Enantioselective approaches to aminocyclopentitols: A total synthesis of (+)-6-epitrehazolin and a formal total synthesis of (+)-trehazolin

Article abstract of DOI:10.1021/jo980050a

Potent inhibitors of trehalase, such as trehazolin and its congeners, represent an attractive approach to the design of effective new insect control agents. In this report, enantioselective total syntheses of (-)-6- epitrehazolin and (+)-trehazolin were achieved using the asymmetric heterocycloaddition between [(benzyloxy)methyl]cyclopentadiene and the acylnitroso compound arising from in situ oxidation of (S)-mandelohydroxamic acid with tetrabutylammonium periodate. Further functionalization of the resulting 3,4,5-trisubstituted cyclopentene, either involving osmylation or epoxidation of the double bond, efficiently created pentasubstituted cyclopentanes. Introduction of the quaternary carbon in both synthesis targets was achieved via stereoselective osmylation of an intermediate 2,3,4,5-substituted 1-methylenecyclopentane.

Full text of DOI:10.1021/jo980050a

J . Org. Chem. 1998, 63, 3403-3410
3403
En a n tioselective Ap p r oa ch es to Am in ocyclop en titols: A Tota l
Syn th esis of (+)-6-Ep itr eh a zolin a n d a F or m a l Tota l Syn th esis of
(+)-Tr eh a zolin
J un Li, Fengrui Lang, and Bruce Ganem*
Department of Chemistry, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301
Received J anuary 9, 1998
Potent inhibitors of trehalase, such as trehazolin and its congeners, represent an attractive approach
to the design of effective new insect control agents. In this report, enantioselective total syntheses
of (-)-6-epitrehazolin and (+)-trehazolin were achieved using the asymmetric heterocycloaddition
between [(benzyloxy)methyl]cyclopentadiene and the acylnitroso compound arising from in situ
oxidation of (S)-mandelohydroxamic acid with tetrabutylammonium periodate. Further function-
alization of the resulting 3,4,5-trisubstituted cyclopentene, either involving osmylation or epoxidation
of the double bond, efficiently created pentasubstituted cyclopentanes. Introduction of the
quaternary carbon in both synthesis targets was achieved via stereoselective osmylation of an
intermediate 2,3,4,5-substituted 1-methylenecyclopentane.
Sch em e 1
In tr od u ction
Inhibitors of glycosidases, which are the enzymes that
catalyze the hydrolysis of glycosidic bonds, figure promi-
nently in many of the major advances of modern glyco-
biology.1 Recently, several new aminocyclopentitol-
containing natural products have been discovered that
display potent and selective effects on a variety of
biologically important glycosidases. Examples include
mannostatins A and B (1-2, Scheme 1), which are
selective mannosidase inhibitors,2 allosamidin (3), rep-
resenting a new family of pseudotrisaccharide chitinase
inhibitors,3 and trehazolin (4),4 which inhibits the tre-
halase-catalyzed breakdown of trehalose to two molecules
of glucose.
Apart from 4, known trehalase inhibitors include
validoxylamine A,5 salbostatin,6 and 1-deoxynojirimycin,7
the last being much less active. Potent, substrate-specific
inhibitors of trehalase represent an attractive approach
to the design of effective new insect control agents, since
trehalose is the principal blood sugar and mobile energy
(1) (a) McGarvey, G. J .; Wong, C.-H. Liebigs. Ann./ Receuil 1997,
1059-1074. (b) Winchester, B.; Fleet, G. W. J . Glycobiology 1992, 2,
199-210.
source of insects. Moreover, trehalase inhibitors should
exhibit little human toxicity, since trehalose plays no
significant role in mammalian metabolism.8
(2) (a) Aoyagi, T.; Yamamoto, T.; Kojiri, K.; Morishima, H.; Nagai,
M.; Hamada, M.; Takeuchi, T.; Umezawa, H. J . Antibiot. 1989, 42,
883-889. (b) Morishima, H.; Kojiri, K.; Yamamoto, T.; Aoyagi, T.;
Nakamura, H.; Iitaka, Y. J . Antibiot. 1989, 42, 1008-1011.
