.4, 4.0 Hz, 1 H), 2.67 (ddd, J ) 14.0, 11.8,
4.8 Hz, 1 H), 2.48-2.38 (m, 1 H), 2.22-1.80 (m, 5 H); 13C NMR
(100 MHz, CDCl3) δ 198.3, 150.4, 148.6, 138.3, 137.3, 128.5,
127.7, 127.6, 124.6, 124.5, 122.2, 117.7, 80.1, 71.4, 70.4, 64.8,
62.6, 33.2, 28.2, 27.9, 25.3; MS (DCI, NH3) m/z (rel intensity)
394 ([M + H]+, 21), 350 (100), 242 (20), 215 (46), 170 (15), 91
(14); HRMS (DCI, NH3) calcd for C23H24NO5 ([M + H]+)
394.1654, found 394.1670.
MeOH); IR (CHCl3) 3459 (w), 1708 (s), 1603 (m), 1214 (s) cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.60-7.10 (m, 8 H), 7.04-6.96
(m, 1 H), 5.82-5.60 (m, 1 H), 5.09 (app d, J ) 9.8 Hz, 1 H),
5.04 (app d, J ) 17.0 Hz, 1 H), 4.51 (s, 2 H), 4.30 (br s, 1 H),
3.80 (s, 3 H), 3.78-3.72 (m, 1 H), 3.64-3.56 (m, 1 H), 3.52-
3.46 (m, 1 H), 3.36-3.28 (m, 1 H), 2.92-1.72 (m, 12 H); 13C
NMR (400 MHz, CDCl3) δ 154.7, 140.7, 138.8, 135.8, 133.3,
128.5, 128.3, 127.6, 127.5, 127.4, 123.7, 123.1, 119.1, 117.1,
83.5, 76.2, 73.3, 69.9, 65.3, 52.5, 42.0, 38.9, 29.4, 27.0, 25.6;
all attempts at obtaining MS/HRMS spectra by using various
probes failed for this compound.
Cyclic Carbamate 30. Allylmagnesium bromide (0.10 mL
of a 1.0 M solution in diethyl ether, 0.10 mmol) was added to
a solution of diol 28 (10 mg, 0.024 mmol) in THF (1 mL) at
-40 °C. The reaction was allowed to warm to room tempera-
ture slowly and stirred overnight. It was quenched with
aqueous saturated NH4Cl and diluted with ether. The etheral
solution was washed with water (1×) and brine (1×), then
dried (MgSO4) and concentrated. Chromatography (60:30:10
hexanes/ethyl acetate/MeOH) produced 6.0 mg (57%) of 30 as
a yellow oil. Rf 0.23 (60:30:10 ethyl acetate/hexanes/MeOH);
IR (CHCl3) 3405 (w), 1707 (s), 1604 (w), 1464 (m), 1417 (m),
1375 (m), 1265 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 7.73 (d,
J ) 8.0 Hz, 1 H), 7.40-7.08 (m, 9 H), 5.69-5.56 (m, 1 H), 5.25
(app d, J ) 10.0 Hz, 1 H), 5.16 (d, J ) 18.3 Hz, 1 H), 4.64-
4.54 (m, 1 H), 4.55 (ABq, ∆υ ) 21.3 Hz, JAB ) 11.9 Hz, 2 H),
4.00 (dd, J ) 13.2, 2.2 Hz, 1 H), 3.74 (dd, J ) 12.8, 3.7 Hz, 1
H), 3.66-3.54 (m, 1 H), 2.80-2.72 (m, 1 H), 2.58 (br s, 1 H),
2.4 (dq, J ) 13.6, 8.0 Hz, 1 H), 2.38-2.30 (m, 2 H), 2.24-1.90
(m, 5 H), 1.72 (td, J ) 11.9, 5.1 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 150.1, 138.6, 138.2, 135.0, 131.6, 129.2, 128.5, 127.8,
127.6, 124.1, 123.6, 121.3, 117.9, 84.2, 71.3, 70.5, 68.8, 61.5,
41.7, 32.8, 29.9, 29.4, 28.8; MS (CI, NH3) m/z (rel intensity)
436 ([M + H]+, 10), 418 (6), 394 (6), 279 (12), 246 (6), 229 (15),
Methyl Acetal 33. Sodium periodate (27 mg, 0.13 mmol)
was added to a solution of the triol 32 (30 mg, 0.064 mmol) in
THF (4 mL) and pH 7 buffer (Na2HPO4/NaH2PO4, 0.8 mL) at
0 °C and allowed to warm to room temperature. After 12 h,
the reaction was diluted with ether and water. The aqueous
layer was separated and extracted with ether (3×). The
combined organic layers were dried (MgSO4) and concentrated.
Without further purification, the crude lactol was dissolved
in methanol (3 mL) and 10-camphorsulfonic acid (74 mg, 0.32
mmol) was added in one portion at room temperature. After 1
h, most of the solvent was removed in vacuo and the residue
was chromatographed (20% ethyl acetate/hexanes) to provide
13 mg (45%) of 33 as a yellow oil. Rf 0.19 (20% ethyl acetate/
hexanes); IR (CHCl3) 1698 (s), 1602 (w), 1484 (s), 1387 (s) cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.66 (br s, 1 H), 7.46-7.20 (m, 7
H), 7.02 (t, J ) 7.3 Hz, 1 H), 5.85-5.70 (m, 1 H), 5.20 (app d,
J ) 17.6 Hz, 1 H), 5.02 (app d, J ) 10.2 Hz, 1 H), 4.68 (s, 1 H),
4.60 (s, 2 H), 3.86 (s, 3 H), 3.82-3.70 (m, 1 H), 3.46-2.88 (m,
3 H), 2.72 (s, 3 H), 2.64-2.50 (m, 1 H), 2.40-2.28 (m, 1 H),
J. Org. Chem, Vol. 69, No. 26, 2004 9117

Pearson et al.
2.24-2.20 (m, 3 H), 1.64-1.50 (m, 1 H); 13C NMR (100 MHz,
CDCl3) δ 152.9, 138.7, 133.4, 132.3, 129.5, 128.4, 127.6, 124.3,
122.5, 116.9, 115.6, 108.5, 92.1, 74.9, 74.7, 70.6, 53.8, 52.4, 40.4,
33.7, 30.1, 29.7; MS (EI, 70 eV) m/z (rel intensity) 449 (M+,
17), 286 (51), 254 (11), 240 (15), 167 (10), 105 (14), 91 (100);
HRMS (EI, 70 eV) calcd for C27H31NO5 (M+) 449.2202, found
449.2218.
The residue was chromatographed (60:30:10 hexanes/ethyl
acetate/MeOH) to afford 80 mg (90%) of 36 as an orange oil.
The relative configuration at C(3) was based on the X-ray
crystal structure of a subsequent compound (14, vide infra).10
Rf 0.17 (60:30:10 hexanes/ethyl acetate/MeOH); IR (CHCl3)
3572 (m), 3394 (s), 1729 (m), 1639 (m), 1609 (m), 1483 (s) cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.68 (d, J ) 8.0 Hz, 1 H), 7.42-
7.12 (m, 7 H), 7.00-6.95 (m, 1 H), 5.74-5.62 (m, 1 H), 5.42 (s,
1 H), 5.03 (dd, J ) 10.2, 0.7 Hz, 1 H), 4.90 (dd, J ) 17.1, 1.4
Hz, 1 H), 4.55 (ABq, ∆υ ) 37.3 Hz, JAB ) 12.1 Hz, 2 H), 3.84-
3.80 (m, 1 H), 3.80 (s, 3 H), 3.53 (dt, J ) 9.5, 2.8 Hz, 1 H),
3.42-3.25 (m, 2 H), 2.82 (t, J ) 10.0 Hz, 1 H), 2.71 (dd, J )
13.6, 6.6 Hz, 1 H), 2.61 (td, J ) 13.9, 2.9 Hz, 1 H), 2.40 (dd, J
) 13.5, 7.3 Hz, 1 H), 2.20-1.50 (m, 6 H), 2.19 (dt, J ) 13.6,
3.0 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 154.1, 140.5, 139.3,
135.2, 133.5, 128.7, 128.3, 127.4, 127.3, 123.6, 122.4, 118.7,
115.1, 83.1, 75.0, 72.5, 69.7, 65.8, 52.4, 44.3, 39.6, 34.9, 27.1,
24.6; MS (DCI, NH3) m/z (rel intensity) 485 ([M + NH4]+, 4),
450 (100), 426 (38), 408 (25), 394 (14), 342 (13), 318 (60), 282
(13), 204 (11), 91 (29); HRMS (DCI, NH3) calcd for C27H37N2O6
([M + NH4]+) 485.2652, found 485.2632.
