Total syntheses of (+)-Fawcettimine and (+)-Lycoposerramine-B

Article abstract of DOI:10.1021/jo100499h

The total synthesis of (+)-fawcettimine was completed in a highly stereoselective manner starting from the oxatricyclo[7.3.0.0^1,5] dodecanedione derivative. The crucial step in this total synthesis involves the efficient construction of the azonane framework by the intramolecular Mitsunobu reaction. Furthermore, the first total synthesis of (+)-lycoposerramine-B was also accomplished via the common synthetic intermediate.

Full text of DOI:10.1021/jo100499h

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Total Syntheses of (+)-Fawcettimine and (+)-Lycoposerramine-B
Yasunari Otsuka, Fuyuhiko Inagaki, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Natural Science and Technology,
Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan
cmukai@kenroku.kanazawa-u.ac.jp
Received March 19, 2010
The total synthesis of (þ)-fawcettimine was completed in a highly stereoselective manner starting
from the oxatricyclo[7.3.0.01,5]dodecanedione derivative. The crucial step in this total synthesis
involves the efficient construction of the azonane framework by the intramolecular Mitsunobu
reaction. Furthermore, the first total synthesis of (þ)-lycoposerramine-B was also accomplished via
the common synthetic intermediate.
SCHEME 1. Fawcettimine (1) and Its Precursor 2
Introduction
Fawcettimine (1, Scheme 1),1,2 one of the representative
compounds of many Lycopodium alkaloids,3 was first iso-
lated by Burnell from Lycopodium fawcetti Lloyd et Under-
wood in 1959.1 Because of an intriguing fused-tetracyclic
structural feature involving four stereogenic centers and the
carbinol amine moiety,4 three total syntheses of fawcettimine
(1) have so far been reported.5-8 In 1979, Inubushi5 and co-
workers completed the first total synthesis of (()-1 via the
Diels-Alder reaction and aldol reaction as crucial steps.
A more efficient and fewer step synthesis of (()-1 was
achieved by Heathcock6 and co-workers. They also revealed
the details6b of an equilibrium between the two precursor
C4-trans- and C4-cis-bicyclo[4.3.0] skeletons 2 (R=H), keto-
amine isomers of 1 possessing an azonane ring (a nine-
membered azacyclic skeleton), in which the former could
spontaneously be transformed into fawcettimine (1) whereas
the latter could not. Very recently, Toste7 and co-workers
accomplished the first asymmetric total synthesis of (þ)-1 by
taking advantage of the organocatalytic asymmetric annula-
tion as a key step; therefore, the absolute stereochemistry of
the natural (þ)-1 was unambiguously established.
(1) Burnell, R. H. J. Chem Soc. 1959, 3091–3093.
(2) (a) Burnell, R. H.; Mootoo, B. S. Can. J. Chem. 1961, 39, 1090–1093.
(b) Burnell, R. H.; Chin, C. G.; Mootoo, B. S.; Taylor, D. R. Can. J. Chem.
1963, 41, 3091–3094.
(3) Ma, X.; Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772.
(4) (a) Inubushi, Y.; Ishii, H.; Harayama, T.; Burnell, R. H.; Ayer, W. A.;
Altenkirk, B. Tetrahedron Lett. 1967, 1069–1072. (b) Nishio, K.; Fujiwara,
T.; Tomita, K.; Ishii, H.; Inubushi, Y.; Harayama, T. Tetrahedron Lett. 1969,
861–864. (c) Inubushi, Y.; Harayama, T.; Yamaguchi, K.; Ishii, H. Chem.
Pharm. Bull. 1981, 29, 3418–3420.
(5) (a) Harayama, T.; Takatani, M.; Inubushi, Y. Tetrahedron Lett. 1979,
20, 4307–4310. (b) Harayama, T; Takatani, M.; Inubushi, Y. Chem. Pharm.
Bull. 1980, 28, 2394–2402.
(6) (a) Heathcock, C. H.; Smith, K. M.; Blumenkopf, T. A. J. Am. Chem.
Soc. 1986, 108, 5022–5024. (b) Heathcock, C. H.; Blumenkopf, T. A.; Smith,
K. M. J. Org. Chem. 1989, 54, 1548–1562.
On the other hand, fawcettimine-related Lycopodium alka-
loid, (þ)-lycoposerramine-B (3) was recently isolated from
the club moss Lycopodium serratum Thunb by Takayama,9
and its structure was unambiguously established by chemical
(7) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed.
2007, 46, 7671–7673.
(8) For the synthetic studies of fawcettimine, see: (a) Mehta, G.; Reddy,
M. S.; Radhakrishnan, R.; Manjula, M. V.; Viswamitra, M. A. Tetrahedron
Lett. 1991, 32, 6219–6222. (b) Liu, K.-M.; Chau, C.-M.; Sha, C.-K. Chem.
Commun. 2008, 91–93.
(9) Katakawa, K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.;
Furihata, K.; Harayama, T.; Takayama, H. J. Org. Chem. 2005, 70, 658–663.
3420 J. Org. Chem. 2010, 75, 3420–3426
Published on Web 04/26/2010
DOI: 10.1021/jo100499h
r
2010 American Chemical Society

Otsuka et al.
JOCArticle
SCHEME 2. Transformation of (-)-Serratinine into
(þ)-Lycoposerramine-B
SCHEME 4. Retrosynthetic Analysis of 1 and 3
SCHEME 3. Syntheses of (-)-Magellanine, (þ)-Magellani-
none, and (þ)-Paniculatine from Common Intermediate 5
should be accompanied by not only the epimerization at the
C4-position but also the ring-closing reaction resulting in the
completion of the total synthesis of (þ)-fawcettimine (1). In
addition, some chemical modifications of the synthetic inter-
mediate 7 involving oxidation of the C13-hydroxyl group and
oxime formation of the C5-carbonyl functionality would lead
to the first total synthesis of (þ)-lycoposerramine-B (3).
Results and Discussion
At the beginning of this program, the carbonyl group of
511 was converted into a benzyloxy group by the selective
reduction and benzylation to afford 8 in 76% yield. Upon
treatment with LAH, 8 furnished a mixture of the expected
diol derivative and its TBS-migrated isomers. Acid treatment
of these products converged into the triol derivative 9 as a
sole product. The two hydroxyl groups of 9 were selectively
protected with a TBS group, and the MOM group was
introduced on the remaining secondary hydroxyl group.