(3) (a) Sakuda, S.; Isogai, A.; Matsumoto, S.; Suzuki, A.; Koseki, K.;
Kodama, H.; Suzuki, A. Agric. Biol. Chem. 1987, 51, 3251-3259. (b)
Sakuda, S.; Isogai, A.; Makita, T.; Matsumoto, S.; Suzuki, A.; Koseki,
K.; Kodama, H.; Yamada, Y. Agric. Biol. Chem. 1988, 52, 1615-1617.
(4) Ando, O.; Satake, H.; Itoi, K.; Sato, A.; Nakajima, M.; Takahashi,
S.; Haruyama, H.; Okuma, Y.; Kinoshita, Y.; Enokita, R. J . Antibiot.
1991, 44, 1165-1168.
The chemical and biological properties of trehazolin
have been studied by several research groups,9 from
which have emerged some interesting synthetic ana-
logues, such as (+)-6-epitrehazolin 5,10 as well as a
variety of useful structure-activity relationships.11 Sev-
eral partial or total enantioselective syntheses of tre-
hazolin, whose correct absolute configuration is depicted
in 4, have also been reported.,12-15 In most syntheses,
(5) Asano, N.; Takeuchi, M.; Kameda, Y.; Matsui, K.; Kono, Y. J .
Antibiot. 1990, 43, 722-726.
(6) Ve´rtesy, L.; Fehlhaber, H.-W.; Schulz, A. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1844-46.
(7) Murao, S.; Miyata, S. Agric. Biol. Chem. 1980, 44, 219-221.
(8) Elbein, A. D. Adv. Carbohydr. Chem. Biochem. 1974, 30, 227-
256.
(10) (a) Shiozaki, M.; Kobayashi, Y.; Arai, M.; Haruyama, H.
Tetrahedron Lett. 1994, 35, 887-890. (b) Shiozaki, M.; Arai, M.;
Kobayashi, Y.; Kasuya, A.; Miyamoto, S. J . Org. Chem. 1994, 59, 4450-
4460.
(11) (a) Uchida, C.; Kitahashi, H.; Watanabe, S.; Ogawa, S. J . Chem.
Soc., Perkin Trans. 1 1995, 1707-1717. (b) Uchida, C.; Yamagishi, T.;
Kitahashi, H.; Iwaisaki, Y.; Ogawa, S. Bioorg. Med. Chem. Lett. 1995,
3, 1605-1524. (c) Uchida, C.; Kimura, H.; Ogawa, S. Bioorg. Med.
Chem. Lett. 1997, 5, 921-939.
(9) (a) Knapp, S.; Purandare, A.; Rupitz, K.; Withers, S. G. J . Am.
Chem. Soc. 1994, 116, 7461-7462. (b) Shiozaki, M.; Arai, M.; Koba-
yashi, Y.; Kasuya, A.; Miyamoto, S.; Furukawa, Y.; Takayama, T.;
Haruyama, H. J . Org. Chem. 1994, 59, 4450-4460. (c) Miyazaki, H.;
Kobayashi, Y.; Shiozaki, M.; Ando, M.; Nakajima, M.; Hanzawa, H.;
Haruyama, H. J . Org. Chem. 1995, 60, 6103-6109.
S0022-3263(98)00050-4 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/22/1998

3404 J . Org. Chem., Vol. 63, No. 10, 1998
Li et al.