(1′R*,3′R*,4′S*)-1-Methoxycarbonyl-1,2-dihydroindol-
3-one-2-spiro-4′-(1′-benzyloxy-3′-vinylcyclohexane) (34).
tert-Butyllithium (0.13 mL of a 1.7 M solution in pentane, 0.22
mmol) was added in a dropwise fashion to a solution of the
indoxyl 15 (48 mg, 0.14 mmol) in THF (2 mL) at -10 °C. After
15 min, a solution of methyl chloroformate (54 mg, 0.58 mmol)
in THF (0.5 mL) was added at -10 °C. The reaction was
quenched with aqueous saturated NH4Cl (1 mL) after 30 min.
The aqueous layer was extracted with ether (3×) and the
etheral solution was washed with brine (1×), dried (MgSO4),
and concentrated. Chromatography (15% to 20% ethyl acetate/
hexanes gradient) gave 50 mg (89%) of 34 as a yellow oil. Rf
0.26 (20% ethyl acetate/hexanes); IR (CHCl3) 1701 (s), 1640
(m), 1608 (w), 1495 (m) cm-1 1H NMR (360 MHz, CDCl3) δ
;
8.16 (br s, 1 H), 7.68 (dd, J ) 7.7, 0.7 Hz, 1 H), 7.65-7.58 (m,
1 H), 7.46-7.28 (m, 5 H), 7.12 (td, J ) 7.1, 0.6 Hz, 1 H), 5.37
(ddd, J ) 17.0, 10.2, 8.6 Hz, 1 H), 4.96 (d, J ) 16.8 Hz, 1 H),
4.82 (dd, J ) 10.1, 1.0 Hz, 1 H), 4.58 (s, 2 H), 3.90-3.70 (m, 5
H), 2.95-2.85 (m, 1 H), 2.50-2.25 (m, 2 H), 2.05-1.90 (m, 2
H), 1.50-1.40 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 201.0,
152.5, 139.3, 136.9, 136.3, 128.2, 127.3, 127.26, 123.4, 123.2,
123.1, 117.4, 117.1, 71.9, 71.8, 69.6, 52.6, 38.6, 30.1, 24.4, 23.9;
MS (EI, 70 eV) m/z (rel intensity) 391 (M+, 12), 300 (28), 283
(27), 246 (36), 204, (37), 203 (40), 170 (12), 146 (22), 130 (21),
91 (100); HRMS (EI, 70 eV) calcd for C24H25NO4 (M+) 391.1784,
found 391.1774.
Methyl Acetal 14. A solution of the triol 36 (50 mg, 0.11
mmol) in THF (5 mL) and pH 7 buffer (Na2HPO4/NaH2PO4, 1
mL) was cooled to 0 °C and sodium periodate (46 mg, 0.22
mmol) was added in one portion. The reaction was allowed to
warm to room temperature slowly and stirred overnight. The
reaction was then extracted with ether (3×) and the combined
ether layers were washed with brine (1×), dried (MgSO4), and
concentrated to provide 45 mg (100%) of the crude lactol. The
crude lactol was dissolved in methanol (2 mL) and 10-
camphorsulfonic acid (124 mg, 0.53 mmol) was added in one
portion at room temperature. After the solution was stirred
for 1 h, most of the solvent was removed in vacuo and the
residue was directly chromatographed (15% ethyl acetate/
hexanes) to provide 29 mg (59% from the triol) of 14 as
colorless needle crystals (mp 168.5-170 °C). The relative
configuration was established by single-crystal X-ray diffrac-
tion analysis.10 Rf 0.20 (15% ethyl acetate/hexanes); IR (CHCl3)
1698 (s), 1602 (m), 1481 (s), 1442 (s) cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.90-7.82 (m, 1 H), 7.42-7.30 (m, 5 H), 7.30-7.26
(m, 2 H), 6.88 (td, J ) 7.5, 1.1 Hz, 1 H), 5.80-5.70 (m, 1 H),
5.12 (br dt, J ) 1.5, 17.2 Hz, 1 H), 4.97 (br dt, J ) 1.8, 10.3
Hz, 1 H), 4.63 (s, 1 H), 4.54 (ABq, ∆υ ) 5.5 Hz, JAB ) 11.5 Hz,
2 H), 3.79 (m, 1 H), 3.55 (s, 3 H), 3.42 (dd, J ) 6.2, 12.4 Hz, 1
H), 3.20-3.12 (m, 1 H), 2.84 (dd, J ) 9.4, 16.0 Hz, 1 H), 2.70
(s, 3 H), 2.67 (td, J ) 14.2, 5.8 Hz, 1 H), 2.31-2.20 (m, 1 H),
2.02-1.92 (m, 1 H), 1.90-1.80 (m, 1 H), 1.64 (tdd, J ) 14.1,
5.1, 2.9 Hz, 1 H), 1.45 (ddd, J ) 13.0, 10.8, 2.2 Hz, 1 H); 13C
NMR (100 MHz, CDCl3) δ 153.1, 142.6, 138.8, 133.4, 131.7,
129.5, 128.3, 127.6, 127.4, 123.8, 122.1, 116.6, 115.7, 108.8,
92.3, 75.1, 70.5, 69.9, 53.8, 51.9, 44.5, 40.7, 30.7, 27.1, 22.2;
MS (EI, 70 eV) m/z (rel intensity) 449 (M+, 22), 368 (30), 333
(40), 290 (100), 268 (15), 192 (90), 175 (30), 150 (61), 91 (71);
HRMS (EI, 70 eV) calcd for C27H31NO5 (M+) 449.2202, found
449.2207.
(1′S*,3′R*,4′R*)-1-Methoxycarbonyl-1,2-dihydroindol-
3-one-2-spiro-4′-[1′-benzyloxy-3′-(1,2-dihydroxyethyl)cy-
clohexane] (35). N-Methylmorpholine N-oxide (24 mg, 0.21
mmol) was dissolved in a solution of the carbamate 34 (67 mg,
0.17 mmol) in acetone (5 mL), followed by addition of osmium
tetroxide (122 mg of a 2.5 wt % solution in 2-propanol, 0.012
mmol). The reaction was stirred at room temperature over-
night and quenched with aqueous 10% Na2SO3. The mixture
was stirred for an additional 15 min and diluted with chloro-
form. The organic phase was dried (MgSO4) and concentrated.