The allyl moiety was then transformed into a hydroxypropyl
residue by hydroboration and oxidation to yield 10 in a
45% overall yield from 8. The Mitsunobu reaction of 10 with
o-nitrobenzenesulfonamide (NsNH2) followed by selective
desilylation on a primary hydroxyl group led to 11 in 86%
yield. The one-carbon homologation of 11 that occurred
under conventional conditions produced 12 in 43% yield
(Scheme 5).
The efficient construction of the azonane framework must
be one of the critical steps for this synthesis.12 With the
Ns-hydroxyl derivative 12 in hand, our endeavor focused on
the ring-closing reaction using the intramolecular Mitsuno-
bu reaction.13 After screening several conditions, we found
that the azonane derivative 13 was obtained in a highly
efficient manner (96%) under the typical Mitsunobu condi-
tions using diethyl azodicarboxylate and triphenylphosphine
in toluene at room temperature (Scheme 6).
transformation from the known (-)-serratinine,10 via con-
secutive dehydroxylation, oxidation, C-N bond cleavage,
and oxime formation (Scheme 2). Takayama9 proposed the
hypothetical biogenetic route of 3, in which fawcettimine (1)
was regarded as a biogenetic precursor.
We have recently developed a highly stereoselective
method11 for the preparation of the bicyclo[4.3.0]nonenone
derivative 5 starting from diethyl L-tartrate through the
Pauson-Khand reaction of the corresponding enyne deri-
vative 4. The oxatricyclo[7.3.0.01,5]dodecanedione derivative
5 was then successfully transformed into three Lycopodium
alkaloids, (-)-magellanine, (þ)-magellaninone, and (þ)-
paniculatine, in a stereoselective manner (Scheme 3).
We now envisaged our retrosynthetic analysis of the total
syntheses of two Lycopodium alkaloids, (þ)-fawcettimine (1)
and (þ)-lycoposerramine-B (3) from the common starting
material 5 as outlined in Scheme 4. The appropriate chemical
modification of the functional groups of 5 would lead to 6,
the intramolecular Mitsunobu reaction of which should
produce the azonane derivative 7. The transformation of
7 into 2 would be realized via the construction of the
R,β-unsaturated carbonyl functionality and introduction of
a methyl group at the C15-position by the Michael reaction.
Removal of the protecting group on the nitrogen atom of 2
The next task was the introduction of a methyl group at
the C15-position. Thus, the production of the double bond on
the cyclohexane ring of 13 was achieved by removal of the
(10) (a) Inubushi, Y.; Ishii, H.; Yasui, B.; Hashimoto, M. Tetrahedron
Lett. 1966, 7, 1537–1549. (b) Inubushi, Y.; Ishii, H.; Harayama, T. Tetra-
hedron Lett. 1966, 7, 1551–1559. (c) Inubushi, Y.; Ishii, H.; Yasui, B.;
Hashimoto, M.; Harayama, T. Chem. Pharm. Bull. 1968, 16, 82–91. (d)
Inubushi, Y.; Ishii, H.; Yasui, B.; Hashimoto, M.; Harayama, T. Chem.
Pharm. Bull. 1968, 16, 92–100. (e) Inubushi, Y.; Ishii, H.; Yasui, B.;
Harayama, T. Chem. Pharm. Bull. 1968, 16, 101–112.
(12) In the previous three total syntheses,5-7 construction of the azonane
ring was attained in moderate yields.
(13) During this program ongoing, Takayama reported the similar
Mitsunobu reaction for the formation of the azonane framework in the total
synthesis of lycoposerramine-C and phlegmariurine-A; see: Nakayama, A.;
Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett. 2009, 11, 5554–5557.
(11) Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72,
10147–10154.
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SCHEME 5. Conversion of 5 into 12
SCHEME 7. Preparation of Compound 17
alternative route was devised. The removal of the MOM
group of 14 with B-bromocatecholborane was followed by
treatment with cesium thiophenoxide to afford the allyl
alcohol-secondary amine derivative 16, which was sub-
sequently protected with a Boc group, oxidized, and reacted
with Me2Cu(CN)Li2 to produce the desired C15-methylated
17 in a 38% overall yield from 14 in a highly stereoselective
manner (Scheme 7).
SCHEME 6. Formation of Perhydroazonine Framework 13
The benzyloxy functionality of 17 was then converted into
a keto group under standard conditions to give 18 in 74%
yield. Finally, according to the literature precedents,5-7 the
acid-catalyzed conversion of 18 into the target natural
product was executed. Compound 18 was treated with
formic acid in methylene chloride at room temperature that
involved the following three-step transformation: (i) removal
of the Boc group, (ii) isomerization at the C4-position
forming 19, and (iii) the carbinol-amine formation resulting
in the efficient production of (þ)-fawcettimine (1)18 in 81%
yield (Scheme 8).
In connection with the total synthesis of (þ)-fawcettimine
(1), we were very much interested in the first total synthesis of
the fawcettimine-related alkaloid, lycoposerramine-B (3).
Thus, debenzylation of the synthetic intermediate 17 under
a hydrogen atmosphere was followed by removal of the Boc
group to afford the corresponding secondary amine deriva-
tive, which was subsequently exposed to the reductive
methylation conditions producing 20. PCC oxidation of 20
furnished 2119 in a 50% overall yield from 17. Takayama9
had regio- and stereoselectively transformed 21 into
(þ)-lycoposerramine-B under the devised oxime formation
conditions. By referring to Takayama’s procedure, we indepen-
dently converted 21 into (þ)-3. The treatment of 21 with
TBS group, followed by treatment with Martin sulfurane14
to give 14 in 85% yield. Compound 14 was then exposed to B-
bromocatecholborane15 at -78 °C and Dess-Martin peri-
odinane (DMP) to produce 15 in 63% yield. Although the
1,4-conjugation addition of Me2Cu(CN)Li2 to 15 occurred
as expected under the standard conditions, the Ns group
seemed to concomitantly react with the reagents that pro-
duced an intractable mixture.16 In order to change the Ns
group to a suitable protecting group, 15 was exposed to
cesium thiophenoxide.17 Although the desired NH analogue
of 15 could be detected in the reaction mixture, considerable
amounts of the 1,4-conjugated adducts of thiophenoxide
at the C15-position were formed as well. Therefore, an
(14) (a) Arhart, R. J.; Martin, J. C. J. Am. Chem. Soc. 1972, 94, 5003–
5010. (b) Kuramochi, A.; Usuda, H.; Yamatsugu, K.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2005, 127, 14200–14201. (c) Tokumaru, K.; Arai, S.;
Nishida, A. Org. Lett. 2006, 8, 27–30.