Sch em e 2
Sch em e 3
access to the core aminocyclopentitol was achieved either
by (a) functionalization of an enantiomerically pure
starting material, typically a carbohydrate, drawn from
the chiral pool16 or (b) hydroxylation of preassembled di-
and trisubstituted cyclopentenes using osmylation or
epoxidation reactions.17
Our own approach to the synthesis of trehazolin, as
developed in earlier syntheses of cyclopentane-based
glycosidase inhibitors,14,18,19 focused on the enantioselec-
tive heterocycloaddition of substituted cyclopentadienes
or fulvenes to create 3,4,5-trisubstituted cyclopentenes,
which undergo stereoselective additions with strongly
electrophilic reagents syn to the allylic substituents, thus
resulting in pentasubstituted cyclopentanes.20 Here, we
report enantioselective syntheses of (+)-trehazolin (4) and
(+)-6-epitrehazolin (5) in which we demonstrate the
practicality of our approach in assembling the requisite
hexasubstituted aminocyclopentitol components.
from thallous cyclopentadienide, and the acylnitroso
compound arising from in situ oxidation of (S)-mande-
lohydroxamic acid 9 with tetrabutylammonium periodate.
Cycloaddition led to a mixture of the desired product 10
together with its diastereomer (not shown). The insepa-
rable mixture was reduced using sodium amalgam to
afford pure cyclopentene 11, which was characterized as
its diacetate 12, in 40% overall yield from thallous
cyclopentadienide. The minor cycloadduct 13 was also
obtained in 11% yield. Consistent with an earlier
precedent,19 the catalytic osmylation of 11 favored syn
addition. However, the osmylation of diacetate 12 was
more selective and nearly quantitative, affording 14 and
15 in >5:1 ratio after acetylation. Pure 14 was obtained
in 82% overall yield from 12 after chromatography.
Nuclear Overhauser enhancements observed between the
four cis methine ring hydrogens confirmed the assigned
relative stereochemistry in 14.
This five-step route to enantiomerically pure, differ-
entially protected amidocyclopentitol 14 made it possible
to introduce stereoselectively the quarternary center in
6-epitrehazolin, as shown in Scheme 4. Catalytic hydro-
genolysis of both the benzylic ether and acetate groups
in 14 using palladium hydroxide furnished alcohol 16 in
quantitative yield. Using the method of Grieco et al.,23
nitrophenylselenation followed by in situ oxidative elimi-
nation cleanly transformed 16 into alkene 17 in 83%
yield. Flanked by two allylic substituents shielding the
top face of the five-membered ring, the exocyclic alkene
in 17 underwent vicinal hydroxylation exclusively from
the opposite face using OsO4 and N-methylmorpholine
N-oxide to afford diol 18. Further evidence for its
structure came from the observation that 18 underwent
slow intramolecular 1,5-acetyl migration to the corre-
sponding primary acetate. The resulting mixture was
converted to a single pentaacetate 19 in 96% overall yield
from 17. Exhaustive hydrolysis of 19 furnished ami-
nocyclopentitol 7 (96%).
Syn th esis of (+)-6-Ep itr eh a zolin
The convergent strategy we envisioned was formulated
around a late-stage assembly of the aminooxazoline ring
by the condensation of appropriate carbohydrate and
cyclopentane intermediates. One likely endgame in-
volved reaction of the known tetra-O-benzyl-R-D-glucopy-
ranosylisothiocyanate (6)21 with aminocyclopentitol 7
(Scheme 2) to give a thiourea whose cyclization and
deprotection, following the precedent of Shiozaki et al.,12b
should afford 5.
The enantioselective synthesis of 7 began with an
asymmetric heterocycloaddition between the known [(ben-
zyloxy)methyl]cyclopentadiene 8 (Scheme 3),22 prepared
(12) (a) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M. J . Am. Chem. Soc.
1992, 114, 10065-10066. (b) Kobayashi, Y.; Miyazaki, H.; Shiozaki, M.
J . Org. Chem. 1994, 59, 813-822.
(13) (a) Ogawa, S.; Uchida, C. Chem. Lett. 1993, 173-176. (b)
Uchida, C.; Yamagishi, T.; Ogawa, S. J . Chem. Soc., Perkin Trans. 1
1994, 589-602.