Chromatography (60:40 hexanes/ethyl acetate to 60:30:10
hexanes/ethyl acetate/MeOH, gradient) gave 60 mg (82%) of
1
35 as an orange oil. Both H and 13C spectra showed a single
diastereomer was formed. However, the stereochemistry of
-CH(OH)(CH2OH) could not be determined. Rf 0.22 (60:30:
10 hexanes/ethyl acetate/MeOH); IR (CHCl3) 3601 (m), 1698
(s), 1609 (s), 1469 (s), 1064 (s) cm-1; 1H NMR (400 MHz, CDCl3)
δ 8.08 (br s, 1 H), 7.72-7.68 (m, 1 H), 7.64-7.58 (m, 1 H),
7.44-7.24 (m, 5 H), 7.14 (t, J ) 7.3 Hz, 1 H), 4.55 (ABq, ∆υ )
19.7 Hz, JAB ) 12.1 Hz, 2 H), 3.88-3.80 (m, 1 H), 3.82 (s, 3
H), 3.50-3.30 (m, 4 H), 2.95 (dt, J ) 13.5, 4.0 Hz, 1 H), 2.36
(dt, J ) 13.2, 2.2 Hz, 1 H), 2.24-2.04 (m, 2 H), 2.00-1.80 (m,
3 H), 1.40-1.30 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 201.4,
152.6, 139.2, 136.8, 128.4, 128.3, 127.5, 127.4, 123.6, 123.2,
123.1, 117.4, 74.2, 71.9, 70.6, 69.7, 65.0, 52.7, 37.0, 28.4, 25.9,
23.6; MS (EI, 70 eV) m/z (rel intensity) 425 (M+, 15), 393 (7),
334 (17), 286 (10), 256 (10), 204 (36), 192 (11), 145 (17), 125
(14), 91 (100); HRMS (EI, 70 eV) calcd for C24H27NO6 (M+)
425.1838, found 425.1831.
Lactone 37. A solution of freshly prepared22 dimethylboron
bromide (excess) in CH2Cl2 (0.10 mL) was added to a solution
of 14 (10 mg, 0.023 mmol) in CH2Cl2 (1 mL) at -78 °C. After
1 h at -78 °C the reaction was quenched with a mixture of
THF and saturated aqueous NaHCO3 (1:1 v/v) at -78 °C. The
reaction was then extracted with ether (3×) and the combined
organic layers were dried (MgSO4) and concentrated. The
residue was dissolved in benzene (2 mL), treated with Fe´tizon’s
reagent23 (Ag2CO3/Celite, ∼1 mmol of Ag2CO3/0.57 g of re-
agent), and heated at reflux. After 12 h, the reaction was cooled
to room temperature, filtered through a pad of Celite, and
concentrated. Chromatography (30% ethyl acetate/hexanes) of
the residue yielded 7.0 mg (70%) of 37 as a yellow oil. Rf 0.17
(20% ethyl acetate/hexanes); IR (CHCl3) 1767 (s), 1710 (s), 1605
(1′S*,3′R*,4′R*,3R*)-3-Hydroxy-1-methoxycarbonyl-3-
(2-propenyl)-2,3-dihydro-1H-indole-2-spiro-4′-[1′-benzyl-
oxy-3′-(1,2-dihydroxyethyl)cyclohexane] (36). Allylmag-
nesium bromide (0.66 mL of a 1.0 M solution in ether, 0.66
mmol) was added to a solution of ketone 35 (81 mg, 0.19 mmol)
in THF (5 mL) at -40 °C. The resulting solution was allowed
to warm to room temperature slowly and stirred overnight.
The reaction was quenched with aqueous saturated NH4Cl and
diluted with ether. The etheral solution was washed with
water (1×) and brine (1×), dried (MgSO4), and concentrated.
1
(w) cm-1; H NMR (400 MHz, CDCl3) δ 7.86 (d, J ) 18.4 Hz,
1 H), 7.48 (dd, J ) 7.7, 0.7 Hz, 1 H), 7.42-7.20 (m, 6 H), 7.08
(td, J ) 7.3, 0.7 Hz, 1 H), 5.82 (dddd, J ) 17.2, 10.2, 8.8, 4.8
9118 J. Org. Chem., Vol. 69, No. 26, 2004

Total Synthesis of (()-Lapidilectine B
Hz, 1 H), 5.21 (app d, J ) 17.2 Hz, 1 H), 5.14 (app d, J ) 10.2
Hz, 1 H), 4.60 (ABq, ∆υ ) 22.0 Hz, JAB ) 11.2 Hz, 2 H), 3.82-
3.76 (m, 1 H), 3.68 (s, 3 H), 3.61 (dd, J ) 9.4, 6.8 Hz, 1 H),
3.24-3.15 (m, 1 H), 2.90 (dd, J ) 15.3, 8.8 Hz, 1 H), 2.62-
2.45 (m, 2 H), 2.14-1.98 (m, 2 H), 1.90 (dt, J ) 15.1, 4.8 Hz,
1 H), 1.82-1.70 (m, 1 H); 13C NMR (100 MHz, CDCl3) δ 176.6,
158.0, 153.0, 142.2, 138.4, 131.5, 131.0, 128.4, 127.73, 127.67,
127.6, 125.2, 123.4, 119.0, 116.2, 92.9, 73.08, 70.3, 52.5, 42.6,
38.9, 29.7, 26.8, 21.9; MS (CI, NH3) m/z (rel intensity) 451 ([M
+ NH4]+, 14), 434 ([M + H]+, 100), 419 (11), 360 (6), 332 (10),
77 (13); HRMS (CI, NH3) calcd for C26H28NO5 (M + H+)
434.1967, found 434.1982.
Lactone 38. A solution of freshly prepared22 dimethylboron
bromide (excess) in CH2Cl2 (0.10 mL) was added to a solution
of 33 (13 mg, 0.029 mmol) in CH2Cl2 (1 mL) at -78 °C. After
1 h at -78 °C the reaction was quenched with a mixture of
THF and saturated aqueous NaHCO3 (1:1 v/v) at -78 °C. The
reaction was extracted with ether (3×) and the combined
organic layers were dried (MgSO4) and concentrated. The
residue was dissolved in CH2Cl2 and treated with pyridinium
chlorochromate (30 mg, 0.12 mmol) and silica gel (30 mg) at
room temperature. After 6 h the reaction was diluted with
ether and filtered through a pad of silica and concentrated.
Chromatography (15% ethyl acetate/hexanes) of the residue
afforded 8.0 mg (64%) of 38 as a yellow oil. Rf 0.50 (30% ethyl
acetate/hexanes); IR (CHCl3) 1768 (m), 1696 (m), 1442 (m),
1412 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 7.70-7.60 (m, 1
H), 7.55-7.50 (m, 1 H), 7.40-7.27 (m, 5 H), 7.10-7.00 (m, 2
H), 5.95-5.90 (m, 1 H), 5.26 (app d, J ) 17.2 Hz, 1 H), 5.15
(app d, J ) 10.3 Hz, 1 H), 4.60 (ABq, ∆υ ) 51.3 Hz, JAB ) 11.7
Hz, 2 H), 3.88 (s, 3 H), 3.87-3.72 (m, 1 H), 3.59 (dd, J ) 10.2,
7.3 Hz, 1 H), 3.30 (ddt, J ) 15.4, 4.4, 2.2 Hz, 1 H), 3.04 (dd, J
) 15.6, 9.0 Hz, 1 H), 2.66-2.52 (m, 1 H), 2.44-2.12 (m, 3 H),
2.10-1.95 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 176.1, 152.8,
141.6, 138.4, 131.6, 131.0, 128.5, 128.4, 127.8, 128.7, 127.6,
125.5, 123.5, 118.9, 115.9, 92.7, 77.2, 72.8, 70.6, 52.8, 44.0, 38.7,
30.9, 28.7, 24.3; MS (CI, NH3) m/z (rel intensity) 434 ([M +
H]+, 100), 328 (9), 219 (10); HRMS (CI, NH3) calcd for C26H28-
NO5 ([M + H]+) 434.1967, found 434.1954.