(15) Boeckman, R. K., Jr.; Potenza, J. C. Tetrahedron Lett. 1985, 26,
1411–1414.
(16) Spectral analysis of the isolated products tentatively indicated that
the Ns group was converted into some functionality, although their struc-
tures are uncertain yet.
(18) The synthetic (þ)-fawcettimine (1) was identical with the natural
compound by comparison with their spectral data.
(19) The synthetic 21 was identical with the compound9 derived from
(-)-serratinine, by comparison of their spectral data.
(17) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353–359.
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SCHEME 8. Completion of Total Synthesis of
(þ)-Fawcettimine (1)
CDCl3. CHCl3 (7.26 ppm) for silyl compounds and tetramethyl-
silane (0.00 ppm) for compounds without a silyl group were used
as internal standards unless otherwise stated. 13C NMR spectra
were recorded in CDCl3 with CDCl3 (77.00 ppm) as an internal
standard unless otherwise stated. All reactions were carried out
under a nitrogen atmosphere. Silica gel (silica gel 60, 230-400
mesh), Al2O3, and amino silica gel were used for chromatogra-
phy. Organic extracts were dried over anhydrous Na2SO4.
(1S,5S,6S,9S,11R,12R)-11-Benzyloxy-6-tert-butyldimethyl-
silyloxy-12-(2-propenyl)-4-oxatricyclo[7.3.0.01,5]dodecan-3-one
((-)-8). To a solution of (-)-511 (1.09 g, 2.99 mmol) in MeOH
(30 mL) was added NaBH4 (226 mg, 5.98 mmol) at -40 °C. The
reaction mixture was stirred for 5 h at the same temperature,
quenched by addition of acetone, extracted with AcOEt, washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to afford the crude alcohol. To a solution
of the crude alcohol in THF (3 mL) was added NaH (60% in oil;
180 mg, 4.50 mmol) at 0 °C. The reaction mixture was stirred for
30 min at the same temperature, and then BnBr (1.0 mL,
8.4 mmol), TBAI (554 mg, 1.50 mmol), and HMPA (0.6 mL,
3 mmol) were added to the reaction mixture at 0 °C. The reaction
mixture was stirred for 24 h at 60 °C, quenched by addition of
saturated aqueous Na2S2O3, extracted with AcOEt, washed
with water and brine, dried, and concentrated to dryness. The
residue was chromatographed on silica gel with hexane-AcOEt
(10:1) to give (-)-8 (1.04 g, 76% from (-)-5) as a colorless oil:
SCHEME 9. Completion of Total Synthesis of (þ)-Lycopos-
erramine-B (3)
[R]26 -22.6 (c 0.44, CHCl3); IR 1782, 1765, 1639 cm-1
;
D
1H NMR δ 7.34-7.30 (m, 4H), 7.27-7.25 (m, 1H), 5.90-5.81
(m, 1H), 5.08 (d, 1H, J=17.1 Hz), 5.00 (d, 1H, J=10.4 Hz), 4.49,
4.37 (ABq, 2H, J=12.2 Hz), 4.32 (d, 1H, J=3.1 Hz), 4.15 (d, 1H,
J=3.1 Hz), 3.59-3.56 (m, 1H), 2.80-2.76 (m, 1H), 2.55, 2.04
(ABq, 2H, J=17.1 Hz), 2.27-2.21 (m, 1H), 2.15-2.06 (m, 2H),
2.01 (ddd, 1H, J = 25.0, 12.8, 4.9 Hz), 1.77-1.72 (m, 1H),
1.62-1.55 (m, 3H), 1.40-1.35 (m, 1H), 0.90 (s, 9H), 0.08 (s,
3H), 0.07 (s, 3H); 13C NMR δ 175.6, 138.8, 137.1, 128.2, 127.24,
127.22, 115.9, 84.5, 81.7, 71.1, 66.9, 50.6, 46.2, 41.3, 37.6, 35.0,
34.8, 27.3, 25.7, 22.6, 17.9, -5.0, -5.1; FAB MS m/z 457 (Mþ þ
1, 7.0); FAB HRMS calcd for C27H41O4Si 457.2774, found
457.2779.
(1S,2S,3S,6S,8R,9R)-8-Benzyloxy-3-tert-butyldimethylsilyl-
oxy-1-(2-tert-butyldimethylsilyloxyethyl)-9-(3-hydroxypropyl)-
2-methoxymethoxybicyclo[4.3.0]nonane ((-)-10). To a suspen-
sion of LiAlH4 (962 mg, 25.4 mmol) in THF (37 mL) was added
lactone (-)-8 (3.86 g, 8.45 mmol) in THF (19 mL) at 0 °C. The
reaction mixture was stirred for 1 h at room temperature, 10%
aqueous HCl was added at 0 °C, and the mixture was stirred for
1 h at room temperature, extracted with AcOEt, washed with
water, saturated aqueous NaHCO3, and brine, dried, and con-
centrated to dryness. The residue was passed through a short
pad of silica gel with hexane-AcOEt (1:1) to afford the crude
triol. To a solution of crude triol in CH2Cl2 (4 mL) were added
TBSCl (3.17 g, 21.1 mmol) and imidazole (2.88 g, 42.3 mmol) at
room temperature. The reaction mixture was stirred for 24 h at
the same temperature, quenched by addition of water, extracted
with AcOEt, washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad of
silica gel with hexane-AcOEt (20:1) to afford the crude alcohol.
To a solution of the crude alcohol in CH2Cl2 (17 mL) were added
iPr2NEt (5.9 mL, 34 mmol) and MOMCl (1.9 mL, 25 mmol) at
room temperature. The reaction mixture was refluxed for 12 h,
quenched by addition of saturated aqueous NaHCO3, extracted
with CH2Cl2, washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad of
silica gel with hexane-AcOEt (20:1) to give crude MOM ether.
To a solution of crude MOM ether in THF (28 mL) was added
(Sia)2BH (1.0 M in THF; 8.5 mL, 8.5 mmol) at 0 °C. The
reaction mixture was warmed to room temperature and stirred
diethyamine and N,O-bis(trimethylsilyl)hydroxylamine
in ethanol at -40 °C produced, after purification using amino
silica gel, (þ)-lycoposerramine-B (3)20,21 in 52% yield along
with the (Z)-isomer (33%). Thus, we have accomplished the first
total synthesis of (þ)-lycoposerramine-B (3) in a stereoselective
manner (Scheme 9).