(14) Goering, B. K.; Li, J .; Ganem, B. Tetrahedron Lett. 1995, 36,
8905-8908.
(15) Ledford, B. E.; Carreira, E. M. J . Am. Chem. Soc. 1995, 117,
11811-11812.
(16) (a) Ito, H.; Motoki, Y.; Taguchi, T.; Hanzawa, Y. J . Am. Chem.
Soc. 1993, 115, 8835-8836. (b) Perrin, E.; Mallet, J .-M.; Sinay, P.
Carbohydr. Lett. 1995, 1, 215-216. (c) Marco-Contelles, J .; Destabel,
C.; Gallego, P.; Chiara, J . L.; Bernabe´, M. J . Org. Chem. 1996, 61,
1354-1362.
(17) (a) Hasegawa, A.; Sable, H. Z. J . Org. Chem. 1966, 31, 4154-
4161. (b) Steyn, R.; Sable, H. Z. Tetrahedron 1969, 25, 3579-3597.
(18) Goering, B. K.; Ganem, B. Tetrahedron Lett. 1994, 35, 6997-
7000.
(19) King, S. B.; Ganem, B. J . Am. Chem. Soc. 1994, 116, 562-570.
(20) Nichols, J .; Tralka, T.; Goering, B. K.; Wilcox, C. F.; Ganem,
B. Tetrahedron 1996, 52, 3355-3364.
(21) (a) Camarasa, M. J .; Fernandez-Resa, P.; Garcia-Lopez, M. T.;
De las Heras, F. G.; Mendez-Castrillon, P. P.; Felix, A. S. Synthesis
1984, 509-510. (b) review: Witczak, Z. J . Adv. Carbohydr. Chem.
Biochem. 1986, 44, 91-145.
The overall stereochemical configuration of 7 was
unambiguously confirmed by its successful transforma-
tion into (+)-5, as shown in Scheme 5. Condensation of
7 with isothiocyanate 6 gave thiourea 20 (80% yield),
(22) Corey, E. J .; Koelliker, U.; Neuffer, J . J . Am. Chem. Soc. 1971,
1489-1490.
(23) Grieco, P. A.; Gilman, S.; Nishizawa, M. J . Org. Chem. 1976,
41, 1485-1486.

Enantioselective Approaches to Aminocyclopentitols
J . Org. Chem., Vol. 63, No. 10, 1998 3405
Sch em e 4
Sch em e 6
Sch em e 7
Sch em e 5
which could be cyclized to aminooxazoline 21 using yellow
mercuric oxide in 70% yield. Deprotection of 21 by
hydrogenolysis afforded (+)-5 (82%), whose physical and
spectrometric properties agreed with previously pub-
lished values.10 Overall, the synthesis of 5 proceeded in
14 steps and 11% overall yield from cyclopentadiene 8.
dioxirane. In all cases, however, the product was pre-
dominantly or exclusively the undesired syn-epoxide, an
authentic sample of which was prepared in quantitative
yield by the direct epoxidation of 11 itself (vide infra).
To eliminate the hydrogen-bond-donor properties of the
acylamino group, diacetate 12 was transformed to the
corresponding O-methyl imino ether 24. However, ep-
oxidation of 24 afforded a complex mixture of products
that was not investigated further.