ozonide intermediate (Rf 0.10, 20% ethyl acetate/hexanes,
stains maroon in anisaldehyde). The reaction time was typi-
cally 60 s of elapsed ozone bubbling, during which time the
color of the reaction turned from pink to white. Sodium
borohydride (25 mg, 0.67 mmol) was then added at -78 °C
and the solution was allowed to warm to room temperature
and stirred for an additional 2 h. After TLC indicated conver-
sion of the intermediate ozonide to alcohol 40 (Rf 0.07, 20%
ethyl acetate/hexanes, stains green in anisaldehyde), the
reaction was quenched with 10% NaHCO3 and extracted with
CH2Cl2 (3×). The combined organic phases were washed with
brine (1×), dried (Na2SO4), and concentrated. Chromatography
(20% to 50% ethyl acetate/hexanes gradient) afforded 127 mg
(84%) of 40 as a colorless oil. Rf 0.40 (60:30:10 hexanes/ethyl
acetate/MeOH); IR (CHCl3) 3396 (m), 1699 (s), 1602 (m), 1484
(s), 1360 (s), 1113 (s) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.89
(d, J ) 8.2 Hz, 1 H), 7.45-7.20 (m, 7 H), 7.02 (td, J ) 7.6, 0.8
Hz, 1 H), 4.71 (s, 1 H), 4.58 (s, 2 H), 4.18-4.06 (m, 1 H), 3.98-
3.86 (m, 1 H), 3.86-3.78 (m, 1 H), 3.59 (s, 3 H), 3.38 (dd, J )
12.1, 6.5 Hz, 1 H), 2.80 (s, 3 H), 2.90-2.70 (m, 1 H), 2.70-
2.50 (m, 2 H), 2.40-2.20 (m, 2 H), 2.20-2.05 (m, 1 H), 1.80-
1.64 (m, 2 H), 1.64-1.45 (m, 2 H); 13C NMR (100 MHz, CDCl3)
δ 153.2, 142.1, 138.8, 132.3, 130.0, 129.6, 128.3, 127.7, 127.5,
124.1, 122.4, 115.8, 109.3, 93.7, 75.5, 70.6, 70.1, 59.4, 54.1, 52.0,
44.7, 38.4, 30.5, 27.7, 23.3; MS (EI, 70 eV) m/z (rel intensity)
453 (M+, 100), 422 (5), 394 (9), 348 (26), 286 (15), 242 (11),
192 (13), 161 (17), 91 (79); HRMS (EI, 70 eV) calcd for C26H31-
NO6 (M+) 453.2151, found 453.2144.
Silyl Ether 41. tert-Butylchlorodiphenylsilane (113 mg,
0.413 mmol) was added to a solution of the alcohol 40 (125
mg, 0.276 mmol) and imidazole (28 mg, 0.413 mmol) in CH2-
Cl2 (6 mL) at room temperature and the reaction mixture was
stirred for 2 h. The reaction mixture was diluted with CH2-
Cl2, washed with water (2×) and brine (1×), dried (Na2SO4),
and concentrated. Chromatography (10% to 30% ethyl acetate/
hexanes) yielded 167 mg (87%) of 41 as a white solid (mp 174-
175 °C). Rf 0.25 (20% ethyl acetate/hexanes); IR (CHCl3) 1701
(s), 1484 (s), 1360 (s), 1060 (s) cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.82 (d, J ) 8.2 Hz, 1 H), 7.65-7.60 (m, 4 H), 7.45-7.10 (m,
13 H), 6.89 (td, J ) 7.4, 1.1 Hz, 1 H), 4.59 (s, 1 H), 4.54 (d, J
) 1.7 Hz, 2 H), 3.95-3.80 (m, 1 H), 3.75-3.62 (m, 2 H), 3.58
(s, 3 H), 3.35 (dd, J ) 12.3, 6.0 Hz, 1 H), 2.95-2.80 (m, 1 H),
2.75-2.50 (m, 2 H), 2.70 (s, 3 H), 2.50-2.38 (m, 1 H), 2.26-
2.18 (m, 1 H), 1.60-1.30 (m, 3 H), 1.04 (s, 9 H); 13C NMR (100
MHz, CDCl3) δ 153.1, 142.2, 138.8, 135.59, 135.58, 135.57,
133.7, 133.6, 131.6, 129.6, 129.4, 128.3, 127.7, 127.67, 127.64,
127.63, 127.61, 127.4, 123.7, 122.3, 115.6, 108.9, 92.8, 75.0,
70.6, 69.9, 59.9, 53.8, 51.9, 44.7, 39.6, 30.5, 27.2, 26.8, 22.8,
19.0; MS (EI, 70 eV) m/z (rel intensity) 691 (M+, 5), 634 (54),
574 (75), 383 (12), 290 (9), 213 (38), 199 (44), 91 (100); HRMS
(EI, 70 eV) calcd for C42H49NO6Si (M+) 691.3329, found
691.331.
Ketone 39. Palladium hydroxide on carbon (1.0 mg, con-
taining ∼20% Pd, 0.014 mmol) and glacial acidic acid (1 drop)
was added to a solution of lactone 37 (15 mg, 0.035 mmol) in
THF (0.5 mL) and absolute EtOH (1 mL). The reaction flask
was purged with N2, equipped with a hydrogen balloon, and
stirred at room temperature. After 15 h the reaction mixture
was filtered through a pad of Celite and concentrated. Without
further purification, the residue was dissolved in CH2Cl2 (2
mL) and treated with pyridinium chlorochromate (35 mg, 0.14
mmol) and silica gel (35 mg) at room temperature. After 5 h
the reaction was diluted with ether, filtered through a pad of
silica gel, and concentrated. Chromatography (30% ethyl
acetate/hexanes) afforded 10 mg (65%) of 39 as a yellow oil.
The same reaction sequence cound be performed from 38 to
give 39 in 77% yield. Rf 0.19 (30% ethyl acetate/hexanes); IR
Alcohol 42. The benzyl ether 41 (20 mg, 0.029 mmol) was
dissolved in THF (0.25 mL), EtOH (1 mL), and cyclohexene
(0.25 mL). Palladium hydroxide on carbon (20% Pd, 4.0 mg,
0.006 mmol) was added and the mixture was heated at reflux.
The reaction was followed by TLC until all of the starting
material disappeared (4-20 h). The reaction mixture was
cooled to room temperature, filtered though a short pad of
Celite, and concentrated. Chromatography (1:4 ethyl acetate/
hexanes to 5:5:1 ethyl acetate/hexanes/MeOH, gradient) gave
16 mg (92%) of 42 as a colorless oil. Rf 0.25 (40% ethyl acetate/
hexanes); IR (CHCl3) 3312 (br, m), 1703 (s), 1379 (s) cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.65-7.60 (m, 4 H), 7.60-7.45 (m,
1 H), 7.45-7.30 (m, 6 H), 7.30-7.18 (m, 2 H), 6.92 (td, J )
7.7, 0.7 Hz, 1 H), 4.58 (s, 1 H), 4.08-3.99 (m, 2 H), 3.89 (s, 3
H), 3.90-3.82 (m, 1 H), 3.20 (dd, J ) 13.5, 6.6 Hz, 1 H), 2.64
(s, 3 H), 2.60-2.30 (m, 4 H), 2.20-2.00 (m, 1 H), 1.90-1.80
(m, 2 H), 1.47-1.36 (m, 1 H), 1.30-1.15 (m, 1 H); 13C NMR
(100 MHz, CDCl3) δ 135.6, 133.6, 129.7, 129.4, 127.7, 127.6,
124.0, 122.7, 115.2, 109.1, 92.9, 73.6, 64.4, 60.2, 53.7, 52.9, 44.1,
39.2, 33.3, 30.3, 26.8, 21.9, 19.0; MS (DCI, CH4) m/z (rel
1
(CHCl3) 1775 (s), 1717 (s), 1483 (s) cm-1; H NMR (400 MHz,
CDCl3) δ 7.65 (d, J ) 8 Hz, 1 H), 7.45-7.30 (m, 2 H), 7.20-
7.10 (m,1 H), 3.95 (s, 3 H), 3.40-3.10 (m, 3 H), 2.95 (dd, J )
18.0, 2.5 Hz, 1 H), 2.70-1.80 (m, 5 H), 1.40-1.00 (m, 2 H),
0.90 (t, J ) 7 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 207.0,
175.2, 153.4, 130.9, 128.6, 125.2, 124.0, 115.6, 92.8, 53.2, 46.6,
38.5, 38.3, 36.1, 29.7, 22.6, 17.3, 16.2; MS (EI, 70 eV) m/z (rel
intensity) 343 (M+, 35), 270 (56), 229 (88), 199 (20), 159 (51),
132 (100), 105 (55); HRMS (EI, 70 eV) calcd for C19H21NO5
(M+) 343.1420, found 343.1429.