In conclusion, we have completed the total syntheses of
two Lycopodium alkaloids, (þ)-fawcettimine (1) and (þ)-lyco-
poserramine-B (3), in a stereoselective manner from the lactone
derivative 5, which was derived from the Pauson-Khand
product of the enyne compound 4. In combination with
the previous total syntheses of three Lycopodium alkaloids,
(-)-magellanine, (þ)-magenallinone, and (þ)-paniculatine,
the present total syntheses of additional two Lycopodium alka-
loids, (þ)-fawcettimine and (þ)-lycoposerramine-B, strongly
indicate that the lactone derivative 5 is a useful synthetic
intermediate for the total syntheses of Lycopodium alkaloids.
Experimental Section
General Methods. Melting points are uncorrected. IR spectra
were measured in CHCl3. 1H NMR spectra were taken in
(20) The synthetic (þ)-lycoposerramine-B (3) was identical with the
natural compound9 by comparison of their spectral data.
(21) The synthetic (þ)-lycoposerramine-B shows [R]24 þ149 (c 0.20,
D
CHCl3). No description on the [R]D value of the natural lycoposerramine-B is
available, although its CD spectral data were recorded.9
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Otsuka et al.
JOCArticle
for 1 h. The reaction mixture was then cooled to 0 °C, and 30%
aqueous H2O2 (8 mL) and aqueous 3 M NaOH (8 mL) were
slowly added. The reaction mixture was warmed to room
temperature, stirred for 1 h, extracted with AcOEt, washed with
water and brine, dried, and concentrated to dryness. The residue
was chlomatographed on silica gel with hexane-AcOEt (4:1) to
reaction mixture was stirred for 30 min at the same temperature,
quenched by addition of saturated aqueous NH4Cl, extracted
with AcOEt, washed with water and brine, dried, and concen-
trated to dryness. The residue was passed through a short pad of
silica gel with hexane-AcOEt (4:1) to afford the crude olefin
compound. To a solution of the crude olefin compound in THF
give (-)-10 (2.19 g, 45% from (-)-8) as a colorless oil: [R]28
(10 mL) was added BH3 Me2S (1 M in THF; 1.0 mL, 1.0 mmol)
3
D
-27.5 (c 0.94, CHCl3); IR 3448 cm-1; 1H NMR δ 7.41-7.36 (m,
4H), 7.32-7.29 (m, 1H), 4.79, 4.73 (ABq, 2H, J=6.4 Hz), 4.57,
4.47 (ABq, 2H, J=12.0 Hz), 4.05-3.99 (m, 1H), 3.85-3.80 (m,
1H), 3.79-3.77 (m, 1H), 3.74-3.68 (m, 3H), 3.64 (d, 1H, J=8.8
Hz), 3.43 (s, 3H), 2.52 (d, 1H, J=12.5 Hz), 2.17 (dt, 1H, J=13.7,
8.1 Hz), 2.00-1.89 (m, 2H), 1.83-1.74 (m, 3H), 1.67-1.59 (m,
6H), 1.52 (ddd, 1H, J=14.5, 10.5, 3.7 Hz), 0.96 (s, 9H), 0.94 (s,
9H), 0.13-0.12 (m, 12H); 13C NMR δ 139.0, 128.2, 127.5, 127.2,
99.5, 85.6, 85.0, 72.5, 70.9, 63.0, 61.3, 55.7, 50.4, 49.2, 42.1, 36.4,
35.5, 31.3, 29.8, 26.1, 25.9, 25.2, 22.3, 18.5, 18.0, -4.6, -4.7,
-5.1, -5.2; FAB MS m/z 659 (Mþ þ 23, 9.2); FAB HRMS calcd
for C35H65O6Si2 637.4320, found 637.4322.
at 0 °C, and the mixture was stirred for 30 min at the same
temperature. To the reaction mixture were added H2O (3 mL)
and NaBO3 4H2O22 (150 mg, 1.46 mmol) at the same tempera-
3
ture, and the reaction mixture was warmed to room tempera-
ture, stirred for 1 h, extracted with AcOEt, washed with water
and brine, dried, and concentrated to dryness. The residue was
chromatographed on silica gel with hexane-AcOEt (2:1) to give
(-)-12 (304 mg, 43% from (-)-11) as a colorless oil: [R]28
D
-13.5 (c 0.51, CHCl3); IR 3602, 3381, 1543 cm-1; 1H NMR δ
8.10-8.08 (m, 1H), 7.79-7.77 (m, 1H), 7.69-7.66 (m, 2H),
7.34-7.26 (m, 5H), 5.51 (t, 1H, J=5.6 Hz), 4.73, 4.68 (ABq, 2H,
J=6.3 Hz), 4.40 (s, 2H), 3.80-3.57 (m, 1H), 3.63-3.76 (m, 4H),
3.54 (d, 1H, J=8.0 Hz), 3.34 (s, 3H), 3.12-3.10 (m, 2H), 2.44 (d,
1H, J = 11.8 Hz), 2.04-1.98 (m, 1H), 1.91-1.87 (m, 1H),
1.74-1.49 (m, 11H), 1.31-1.26 (m, 1H), 1.11-1.04 (m, 1H),
0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR δ 148.0, 138.9,
133.9, 133.3, 132.6, 131.0, 128.2, 127.4, 127.3, 125.2, 99.5,
86.4, 85.2, 72.4, 70.8, 63.8, 55.7, 50.0, 49.9, 44.0, 40.7, 35.2,
29.5, 29.3, 28.3, 28.2, 26.4, 25.9, 22.4, 18.0, -4.6, -4.7; FAB MS
m/z 743 (Mþ þ 23, 3.2); FAB HRMS calcd for C36H57N2O9SSi
721.3554, found 721.3550.