6-Br om o-6-d eoxytr eh a zolin Ap p r oa ch to
Tr eh a zolin
On the basis of the successful synthesis of (+)-5, an
attractive route to (+)-4 was envisioned (Scheme 6)
involving condensation of isothiocyanate 6 with the
trehazolin aminocyclopentitol 22, which had previously
been synthesized.12b Compound 22 was expected to arise
from amide carbonyl participation in the opening of
epoxide 23, for which we hoped to develop a synthesis
from diacetate 12 (Scheme 3) or some other protected
form of diol 11. Peracids are known to interact more
strongly with secondary allylic amides than with allylic
hydroxyl groups in effecting syn epoxidation reactions.17a,24
To ascertain whether steric hindrance at the remaining
allylic carbon could override the syn directing effect of
the mandelamide group, the epoxidation of several ether
derivatives of 11 (R) tert-butyldimethylsilyl, triisopro-
pylsilyl, trityl) was studied using using m-chloroperoxy-
benzoic acid, CF3CO3H, HOF-CH3CN,25 and dimethyl-
As expected, reaction of N-bromosuccinimide-H2O
with amide 11 occurred with anchimeric participation by
the mandelamide carbonyl as depicted in 25 (Scheme 7)
to afford a single HOBr adduct 26 in 85% yield. It
occurred to us that a sequence of steps paralleling those
in Schemes 4 and 5 might be used to transform 26 into
6-bromo-6-deoxytrehazolin, which itself might serve as
a potential precursor for trehazolin (vide infra). Follow-
ing that rationale, 26 was exhaustively acetylated to give
triester 27. When subjected to hydrogenolysis conditions,
27 underwent benzylic deoxygenation with no trace of
dehalogenation to afford 28 in quantitative yield. Sel-
enation of 27 with subsequent oxidative elimination
furnished 29 in 80% yield. Vicinal dihydroxylation of 29
was highly stereoselective, with acetylation of the product
affording pure hexasubstituted cyclopentane 30 in 83%
(25) Rozen, S.; Bareket, Y.; Dayan, S. Tetrahedron Lett. 1996, 37,
531-534.
(24) Berti, G. Topics Stereochem. 1973, 7, 93-251.

3406 J . Org. Chem., Vol. 63, No. 10, 1998
Li et al.
Sch em e 8
Sch em e 9
Sch em e 10
yield after chromatography. No trace of any isomeric
product was detected.
Hydrolysis of 30 in dilute HCl afforded the correspond-
ing aminobromocyclopentitol, which, without purification,
was reacted as before with glucosylisothiocyanate 6. The
desired thiourea 31 (Scheme 8) was obtained in 50% yield
and was cyclized using yellow HgO to aminooxazoline 32
(60% yield), which represents a protected form of 6-bromo-
6-deoxytrehazolin. To cyclize the trans-bromohydrin
unit, 32 was stirred in a suspension of potassium carbon-
ate-methanol and thus formed epoxide 33 in 81% yield.
Our interest in epoxide 33 as a precursor to (+)-
trehazolin arose from the knowledge that electronegative
substituents strongly influence the direction of acid-
catalyzed epoxide opening.16a,26 Adjacent hydroxy and
acyloxy groups have been shown to destabilize the
incipient positive charge in such openings, causing the
incoming nucleophile to bond at the more remote epoxide
carbon. In the case of 33, it was hoped that the
combination of steric hindrance from the quaternary
center, together with the two electron-withdrawing hy-
droxyl groups,26b would outweigh the inductive effect of
the iminocarbamate substituent and thus favor the
stereochemical outcome shown in 34. In the event, a
dilute solution of epoxide 33 in 10:1 water-trifluoroacetic
acid (TFA) was unchanged upon prolonged stirring at
room temperature. Even in 1:1 H2O/TFA, little or no
hydrolysis of 33 was evident after 24 h at room temper-
ature. Control experiments in our laboratory had previ-
ously established that the glycosidic linkage in 4 and 5
was stable to these conditions. Unfortunately, the use
of 1:1 H2O/TFA under more forcing conditions (50-60 °C)
led to fragmentation of the aminoisoxazoline linkage,
judging from the thin layer chromatogram, in which a
spot appeared that comigrated with tetrabenzyl-D-glu-
copyranose. Similar results were observed in reactions
of 33 with dilute perchloric acid in tetrahydrofuran, and
no trace of the desired epoxide hydrolysis product could
be detected under any conditions tested.