Alcohol 40. A solution of olefin 14 (150 mg, 0.334 mmol)
in CH2Cl2/MeOH (4 mL, 1:1 v/v) was treated with a solution
of Sudan Red III in CH2Cl2 (1 drop) as an indicator of complete
reaction.26 The solution was cooled to -78 °C and ozone was
bubbled through it for 20-s periods, between which the reaction
was closely monitored by TLC. The ozone flow was stopped
upon complete conversion of starting olefin 14 (Rf 0.24, 20%
ethyl acetate/hexanes, stains black in anisaldehyde) to the
J. Org. Chem, Vol. 69, No. 26, 2004 9119

Pearson et al.
intensity) 630 ([M + C2H5]+, 3), 601 (M+, 8), 570 (36), 544 (75),
484 (100), 464 (17), 314 (27), 288 (12), 213 (36), 135 (18), 91
(17); HRMS (DCI, CH4) calcd for C37H48NO6Si ([M + C2H5]+)
630.3251, found 630.3254.
(s), 1327 (s), 1110 (s), 1103 (s), 1042 (m), 835 (m), 748 (m),
1
700 (m) cm-1; H NMR (500 MHz, CDCl3) δ 8.30 (br, 2 H ×
0.15), 8.10 (app d, J ) 7.5 Hz, 2 H × 0.85), 7.46-7.65 (m, 8
H), 7.42-7.28 (m, 7 H), 7.26-7.19 (m, 1 H), 6.98-6.90 (m, 1
H), 4.86 (s, 1 H × 0.04), 4.84 (s, 1 H × 0.15), 4.78 (s, 1 H ×
0.15), 4.75 (s, 1 H × 0.50), 4.70 (s, 1 H × 0.08), 4.39-4.10 (m,
2 H), 3.95 (s, 3 H × 0.15), 3.93 (s, 3 H × 0.85), 3.66-3.56 (m,
4 H), 3.64-3.56 (m, 2 H × 0.20), 3.54-3.44 (m, 2 H × 0.80),
3.18-3.10 (m, 1 H × 0.20), 3.05-2.95 (m, 1 H), 2.88-2.81 (m,
1 H), 2.73 (s, 3 H × 0.15), 2.71 (s, 3 H × 0.50), 2.65 (s, 3 H ×
0.30), 2.70-2.59 (m, 2 H), 2.12 (dd, J ) 14.0, 7.5 Hz, 1 H),
1.99-1.81 (m, 2 H), 1.36-1.15 (m, 3 H), 1.01-0.99 (m, 9 H),
0.05 (s, 9 H × 0.15), 0.04 (s, 9 H × 0.85); 13C NMR (100 MHz,
CDCl3) δ 154.1, 153.2, 142.8, 141.0, 135.7, 133.6, 130.3, 129.4,
129.3, 128.8, 127.6, 125.3, 124.9, 122.7, 115.5, 109.0, 74.5, 67.4,
64.9, 62.6, 59.8, 53.8, 52.4, 47.9, 46.4, 38.4, 30.6, 30.4, 29.7,
26.8, 24.8, 21.0, 19.0, 17.7, 14.3, -1.4; MS (FAB + Na, 70 eV)
m/z (rel intensity) 931 ([M + Na]+, 2), 849 (4), 805 ([M + Na
- SOPh]+, 3), 739 (3), 607 (5), 197 (42), 135 (100); HRMS (FAB
+ Na, 70 eV) calcd for C50H64N2O8NaSi2S ([M + Na]+)
931.3820, found 931.3844.
Alkene 50. Sulfoxide 49 (51 mg, 0.056 mmol) was dissolved
in tetrachloroethylene (3 mL) and pyridine (0.1 mL) and heated
at reflux for 4 h. The reaction was cooled and diluted with
CH2Cl2, washed with 10% aqueous Na2CO3 (2×) and brine
(1×), dried (Na2SO4), and concentrated. Chromatography (10%
to 20% ethyl acetate/hexanes, gradient) yielded 37 mg (87%)
of alkene 50 as a clear colorless oil. Judging by variable-
temperature 1H NMR alkene 50 was a single diastereomer that
at room temperature in CDCl3 appeared as a 3:2 ratio of
rotamers due to the N-Teoc carbamate (coalescence point: 60
°C) (see the Supporting Information). An additional set of
rotamers from the methyl carbamate was observed in CDCl3
with a coalescence point of about 20 °C.33 Rf 0.31 (20% ethyl
acetate/hexanes); IR (CH2Cl2) 1697 (s), 1600 (m), 1484 (s), 1359
(s), 1322 (m), 1110 (s), 1099 (s), 1043 (m), 836 (m), 702 (m)
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64-7.59 (m, 3 H), 7.59-
7.55 (m, 2 H), 7.43-7.28 (m, 8 H), 7.25-7.17 (m, 1 H), 6.95-
6.89 (m, 1 H), 6.94-6.86 (br, 1 H), 5.84 (d, J ) 6.4 Hz, 1 H ×
0.40), 5.76 (d, J ) 6.8 Hz, 1 H × 0.60), 4.60 (s, 1 H × 0.40),
4.57 (s, 1 H × 0.60), 4.40-4.31 (m, 1 H × 0.40), 4.28 (br s, 1 H
× 0.60), 4.26-4.14 (m, 2 H), 3.88 (s, 3 H × 0.60), 3.87 (s, 3 H
× 0.40), 3.84-3.77 (m, 1 H × 0.40), 3.72-3.64 (m, 1 H × 0.60),
3.56-3.42 (m, 1 H), 3.06-2.56 (m, 4 H), 2.69 (s, 3 H × 0.40),
2.68 (s, 3 H × 0.60), 1.93-1.82 (m, 1 H), 1.81-1.74 (m, 1 H ×
0.60), 1.74-1.66 (m, 1 H), 1.51-1.45 (m, 1 H × 0.40), 1.43-
1.35 (m, 1 H × 0.60), 1.29-1.24 (m, 1 H × 0.40), 1.21-1.13
(m, 1 H), 1.01 (s, 9 H × 0.60), 1.00 (s, 9 H × 0.40), 0.05 (s, 9 H
× 0.60), 0.03 (s, 9 H × 0.40); 13C NMR (100 MHz, CDCl3) δ
155.0, 153.8, 135.6, 135.5, 135.4, 133.7, 133.6, 133.3, 133.2,
129.7, 129.4, 129.2, 127.7, 127.57, 127.56, 124.6, 123.2, 122.5,
115.8, 115.6, 108.8, 74.9, 74.6, 69.1, 68.4, 63.7, 62.5, 59.9, 59.7,
54.9, 54.0, 53.9, 53.8, 52.5, 52.4, 46.4 (br), 38.7, 38.6, 35.2, 34.1,
31.7, 30.5, 26.8, 25.4 (br), 19.1, 18.2, 17.8, -1.4, -1.6; MS (FAB
+ Na, 70 eV) m/z (rel intensity) 805 ([M + Na]+, 10), 751 ([M
- OMe]+, 5), 697 (19), 679 (10), 665 (14), 637 (6), 213 (14),
199 (21), 197 (41), 135 (100); HRMS (FAB + Na, 70 eV) calcd
for C44H58N2O7NaSi2 ([M + Na]+) 805.3680, found 805.3709.