(1S,2S,3S,6S,8R,9R)-8-Benzyloxy-3-tert-butyldimethylsilyl-
oxy-1-(2-hydroxyethyl)-2-methoxymethoxy-9-[3-(2-nitrobenzene-
sulfonylamino)propyl]bicyclo[4.3.0]nonane ((-)-11). To a mixture
of the alcohol (-)-10 (307 mg, 0.482 mmol), 2-nitrobenzenesul-
fonamide (292 mg, 1.45 mmol), and PPh3 (164 mg, 0.626 mmol)
in THF (5 mL) was added DIAD (127 mg, 0.626 mmol) at room
temperature. The reaction mixture was heated at 70 °C and
stirred for 6 h. The reaction mixture was filtered through a pad
of Celite, and the filtrate was concentrated to dryness. The
residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to afford the crude sulfonamide. To a
solution of the crude sulfonamide in THF (5 mL) was added
dropwise TBAF (1.0 M in THF; 0.5 mL, 0.5 mmol) at room
temperature. The reaction mixture was stirred for 12 h at the
same temperature, quenched by addition of saturated aqueous
NH4Cl, extracted with AcOEt, washed with water and brine,
dried, and concentrated to dryness. The residue was chromato-
graphed on silica gel with hexane-AcOEt (2:1) to give (-)-11
(291mg, 86% from (-)-10) as a colorless oil: [R]30D -2.53 (c 0.96,
(1S,2S,3S,6S,8R,9R)-8-Benzyloxy-3-tert-butyldimethylsilyl-
oxy-2-methoxymethoxy-13-(2-nitrobenzenesulfonyl)-13-azatri-
cyclo[7.7.0.01,6]hexadecane ((þ)-13). To a mixture of (-)-12
(86.1 mg, 0.119 mmol) and PPh3 (93.5 mg, 0.355 mmol) in
toluene (8 mL) was added DEAD (40% in toluene; 0.16 mL,
0.35 mmol) at room temperature. The mixture was stirred for
30 min at the same temperature. The reaction mixture was
filtered through a pad of Celite and concentrated under reduced
pressure. The residue was chromatographed on silica gel with
hexane-AcOEt (2:1) to give (þ)-13 (81.0 mg, 96%) as a color-
less oil: [R]26D þ1.39 (c 0.42, CHCl3); IR 1547 cm-1; 1H NMR
δ 7.91-7.89 (m, 1H), 7.68-7.63 (m, 2H), 7.58-7.56 (m, 1H),
7.36-7.31 (m, 4H), 7.27-7.24 (m, 1H) 4.76, 4.72 (ABq, 2H, J=
6.1 Hz), 4.58, 4.43 (ABq, 2H, J=4.4 Hz), 3.78-3.66 (m, 3H),
3.57-3.53 (m, 2H), 3.38 (s, 3H), 3.13-3.03 (m, 2H), 2.40 (d, 1H,
J=8.0 Hz), 2.22-2.16 (m, 1H), 2.05-1.93 (m, 4H), 1.89-1.85
(m, 1H), 1.79-1.71 (m, 4H), 1.69-1.65 (m, 2H), 1.62-1.55 (m,
2H), 1.51-1.47 (m, 1H), 0.89 (s, 9H), 0.07 (s, 3H), 0.06 (s, 3H);
13C NMR δ 148.4, 139.0, 133.2, 132.6, 131.3, 130.5, 128.3, 127.6,
127.3, 123.9, 100.2, 88.5, 86.3, 73.0, 71.1, 56.2, 51.8, 50.5, 50.2,
47.9, 42.6, 34.5, 30.4, 28.3, 25.91, 25.86, 25.3, 24.5, 21.8, 18.0,
-4.5, -4.6; FAB MS m/z 725 (Mþ þ 23, 5.6). FAB HRMS calcd
for C36H55N2O8SSi 703.3448, found 703.3447.
(1S,2S,6S,8R,9R)-8-Benzyloxy-2-methoxymethoxy-13-(2-nitro-
benzenesulfonyl)-13-azatricyclo[7.7.0.01,6]hexadecan-3-ene ((-)-14).
To a solution of (þ)-13 (698 mg, 0.933 mmol) in THF (9 mL) was
added TBAF (1.0 M in THF; 1.4 mL, 1.4 mmol) at room
temperature. The reaction mixture was stirred for 6 h at 60 °C,
quenched by addition of saturated aqueous NH4Cl, extracted with
AcOEt, washed with water and brine, dried, and concentrated
to dryness. The residue was passed through a short pad of silica
gel with hexane-AcOEt (1:2) to afford the crude alcohol. To a
solution of the crude alcohol in benzene (1 mL) was added
Martin sulfurane (1.00 g, 1.49 mmol) at room temperature. The
reaction mixture was stirred for 6 h at 50 °C, quenched by
1
CHCl3); IR 3454, 3390, 1543 cm-1; H NMR δ 8.11-8.07 (m,
1H), 7.82-7.78 (m, 1H), 7.69-7.66 (m, 2H), 7.36-7.31 (m, 4H),
7.29-7.26 (m, 1H), 5.45 (t, 1H, J=5.9 Hz), 4.79, 4.77 (ABq, 2H,
J=6.1 Hz), 4.46, 4.35 (ABq, 2H, J=11.7 Hz), 3.88-3.83 (m, 1H),
3.80-3.78 (m, 1H), 3.72 (d, 1H, J=9.3 Hz), 3.68-3.61 (m, 3H),
3.37 (s, 3H), 3.20-3.14 (m, 1H), 3.10-3.03 (m, 1H), 2.45 (d, 1H,
J=12.5 Hz), 2.13-2.05 (m, 1H), 1.89 (ddd, 1H, J=15.9, 7.1, 4.2
Hz), 1.80-1.74 (m, 4H), 1.67-1.56 (m, 3H), 1.53-1.45 (m, 3H),
1.41-1.35 (m, 1H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H); 13C
NMR δ 148.0, 138.8, 133.9, 133.4, 132.6, 130.9, 128.3, 127.5,
127.4, 125.2, 99.9, 85.4, 84.3, 72.0, 70.8, 60.4, 56.2, 51.0, 48.7,
43.8, 43.6, 36.0, 35.4, 30.1, 28.0, 25.83, 25.81, 21.8, 17.9, -4.6,
-4.7; FAB MS m/z 729 (Mþ þ 23, 2.7); FAB HRMS calcd for
C35H55N2O9SSi 707.3397, found 707.3394.