varying the electronegativity of adjacent substituents on
the regiochemistry of epoxide ring opening was explored
using mandelamide 35 and trichloroacetamide 38 (Scheme
9). Starting from trisubstituted cyclopentene 11, syn-
epoxidation with m-chloroperoxybenzoic acid (m-CPBA)
afforded 35 in 96% yield. In addition, alkaline hydrolysis
of 11 furnished 36, which could be trichloroacetylated
using hexachloroacetone to afford 37 in 36% yield from
36. Treatment of 37 with Oxone formed the correspond-
ing syn-epoxide 38 (60% yield).
Not surprisingly, epoxide 35 proved resistant to acid
but did undergo slow hydrolysis using 2:1 H2O/TFA (rt,
60 h) to afford a 1:1.6 ratio of the desired product 39
(32%) and its isomer 40 (52%, Scheme 10), which for
further characterization were transformed to the corre-
sponding peracetates 43 (93%) and 44 (90%). Under
similar conditions, the combined halogen electron-
withdrawing effects in epoxytrichloroacetamide 38, which
were expected to influence the regiochemistry of opening,
had only a modest effect on the product distribution,
leading to a 1:1 ratio of 41 and 42. Therefore, the
synthesis of 22 was completed from the more readily
available 43.
The route to 22 (Scheme 11) closely paralleled the
synthesis of 7 shown in Scheme 4. Reductive cleavage
of both the benzylic ether and ester substituents in 43
by hydrogenolysis with palladium hydroxide gave hy-
droxy phenylacetamide 45 in quantitative yield. Nitro-
phenylselenation of the primary alcohol in 45 followed
by in situ oxidative elimination furnished alkene 46 in
95% yield. Stereoselective osmylation of the exocyclic
alkene in 46 using OsO4-N-methylmorpholine N-oxide
gave diol 47, which was additionally characterized as its
pentaacetate ester 48 (65% yield). Acidic hydrolysis of
48 furnished aminocyclopentitol (+)-22 (87%), whose
F or m a l Tota l Syn th esis of (+)-Tr eh a zolin
To investigate an alternative approach to aminocyclo-
pentitol 22 for the synthesis of trehazolin, the effect of
(26) (a) Franks, J . A., J r.; Tolbert, B.; Steyn, R.; Sable, H. Z. J . Org.
Chem. 1965, 30, 1440-1446. (b) Tolbert, B.; Steyn, R.; Franks, J . A.,
J r.; Sable H. Z. Carbohydr. Res. 1967, 5, 62-81.

Enantioselective Approaches to Aminocyclopentitols
J . Org. Chem., Vol. 63, No. 10, 1998 3407
H), 4.52 (s, 2H), 3.70-3.57 (m, 3 H), 3.30 (d, 1 H, J ) 3.4 Hz),
2.67 (d, 1 H, J ) 5.9 Hz), 2.19-2.13 (m, 1 H); 13C NMR (CDCl3,
100 MHz) δ 172.1, 139.4, 137.8, 135.6, 132.7, 128.6, 128.4,
127.7, 127.6, 126.7, 78.3, 74.0, 73.1, 70.5, 56.2, 55.9; IR (CDCl3)
3600, 3400, 3100, 3050, 2750, 1660, 1525, 1100 cm-1; HRMS
(FAB) for C21H24NO4 (M + 1) calcd 354.1705, found 354.1701.