Ketone 43. N-Methylmorpholine N-oxide (32 mg, 0.28
mmol) was added to a solution of the alcohol 42 (138 mg, 0.229
mmol) in CH2Cl2 (5 mL) at room temperature. Tetrapropyl-
ammonium perruthenate (16 mg, 0.046 mmol) was then added,
followed by powdered 4 Å molecular sieves (140 mg). After 1
h the reaction mixture was filtered though a short pad of silica
gel, washed well with 1% MeOH/CH2Cl2, and concentrated.
The residue was chromatographed (10% to 30% ethyl acetate/
hexanes, gradient) to afford 130 mg (95%) of 43 as a colorless
foam. Rf 0.25 (30% ethyl acetate/hexanes); IR (CHCl3) 1711
1
(s), 1362 (s) cm-1; H NMR (400 MHz, CDCl3) δ 7.61 (br d, J
) 8.0 Hz, 1 H), 7.58-7.53 (m, 2 H), 7.53-7.48 (m, 2 H), 7.45-
7.30 (m, 6 H), 7.30-7.20 (m, 1 H), 7.15 (dd, J ) 7.3, 0.7 Hz, 1
H), 6.97 (td, J ) 7.3, 0.7 Hz, 1 H), 4.56 (d, J ) 1.8 Hz, 1 H),
3.85 (s, 3 H), 3.57-3.47 (m, 1 H), 3.47-3.37 (m, 1 H), 3.10-
2.95 (m, 1 H), 2.98 (s, 3 H), 2.91 (td, J ) 6.0, 1.8 Hz, 1 H),
2.90-2.70 (m, 1 H), 2.65 (td, J ) 18.3, 5.5 Hz, 1 H), 2.42-2.10
(m, 5 H), 0.98 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ 210.9,
154.5, 140.2, 135.53, 135.51, 133.3, 131.6, 129.7, 129.5, 127.68.
127.64, 123.6, 123.1, 115.5, 108.8, 93.2, 74.1, 59.4, 54.3, 52.7,
52.2, 41.2, 39.6, 36.4, 29.6, 26.7, 24.2, 18.9; MS (DCI, NH3)
m/z (rel intensity) 617 ([M + NH4]+, 30), 568 (100), 542 (14),
510 (6), 482 (17), 312 (9), 284 (4), 214 (4); HRMS (DCI, NH3)
calcd for C35H45N2O6Si ([M + NH4]+) 617.3047, found 617.3052.
2-(Trimethylsilyl)ethylcarbamate 48. 2-(Trimethylsilyl)-
ethylchloroformate31 (14 mg, 0.078 mmol) and diisopropyl-
ethylamine (10 mg, 0.078 mmol) were added to 4710 (19 mg,
0.026 mmol) in CH2Cl2 (1 mL) at room temperature. After 1
h, the reaction was diluted with saturated aqueous NaHCO3
and extracted with CH2Cl2 (3×). The combined organic phases
were washed with brine (1×), dried (Na2SO4), and concen-
trated. Chromatography (10% to 20% ethyl acetate/hexanes,
gradient) afforded 21 mg (91%) of 48 as three fractions of
inseparable diastereomers and/or rotamers. Rf 0.55, 0.45, 0.32
(20% ethyl acetate/hexanes). The major fraction (Rf 0.32)
contained 4 inseparable diastereomers and/or rotamers based
on the number of acetal methine 1H NMR resonances observed
at 4.61-4.54 ppm. Data for the major fraction (Rf 0.32, 20%
ethyl acetate/hexanes): IR (CH2Cl2) 1698 (s), 1694 (s), 1598
(m), 1482 (s), 1356 (s), 1103 (s), 1045 (s), 857 (m), 836 (m),
702 (s) cm-1 1H NMR (500 MHz, CDCl3) δ 7.62-7.54 (m, 5
;
H), 7.45-7.29 (m, 11 H), 7.28-7.15 (m, 2 H), 6.93-6.87 (m, 1
H), 4.61-4.54 (m, 1 H), 4.38-4.30 (m, 1 H × 0.33), 4.23-4.10
(m, 2 H), 4.04-3.96 (m, 1 H × 0.33), 3.96-3.89 (m, 1 H), 3.89-
3.60 (m, 5 H), 3.51-3.60 (m, 2 H), 3.04-2.86 (m, 2 H), 2.81-
2.62 (m, 2 H), 2.66 (s, 3 H), 2.56-2.28 (m, 2 H), 2.19-1.92 (m,
1 H), 1.89-1.80 (m, 1 H), 1.74-1.60 (m, 1 H), 1.49-1.42 (m, 1
H), 1.31-1.23 (m, 2 H), 1.19-1.10 (m, 1 H), 1.00 (s, 9 H), 0.03-
0.01 (m, 9 H); 13C NMR (CDCl3, 100 MHz) δ 153.6, 135.6, 133.6,
132.3, 131.7, 131.6, 129.7, 129.4, 129.1, 127.7, 127.6, 127.3,
122.5, 115.6, 108.5, 74.5, 63.1, 62.7, 59.8, 53.8, 52.2, 42.2, 38.6,
33.1, 31.2, 29.7, 27.8, 26.84, 26.76, 19.0, 17.7, 17.5, -1.4; MS
(FAB + Na, 70 eV) m/z (rel intensity) 915 ([M + Na]+, 7), 861
([M - OMe]+, 2), 807 (12), 197 (43), 135 (100); HRMS (FAB +
Na, 70 eV) calcd for C50H64N2O7NaSi2S ([M + Na]+) 915.3871,
found 915.3878.
Lactol 52. Boron trichloride (0.014 mL of a 1.0 M solution
in heptane, 0.014 mmol) was slowly added to a solution of
methyl acetal 50 (8.7 mg, 0.011 mmol) in CH2Cl2 (1.0 mL) at
-30 °C. After 45 min at -30 °C, the reaction was quenched
with aqueous saturated NH4Cl and extracted with CH2Cl2
(3×). The combined organic layers were washed with brine
(1×), dried (Na2SO4), and concentrated. The residue was
chromatographed (10% to 30% ethyl acetate/hexanes gradient)
to afford 5.7 mg (67%) of 52 as a clear, colorless oil. Lactol 52
appeared in the 1H NMR spectrum (CDCl3) as a 2.3:1 mixture
of carbamate rotamers. Rf 0.20 (30% ethyl acetate/hexanes);
IR (CH2Cl2) 3407 (br), 1698 (s), 1695 (s), 1599 (m), 1483 (s),
Sulfoxide 49. m-Chloroperbenzoic acid (1.55 mL of a 0.077
M solution in CH2Cl2, 0.119 mmol) was added at -78 °C to a
solution of phenyl sulfide 48 (106 mg, 0.119 mmol) in CH2Cl2
(2.0 mL) in a dropwise fashion. The reaction was allowed to
warm to room temperature and stirred for 1 h. The reaction
was diluted with aqueous sodium bicarbonate and extracted
with CH2Cl2 (4×). The combined organic phases were washed
with brine (1×), dried (Na2SO4), and concentrated. Chroma-
tography (20% to 50% ethyl acetate/hexanes, gradient) afforded
99 mg (92%) of a complex mixture of diastereomers and/or
rotamers of 49 as a colorless foam. Rf 0.20 and 0.61 (50% ethyl
acetate/hexanes); IR (CH2Cl2) 1690 (s), 1599 (m), 1484 (s), 1363
1
1360 (s), 1318 (s), 1104 (s), 738 (m), 738 (m) cm-1; H NMR
(400 MHz, CDCl3) δ 7.65-7.61 (m, 3 H), 7.60-7.50 (m, 2 H),
9120 J. Org. Chem., Vol. 69, No. 26, 2004

Total Synthesis of (()-Lapidilectine B
7.42-7.29 (m, 7 H), 7.24-7.20 (d, J ) 7.7 Hz, 2 H × 0.70),
7.14 (d, J ) 7.7 Hz, 1 H × 0.30), 6.93 (t, J ) 7.3 Hz, 1 H), 6.82
(br, 1 H), 5.85 (d, J ) 6.2 Hz, 1 H × 0.30), 5.78 (d, J ) 6.2 Hz,
1 H × 0.70), 5.10 (d, J ) 3.7 Hz, 1 H × 0.30), 5.09 (d, J ) 3.3
Hz, 1 H × 0.70), 4.43-4.34 (m, 1 H × 0.30), 4.30-4.26 (m, 1
H × 0.70), 4.25-4.14 (m, 2 H), 3.89 (s, 3 H), 3.84-3.65 (m, 1
H), 3.62-3.47 (m, 1 H), 3.05-2.53 (m, 6 H), 2.00 (d, J ) 3.3,
1 H × 0.30), 1.98 (d, J ) 3.3 Hz, 1 H × 0.70), 1.86-1.68 (m, 2
H), 1.03 (s, 9 H × 0.70), 1.01 (s, 9 H × 0.30), 0.05 (s, 9 H ×
0.70), 0.03 (s, 9 H × 0.30); 13C NMR (100 MHz, CDCl3) δ 153.8,
135.7, 135.5, 135.4, 133.7, 133.6, 129.7, 129.6, 129.4, 127.7,
127.6, 123.4, 123.0, 115.9, 103.2, 69.1, 62.6, 59.8, 54.0, 52.6,
38.6, 33.9, 31.6, 30.3, 29.7, 26.8, 22.6, 19.1, 18.7, 18.2, 17.8,
-1.4, -1.6; MS (FAB + Na, 70 eV) m/z (rel intensity) 791 ([M
+ Na]+, 11), 751 ([M - OH]+, 6), 683 (14), 679 (11), 197 (41),
135 (100); HRMS (FAB + Na, 70 eV) calcd for C43H56N2O7-
NaSi2 ([M + Na]+) 791.3524, found 791.3530.