(1S,2S,3S,6S,8R,9R)-8-Benzyloxy-3-tert-butyldimethylsilyl-
oxy-1-(3-hydroxypropyl)-2-methoxymethoxy-9-[3-(2-nitrobenzene-
sulfonylamino)propyl]bicyclo[4.3.0]nonane ((-)-12). To a solu-
tion of (-)-11 (688 mg, 0.976 mmol) in CH2Cl2 (10 mL) and
pyridine (1 mL) was added Dess-Martin periodinane (434 mg,
1.02 mmol) at room temperature. The reaction mixture was
stirred for 30 min at the same temperature, quenched by
saturated aqueous Na2S2O3, extracted with AcOEt, washed
with 1 N HCl, saturated aqueous NaHCO3, water, and brine,
dried, and concentrated to dryness. The residue was passed
through a short pad of silica gel with hexane-AcOEt (4:1) to
afford the crude aldehyde. To a suspension of (PPh3Me)Br (1.05
g, 2.44 mmol) in THF (9 mL) was added n-BuLi (1.46 M in
hexane; 1.7 mL, 2.4 mmol) at 0 °C. The reaction mixture was
stirred for 30 min at the same temperature, and then a solution of
crude aldehyde in THF (2 mL) was added via cannula. The
(22) Only a trace amount of the desired 12 was obtained when the
resulting organoborane was exposed to 30% aqueous H2O2 and aqueous
3 M NaOH; see: Kabalka, G. W.; Shoup, T. M.; Goudgaon, N. M. J. Org.
Chem. 1989, 54, 5930–5933.
3424 J. Org. Chem. Vol. 75, No. 10, 2010

Otsuka et al.
JOCArticle
addition of saturated aqueous NaHCO3, extracted with AcOEt,
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed on silica gel with hexane-AcOEt
(4:1) to give (-)-14 (429 mg, 85% from (þ)-13) as a colorless oil:
[R]19D -28.1 (c 0.54, CHCl3); IR 1547 cm-1; 1H NMR δ 7.91-7.89
(m, 1H), 7.68-7.63 (m, 2H), 7.58-7.56 (m, 1H), 7.33 (d, 4H, J=4.2
Hz), 7.28-7.25 (m, 1H), 5.67-5.64 (m, 1H), 5.62-5.59 (m, 1H),
4.73, 4.68 (ABq, 2H, J = 6.4 Hz), 4.48 (s, 2H), 4.43 (brs, 1H),
3.75-3.72(m,1H),3.61-3.51 (m, 2H), 3.38 (s, 3H), 3.09 (dt, 1H, J=
14.2, 5.4 Hz), 2.92 (dt, 1H, J=13.9, 3.9 Hz), 2.18-1.86 (m, 9H),
1.82-1.72 (m, 2H), 1.61 (dt, 1H, J=15.4, 5.6 Hz), 1.51 (td, 1H, J=
13.2, 6.1 Hz), 1.42-1.36 (m, 1H); 13C NMR δ 148.1, 138.7, 133.2,
132.6, 131.3, 130.5, 128.3, 127.7, 127.5, 127.4, 125.2, 123.9, 97.3, 88.5,
79.0, 71.2, 55.6, 50.9, 50.4, 48.3, 47.5, 39.8, 36.7, 28.5, 25.6, 25.3, 24.8,
24.7; FAB MS m/z 593 (Mþþ23, 5.7); FAB HRMS calcd for
C30H38N2NaO7S 593.2297, found 593.2304.
(1S,6S,8R,9R)-8-Benzyloxy-13-(2-nitrobenzenesulfonyl)-13-
azatricyclo[7.7.0.01,6]hexadecan-3-en-2-one ((þ)-15). To a solu-
tion of (-)-14 (75.7 mg, 0.132 mmol) in CH2Cl2 (7 mL) at
-78 °C was added B-bromocatecholborane (78.9 mg, 0.397
mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred for
30 min at the same temperature, quenched by addition of 2 M
aqueous NaOH (3 mL), and stirred for 30 min at room tem-
perature. The mixture was extracted with CH2Cl2, washed with
water and brine, dried, and concentrated to dryness. The residue
was passed through a short pad of silica gel with hexane-AcOEt
(1:1) to afford the crude alcohol. To a solution of the crude
alcohol in CH2Cl2 (2 mL) was added Dess-Martin periodinane
(67.2 mg, 0.158 mmol) at room temperature. The reaction
mixture was stirred for 30 min at the same temperature,
quenched by addition of saturated aqueous Na2S2O3, extracted
with AcOEt, washed with water and brine, dried, and concen-
trated to dryness. The residue was chromatographed on silica
gel with hexane-AcOEt (1:1) to give (þ)-15 (43.9 mg, 63% from
(-)-14) as a colorless oil: [R]23D þ107 (c 0.24, CHCl3); IR 1659,
1549 cm-1; 1H NMR δ 7.91 (dd, 1H, J=7.6, 1.7 Hz), 7.72-7.66
(m, 2H), 7.59 (dd, 1H, J = 7.6, 1.7 Hz), 7.32-7.22 (m, 5H),
6.71-6.68 (m, 1H), 5.98 (dd, 1H, J=10.0, 2.0 Hz), 4.45, 4.20
(ABq, 2H, J=11.7 Hz), 3.60-3.52 (m, 3H), 3.17-3.11 (m, 1H),
2.91 (dt, 1H, J=12.9, 4.0 Hz), 2.74 (brs, 1H), 2.59 (ddt, 1H, J=
20.0, 5.4, 2.5 Hz), 2.39-2.17 (m, 4H), 2.07-2.00 (m, 1H),
1.93-1.79 (m, 3H), 1.58-1.47 (m, 3H), 0.99-0.93 (m, 1H);
13C NMR δ 200.5, 148.8, 144.8, 138.4, 133.5, 131.2, 130.9, 130.6,
128.8, 128.2, 127.7, 127.2, 123.9, 86.1, 69.6, 55.9, 50.3, 45.02,
44.98, 39.8, 37.0, 28.8., 26.0, 25.2, 21.6, 21.5; FAB MS m/z 547
(Mþ þ 23, 12.7); FAB HRMS calcd for C28H33N2O6S 525.2059,
found 525.2054.
(1S,4R,6S,8R,9R)-8-Benzyloxy-13-(tert-butoxycarbonyl)-4-
methyl-13-azatricyclo[7.7.0.01,6]hexadecan-3-en-2-one ((þ)-17).
To a solution of (-)-14 (101 mg, 0.177 mmol) in CH2Cl2
(9 mL) at -78 °C was added B-bromocatecholborane (106 mg,
0.531 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred
for 3 h at the same temperature, quenched by addition of 2 M
aqueous NaOH (5 mL), and stirred for 30 min at room tempera-
ture. The mixture was extracted with CH2Cl2, washed with water
and brine, dried, and concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane-AcOEt (1:1)
to afford the crude alcohol. To a solution of the crude alcohol in
MeCN (4 mL) were added Cs2CO3 (173 mg, 0.531 mmol) and
PhSH (0.5 M in MeCN; 0.7 mL, 0.4 mmol) at room temperature.