× 0.20), 2.09 (ddd, J ) 13.1, 7.8, 2.2 Hz, 1 H × 0.80), 1.95-
1.89 (br, 1 H), 1.65-1.54 (m, 1 H), 1.17-1.10 (m, 2 H × 0.20),
1.00 (dd, J ) 9.2, 7.6 Hz, 2 H × 0.80), -0.06 (s, 9 H × 0.20),
-0.05 (s, 9 H × 0.80); 13C NMR (100 MHz, CDCl3) δ 176.1,
154.1, 132.7, 131.1, 125.5, 124.3, 123.7, 116.0, 73.7, 68.5, 63.9,
63.0, 58.73, 58.63, 54.9, 54.1, 53.1, 53.0, 42.1, 36.22, 36.05, 33.9,
32.6, 31.6, 30.6, 29.2, 24.0, 22.6, 18.3, 17.7, -1.4, -1.6; MS
(FAB - Na+, 70 eV) m/z (rel intensity) 551 ([M + Na]+, 29),
529 ([M + H]+, 15), 483 ([M + H - CO2]+, 32), 307 (15), 226
(12), 176 (19), 155 (24), 154 (100), 152 (13), 139 (14), 138 (32),
137 (59), 136 (95), 120 (15), 107 (26), 91 (20), 90 (19), 89 (27),
80 (19), 79 (10), 78 (15), 77 (30); HRMS (FAB - Na+, 70 eV)
calcd for C27H37N2O7Si ([M + H]+) 529.2370, found 529.2382.
Mesylate 55. Diisopropylethylamine (0.032 mL of a 1.0 M
solution in CH2Cl2, 0.032 mmol) and methanesulfonyl chloride
(0.032 mL of a 1.0 M solution in CH2Cl2, 0.032 mmol) were
added at 0 °C to a solution of alcohol 54 (8.4 mg, 0.016 mmol)
in CH2Cl2 (0.15 mL). After 1 h, the reaction was diluted with
water and extracted with CH2Cl2 (4×). The combined organic
phases were washed with brine (1×), dried (Na2SO4), and
concentrated. Chromatography (10% to 50% ethyl acetate/
hexanes, gradient) afforded 8.5 mg (89%) of 55 as a colorless
film. Mesylate 55 appeared in the 1H NMR spectrum (CDCl3)
as a 7:1 mixture of carbamate rotamers. Rf 0.36 (50% ethyl
acetate/hexanes); IR (CH2Cl2) 1776 (s), 1695 (s), 1484 (s), 1360
(s), 1326 (s), 1175 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 7.64
(br, 1 H), 7.53 (d, J ) 7.2 Hz, 1 H), 7.54-7.52 (m, 1 H × 0.15),
7.41 (t, J ) 8 Hz, 1 H × 0.15), 7.39 (td, J ) 8.9, 1.2 Hz, 1 H),
7.17 (t, J ) 7.3 Hz, 1 H × 0.15), 7.15 (td, J ) 7.3, 1.0 Hz, 1 H
× 0.80), 6.79 (br, 1 H), 5.93 (d, J ) 6.8 Hz, 1 H × 0.15), 5.85
(d, J ) 6.6 Hz, 1 H × 0.80), 4.72-4.50 (m, 2 H), 4.32-4.25 (m,
1 H × 0.80), 4.25-4.20 (m, 1.65 H), 4.78-4.14 (m, 1.80 H),
3.94 (s, 3 H × 0.15), 3.93 (s, 3 H × 0.85), 3.30-3.16 (m, 1.25
H), 3.13 (s, 3 H × 0.85), 3.10 (s, 3 H × 0.15), 2.95-2.94 (m, 2
H), 2.87-2.80 (m, 1 H × 0.18), 2.56 (br, 1 H), 2.18 (ddd, J )
13.6, 8.0, 2.4 Hz, 1 H × 0.15), 2.10 (ddd, J ) 13.4, 7.4, 2.2 Hz,
1 H × 0.85), 1.91 (br app d, J ) 16 Hz), 1.36-1.21 (m, 1 H),
1.14-1.08 (m, 2 H × 0.15), 1.00 (dd, J ) 9.5, 7.1 Hz, 2 H ×
0.85), 0.08 (s, 9 H × 0.15), 0.05 (s, 9 H × 0.85); 13C NMR (100
MHz, CDCl3) δ 175.7, 154.0, 131.5, 125.0, 124.5, 123.9, 116.3,
107.6, 91.4, 73.5, 68.3, 65.3, 62.9, 54.0, 53.1, 42.0, 37.8, 32.6,
29.2, 17.7, -1.4, -1.6; MS (FAB + Na+, 70 eV) m/z (rel
intensity) 629 ([M + Na]+, 46), 607 ([M + H]+, 3), 579 ([M +
H - HCtCH]+, 12), 483 ([M - CH2CH2OMs]+, 69), 411 (17),
365 (10), 228 (10), 226 (24), 214 (26), 176 (11), 168 (12), 166
(10), 154 (64), 136 (100), 107 (27), 77 (33); HRMS (FAB + Na,
70 eV) calcd for C28H38N2O9NaSi ([M + Na]+) 629.1965, found
629.1995.
2,5-Dihydropyrrole‚Trifluoroacetate Salt (56) and (()-
Lapidilectine B (1). Trifluoroacetic acid (0.75 mL) was added
to a solution of mesylate 55 (9.4 mg, 0.016 mmol) in CH2Cl2
(2.0 mL) at room temperature. After 30 min the reaction was
diluted with benzene and concentrated. The residue was
codistilled twice with benzene and evaporated under high
vacuum for 30 min. Examination of the residue with 1H NMR
showed the clean conversion of mesylate 55 to the 2,5-
dihydropyrrole‚trifluoroacetate salt 56. The residue was taken
up in CH3CN (2.0 mL) and diisopropylethylamine (19 mg, 0.15
mmol) and allowed to stir at room temperature. After 2 h, the
solution was heated to 60 °C for 10 h in the dark. The reaction
mixture was allowed to cool to room temperature, diluted with
saturated aqueous NaHCO3, and extracted with CH2Cl2 (3×).