The reaction mixture was stirred for 12 h at the same temperature,
the resulting suspension was diluted with CH2Cl2, cooled in an ice
bath, and filtered through a pad of Celite, and the filtrate was
concentrated to afford the crude amine. To the mixture of the
crude amine and Et3N (0.5 mL) in CH2Cl2 (3.5 mL) was added
Boc-ON (89.2 mg, 0.354 mmol) at room temperature. The reaction
mixture was stirred for 12 h at the same temperature, quenched by
addition of water, extracted with AcOEt, washed with water and
brine, dried, and concentrated to dryness. The residue was passed
through a short pad of silica gel with hexane-AcOEt (2:1) to
afford the crude alcohol. To a solution of the crude alcohol in
CH2Cl2 (4 mL) was added Dess-Martin periodinane (90.1 mg,
0.212 mmol) at room temperature. The reaction mixture was
stirred for 30 min at the same temperature, quenched by addition
of saturated aqueous Na2S2O3, extracted with AcOEt, washed
with water and brine, dried, and concentrated to dryness. The
residue was passed through a short pad of silica gel with hexa-
ne-AcOEt (2:1) to afford the crude ketone. To a suspension of
CuCN (47.6 mg, 0.531 mmol) and LiBr (76.9 mg, 0.885 mmol) in
Et2O (5 mL) was added MeLi (1 M in Et2O; 1.0 mL, 1.0 mmol) at
0 °C. The reaction mixture was stirred for 20 min at the same
temperature. To the reaction mixture was added a solution of
crude ketone in Et2O (1 mL) at the same temperature. The reaction
mixture was stirred for 30 min at the same temperature, quenched
by addition of saturated aqueous NH4Cl, and passed through a
short pad of Celite with Et2O. The filtrate was extracted with Et2O,
washed with water and brine, dried, and concentrated to dryness.
The residue was chromatographed on silica gel with hexane-
AcOEt (4:1) to give (þ)-17 (30.6 mg, 38% from (-)-14) as a
1
colorless oil: [R]22 þ99.7 (c 0.55, CHCl3); IR 1684 cm-1; H
D
NMR some peaks doubled and/or broadened due to amide
conformational isomers δ 7.33-7.24 (m, 5H), 4.46, 4.14 (ABq,
2H, J = 12.0 Hz), 3.78-3.71 (m, 1H), 3.58-3.44 (m, 2H),
3.13-3.01 (m, 1H), 2.88-2.83 (m, 1H), 2.26-2.14 (m, 5H),
1.94-1.77 (m, 2H), 1.68-1.41 (m, 19H), 0.93 (d, 3H, J = 6.0
Hz), 13C NMR some peaks doubled due to amide conformational
isomers δ 212.1, 157.1, 138.7, 128.2, 127.5, 127.1, 85.9, 79.2, 68.8,
57.9, 49.0, 47.7, 44.0, 42.7, 36.0, 34.0, 28.5, 27.6, 26.5, 23.4, 22.2,
21.7, 21.4, 20.7; FAB MS m/z 478 (Mþ þ 23, 6.2); FAB HRMS
calcd for C28H42NO4 456.3114, found 456.3112.
(1S,4R,6S,9R)-13-(tert-Butoxycarbonyl)-4-methyl-13-azatri-
cyclo[7.7.0.01,6]hexadecane-2,8-dione ((þ)-18). A mixture of
(þ)-17 (15.9 mg, 3.49 ꢀ 10-2 mmol) and Pd(OH)2 (20 wt % on
carbon; 4 mg) in THF (1 mL) was stirred under hydrogen
atmosphere (1 atm) for 24 h at room temperature. The
reaction mixture was passed through a short pad of Celite,
and the filtrate was concentrated to dryness. The residue was
passed through a short pad of silica gel with hexane-AcOEt
(4:1) to afford the crude alcohol. To a solution of the crude
alcohol in CH2Cl2 (1 mL) was added Dess-Martin period-
inane (17.8 mg, 4.70 ꢀ 10-2 mmol) at room temperature. The
reaction mixture was stirred for 30 min at the same tempera-
ture, quenched by addition of saturated aqueous Na2S2O3
and saturated aqueous NaHCO3, extracted with CH2Cl2,
washed with water and brine, dried, and concentrated to
dryness. The residue was chromatographed on silica gel with
hexane-AcOEt (2:1) to give (þ)-18 (9.4 mg, 74% from (þ)-17)
as a colorless amorphous solid: [R]13D þ143 (c 0.20, CHCl3);
IR 1736, 1701, 1686 cm-1; 1H NMR some peaks doubled and/
or broadened due to amide conformational isomers δ 3.70-
3.41 (m, 2H), 3.02-2.75 (m, 3H), 2.54-2.52 (m, 1H),
2.38-2.08 (m, 5H), 1.97-1.11 (m, 10H), 1.46 (s, 9H), 1.07
(d, 3H, J = 6.4 Hz); 13C NMR some peaks doubled due to
amide conformational isomers δ 219.0, 213.7, 156.8, 79.6,
59.9, 49.5, 47.4, 46.6, 44.7, 42.2, 38.9, 30.9, 30.1, 28.5, 27.9,
25.5, 22.3, 22.1, 21.0; EI MS m/z 363 (Mþ, 5.1); EI HRMS
calcd for C21H33NO4 363.2410, found 363.2404.
Fawcettimine (1). To a solution of (þ)-18 (11.1 mg, 3.05 ꢀ
10-2 mmol) in CH2Cl2 (1 mL) was added HCO2H (1.0 mL,
30 mmol) at 0 °C. The reaction mixture was then warmed to
room temperature and stirred for 12 h at the same temperature,
quenched by addition of saturated aqueous NaHCO3, extracted
with CHCl3, washed with water and brine, dried, and con-
centrated to dryness. The residue was chromatographed on
Al2O3 with hexane-AcOEt (1:1) to give (þ)-1 (6.5 mg, 81%)
as a white foam: [R]19 þ71.0 (c 0.19, MeOH) [lit.1 [R]rt þ89
D
D
J. Org. Chem. Vol. 75, No. 10, 2010 3425

Otsuka et al.
JOCArticle
(c 0.55, MeOH)]; IR 3329, 1728 cm-1; 1H NMR δ 3.49 (ddd, 1H,
J = 13.8, 9.6, 4.1 Hz), 3.29 (td, 1H, J = 15.1, 4.1 Hz), 2.92
(dd, 1H, J=15.1, 5.5 Hz), 2.76 (ddd, 1H, J=14.6, 5.5, 4.6 Hz),
2.66 (dd, 1H, J=17.8, 13,7 Hz), 2.28-2.05 (m, 6H), 1.97-1.85
(m, 4H), 1.64 (d, 1H, J = 14.2 Hz), 1.50-1.22 (m, 6H), 0.96
(d, 3H, J=6.4 Hz); 13C NMR δ 220.3, 60.1, 53.5, 50.0, 48.2,
44.3, 43.2, 41.9, 35.7, 31.9, 28.5, 28.1, 23.7, 22.4, 21.8; EI MS m/z
263 (Mþ, 47.9); EI HRMS calcd for C16H25NO2 263.1885,
found 263.1887. The synthetic fawcettimine (1) was identical
with the natural compound by comparison with their spectral
data.6b,7
colorless prisms: mp 113-114 °C (hexane); [R]24D þ204 (c 0.15,
CHCl3); IR 1734, 1701 cm-1; H NMR δ 2.88-2.87 (m, 1H),
1
2.60-2.50 (m, 2H), 2.42-1.25 (m, 18H), 2.25 (s, 3H), 1.07 (d,
3H, J=6.4 Hz); 13C NMR δ 220.2, 214.2, 60.7, 54.7, 50.2, 48.6,
46.6, 44.3, 42.5, 39.4, 31.1, 30.2, 28.0, 25.3, 22.4, 22.3, 21.6; FAB
MS m/z 278 (Mþ þ 1, 100); FAB HRMS calcd for C17H28NO2
278.2120, found 278.2112. The synthetic (þ)-21 was identical
with the compound9 derived from (-)-serratinine, by compar-
ison of their spectral data.
Lycoposerramine B (3). To a solution of (þ)-21 (4.0 mg, 1.4 ꢀ
10-2 mmol) in EtOH (0.2 mL) were added Et2NH (30 μL, 0.29
mmol) and TMSNHOTMS (10.1 mg, 5.69 ꢀ 10-2 mmol) in
EtOH (0.1 mL) via cannula at -40 °C. The reaction mixture was
stirred for 12 h at the same temperature and concentrated to
dryness. The residue was passed through a short pad of silica gel
with CHCl3-MeOH (10:1) to afford the crude oxime. The crude
oxime was chromatographed on amino silica gel with hexa-
ne-AcOEt (2:1) to give (þ)-3 (2.2 mg, 52% from (þ)-21) as a
colorless amorphous powder: [R]24D þ149 (c 0.20, CHCl3); IR
3281, 1699 cm-1; 1H NMR δ3.17 (d, 1H, J=3.4 Hz), 2.68 (td,
1H, J=13.1, 3.4 Hz), 2.56 (dd, 1H, J=17.9, 10.3 Hz), 2.43-2.39
(m, 1H), 2.30-2.17 (m, 7H), 2.26 (s, 3H), 2.13-2.00 (m, 4H),
1.74-1.62 (m, 3H), 1.47-1.42 (m, 1H), 1.37-1.16 (m, 3H), 1.03
(d, 3H, J=6.8 Hz); 13C NMR δ 213.9, 169.6, 61.6, 55.0, 48.4,
46.7, 44.3, 42.80, 42.77, 31.5, 29.9, 28.6, 27.4, 25.43, 25.37, 22.4,
21.3; MS m/z 293 (Mþ þ 1, 100); FAB HRMS calcd for
C17H29N2O2 293.2229, found 293.2231. The synthetic lycopo-
serramine-B (3) was identical with the natural compound by
comparison with their spectral data.9 Specific rotation was not
reported.
(1S,4R,6S,9R)-4,13-Dimethyl-13-azatricyclo[7.7.0.01,6]hexa-
decane-2,8-dione ((þ)-21). A mixture of (þ)-17 (49.8 mg, 0.109
mmol) and Pd(OH)2 (20 wt % on carbon; 9 mg) in THF (5 mL)
was stirred under hydrogen atmosphere (1 atm) for 12 h at room
temperature. The reaction mixture was passed through a short
pad of Celite, and the filtrate was concentrated to dryness.
The residue was passed through a short pad of silica gel with
hexane-AcOEt (4:1) to afford the crude alcohol. To a solution
of the crude alcohol in CH2Cl2 (1 mL) was added HCO2H
(1.0 mL, 30 mmol) at room temperature. The reaction mixture
was stirred for 12 h at the same temperature, quenched by
addition of saturated aqueous NaHCO3, extracted with CHCl3,
washed with water and brine, dried, and concentrated to dry-
ness. To a solution of residue in MeOH (2 mL) were added
aqueous formaldehyde (37% in H2O; 0.2 mL, 3 mmol) and
NaCNBH3 (13.7 mg, 0.218 mmol) at room temperature. The
mixture was stirred for 1 h and then acidified by HCO2H
(0.2 mL, 5 mmol). The reaction mixture was stirred for 1 h at
the same temperature, quenched by addition of saturated aqu-
eous NaHCO3, extracted with CHCl3, washed with water and
brine, dried, and concentrated to dryness. The residue was
passed through a short pad of Al2O3 with hexane-AcOEt (1:1)
to afford the crude alcohol. To a solution of the crude alcohol in
CH2Cl2 (1 mL) was added PCC (35.2 mg, 0.164 mmol) at room
temperature. The reaction mixture was stirred for 1 h at the same
temperature, diluted with CHCl3, washed with aqueous 1 M
NaOH, water, and brine, dried, and concentrated to dryness.
The residue was chromatographed on silica gel with CHCl3-
MeOH (10:1) to give (þ)-21 (12.4 mg, 50% from (þ)-17) as
Acknowledgment. This work was supported in part by a
Grant-in Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology,
Japan, for which we are thankful.
Supporting Information Available: 1H and 13C NMR spec-
tra for compounds 1, 3, 8, 10-15, 17, 18, and 21. This material is
available free of charge via the Internet at http://pubs.acs.org.
3426 J. Org. Chem. Vol. 75, No. 10, 2010