The combined organic phases were washed with brine (1×),
dried (MgSO4), and concentrated. The residue was chromato-
graphed (20% ethyl acetate/hexanes to ethyl acetate, gradient)
on silica gel to afford 4.2 mg (76%) of (()-lapidilectine B (1) as
a clear, colorless oil that matched the analytical data of natural
(+)-lapidilectine B.37 The analytical data and spectra for
synthetic and natural lapidilectine B were previously reported
by us in our initial communication.10 Partial data for 56: 1H
NMR (400 MHz, CDCl3) δ 9.94 (br s, 1 H), 8.91 (br s, 1 H),
7.53 (d, J ) 8.4 Hz, 1 H), 7.35 (d, J ) 7.7 Hz, 1 H), 7.31 (t, J
Lactone 53. Pyridinium chlorochromate (10 mg, 0.046
mmol) was added to a solution of lactol 52 (15.3 mg, 0.020
mmol) in CH2Cl2 (1.0 mL) at room temperature. After the
solution was stirred for 1 h Celite (60 mg) was added, then
the mixture was diluted with ether (2 mL) and stirred for 10
min. The mixture was filtered through a plug of silica gel and
washed well with 2:1 ether/CH2Cl2. After concentration, the
residue was chromatographed (10% to 20% ethyl acetate/
hexanes, gradient) to yield 14.0 mg (92%) of 53. Lactone 53
1
appeared in the H NMR spectrum (CDCl3) as a 4:1 mixture
of carbamate rotamers. Rf 0.35 (30% ethyl acetate/hexanes);
IR (CH2Cl2) 1775 (s), 1699 (s), 1603 (m), 1483 (s), 1360 (s),
1105 (s), 740 (m), 702 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ
7.71 (app d, J ) 7.5 Hz, 3 H), 7.67-7.61 (m, 1 H), 7.56 (br, 1
H), 7.48-7.27 (m, 8 H), 7.12 (d, J ) 7.6 Hz, 1 H × 0.20), 6.96
(t, J ) 7.6 Hz, 1 H × 0.80), 6.89 (t, J ) 7.6 Hz, 1 H × 0.20),
5.90 (d, J ) 6.3 Hz, 1 H × 0.20), 5.83 (d, J ) 6.3 Hz, 1 H ×
0.80), 4.44-4.37 (m, 1 H × 0.20), 4.35-4.12 (m, 4 H), 4.08-
4.05 (m, 1 H), 4.01-3.95 (m, 2 H), 3.90 (s, 3 H), 3.80-3.73 (m,
1 H × 0.20), 3.22 (t, J ) 13.5 Hz, 1 H × 0.80), 3.15-3.08 (m,
1 H × 0.80), 3.07-2.89 (m, 2 H), 2.66 (td, J ) 13.7, 4.6 Hz, 1
H × 0.20), 2.44 (br, 1 H × 0.80), 2.16 (ddd, J ) 12.3, 7.6, 1.7
Hz, 1 H × 0.20), 2.07 (ddd, J ) 13.4, 7.6, 2.2 Hz, 1 H × 0.80),
1.81 (br d, J ) 14.5 Hz, 1 H × 0.80), 1.75 (br d, J ) 15 Hz, 1
H × 0.20), 1.55-1.50 (m, 1 H × 0.20), 1.47-1.43 (m, 1 H ×
0.80), 1.07 (s, 9 H × 0.80), 1.05 (s, 9 H × 0.20), 0.04 (s, 9 H ×
0.80), 0.00 (s, 9 H × 0.20); 13C NMR (100 MHz, CDCl3,) δ 153.8,
135.73, 135.66, 135.57, 135.45, 133.38, 133.34, 130.8, 129.65,
129.61, 127.89, 127.86, 127.72, 127.67, 123.4, 115.9, 73.6, 73.2,
68.5, 62.8, 59.7, 54.0, 53.0, 52.9, 36.2, 32.7, 29.3, 26.8, 26.8,
19.1, 17.8, -1.4, -1.6; MS (FAB + Na, 70 eV) m/z (rel
intensity) 789 ([M + Na]+, 11), 751 ([M - OH]+, 6); HRMS
(FAB + Na, 70 eV) calcd for C43H54N2O7NaSi2 ([M + Na]+)
789.3367, found 789.3393.
Alcohol 54. Lactone 53 (8.0 mg, 0.010 mmol) was dissolved
in THF (1.0 mL) in a polyethylene vial and HF‚pyridine (2
drops) was added by polyethylene pipet at room temperature.
The reaction was monitored by TLC at 30-min intervals and
additional HF‚pyridine (2 drops) was added at the same time.
After 4 h, the reaction was diluted with CH2Cl2 and carefully
quenched with aqueous sodium bicarbonate. The aqueous
phase was extracted with CH2Cl2 (3×) and the combined
organic layers were washed with brine (1×), dried (Na2SO4),
and concentrated. Chromatography (20% to 50% ethyl acetate/
hexanes gradient) afforded 4.6 mg (84%) of 54 as a colorless
1
film. Alcohol 54 appeared in the H NMR spectrum (CDCl3)
as a 4:1 mixture of carbamate rotamers. Rf 0.16 (30% ethyl
acetate/hexanes); IR (neat) 3440 (br), 1773 (s), 1698 (s), 1630
(m) cm-1; 1H NMR (400 MHz, CDCl3) δ 7.63 (d, J ) 7.7 Hz, 1
H), 7.59 (d, J ) 7.7 Hz, 1 H × 0.44), 7.36 (t, J ) 7.6, 1 H), 7.11
(t, J ) 7.5 Hz, 1 H), 6.80 (br s, 1 H), 5.91 (d, J ) 6.6 Hz, 1 H
× 0.16), 5.85 (d, J ) 6.6 Hz, 1 H × 0.71), 4.30-4.21 (m, 2 H),
4.20-4.03 (m, 4 H), 3.93 (s, 3 H × 0.21), 3.92 (s, 3 H × 0.79),
3.19-2.97 (m, H × 2.4), 2.90-2.80 (m, 1 H), 2.79-2.70 (m, 1
H × 0.29), 2.52 (br, 1 H), 2.15 (ddd, J ) 13.3, 7.6, 2.8 Hz, 1 H
J. Org. Chem, Vol. 69, No. 26, 2004 9121

Pearson et al.
) 8.4 Hz, 1 H), 7.07 (t, J ) 7.7 Hz, 1 H), 6.46 (d, J ) 6.2 Hz,
1 H), 5.87 (d, J ) 5.9 Hz, 1 H), 4.32-4.18 (m, 2 H), 4.11 (br s,
2 H), 3.84 (s, 3 H), 3.59 (t, J ) 7.3 Hz, 1 H), 2.83 (s, 3 H),
2.78-2.65 (m, 1 H), 2.64-2.45 (m, 4 H), 2.27-2.02 (m, 3 H),
1.15 (s, 9 H).
lapidilectine B and Dr. Jeff Kampf of the University of
Michigan (Department of Chemistry) for the X-ray
crystallographic determination of the structure of 14.
Supporting Information Available: General experimen-
tal procedures, copies of 1H spectra for all new compounds
without elemental analysis, experimental procedures for the
synthesis of 10 and 11, procedures for the conversion of 29 to
31, and variable-temperature 1H NMR spectra of 50. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the National Insti-
tutes of Health (GM-52491), the Petroleum Research
Fund, administered by the American Chemical Society,
and the Korea Science and Engineering Foundation
(KOSEF fellowship to Dr. I. Y. Lee) for financial support
of this research. We thank Dr. Khalijah Awang of the
University of Malaya for providing spectra of natural
JO048917U
9122 J. Org. Chem., Vol. 69, No. 26, 2004