Syn th esis of Dia ceta te 12. To a room-temperature solu-
tion of 10 (80 mg, 0.28 mmol) in pyridine (1.5 mL) were added
4-(dimethylamino)pyridine (DMAP, 8 mg, 0.07 mmol) and
acetic anhydride (0.20 mL, 2.12 mmol) under Ar. After the
mixture was stirred for 20 h, the solvent was removed and
the residue was purified by silica gel column (hexanes/EtOAc
Sch em e 11
2:1) to give diacetate 12 (98 mg, 100%) as a clear oil: [R]25
D
1
+53.2° (c 0.5, CH3OH); H NMR (CDCl3, 300 MHz) δ 7.49-
7.22 (m, 10 H), 6.26 (d, 1 H, J ) 8.1 Hz), 6.06 (s, 1 H), 6.00-
5.87 (m, 2 H), 5.54 (d, 1 H, J ) 3.1 Hz), 4.90-4.80 (m, 1 H),
4.51 (s, 2 H), 3.75-3.58 (m, 2 H), 2.30-2.19 (m, 1 H), 2.17,
2.05 (2 s, each 3 H); 13C NMR (CDCl3, 75 MHz) δ 170.5, 169.0,
167.7, 138.1, 135.4, 135.3, 132.6, 129.0, 128.7, 128.3, 127.5,
127.4, 127.3, 79.9, 75.4, 73.2, 69.6, 56.0, 53.1, 21.1, 21.0; IR
(CHCl3) 3410, 3070, 3040, 1730, 1675 cm-1; FABMS m/e 438
(M + 1, 35), 378 (M + 1 - HOAc, 100%).
Osm yla tion of 12: Syn th esis of 14. To a solution of
diacetate 12 (245 mg, 0.55 mmol) and N-methylmorpholine
N-oxide (130 mg, 1.10 mmol) in 10:1 acetone/H2O (11 mL) at
0 °C was added OsO4 (0.35 mL, 5% w/w in H2O). The reaction
was slowly warmed to room temperature and monitored by
TLC. After 48 h, NaHSO3 (0.57 g, 5.50 mmol) in H2O (10 mL)
was added, and the mixture was stirred for 4 h at room
temperature. The acetone was removed under reduced pres-
sure, and the aqueous residue was extracted with CH2Cl2 (4
× 20 mL). The organic layers were combined, washed with
brine, dried over MgSO4, and concentrated in vacuo. The
crude product was dissolved in pyridine (4 mL) and treated
with DMAP (13 mg, 0.11 mmol) and acetic anhydride (0.52
mL, 5.5 mmol) under Ar. The resulting solution was stirred
at room temperature for 24 h and concentrated in vacuo. The
residue was flash chromatographed (2:1 hexanes/EtOAc) to
give tetraacetates 14 (256 mg, 82%) and 15 (52 mg, 16%) as
spectral and physical properties were in agreement with
earlier reported values. Since this unprotected aminocy-
clitol has previously been converted to (+)-trehazolin,12b
a formal total synthesis of 4 was thus achieved.
Con clu sion
In summary, we have shown that the asymmetric
cycloaddition of 1-substituted-2,4-cyclopentadienes with
heterodienophiles, which has previously been used to
construct pentasubstituted cyclopentanes, can also be
extended to the preparation of hexasubstituted cyclopen-
tanes featuring quaternary carbon centers. An enanti-
oselective synthesis of (+)-6-epitrehazolin from thallous
cyclopentadienide was achieved in 14 steps and 11%
overall yield. Aminocyclopentitol (+)-22 was similarly
prepared from 8 in 11 steps, constituting a formal total
synthesis of (+)-trehazolin.
clear oils. For 14: [R]25 +28.7° (c 1.0, CH2Cl2); 1H NMR
D
(CDCl3, 300 MHz) δ 7.50-7.22 (m, 10 H), 6.32 (d, 1 H, J ) 8.3
Hz), 6.06 (s, 1 H), 5.37 (t, 1 H, J ) 4.4 Hz), 5.28-5.18 (m, 2
H), 4.64-4.42 (m, 3 H), 3.59 (ddd, 2 H, J ) 3.8, 9.3, 13 Hz),
2.35-2.22 (m, 1 H), 2.19 (s, 3 H), 2.03, 2.01, 1.93 (3 s, each 3
H); 13C NMR (CDCl3, 75 MHz) δ 169.8, 169.1, 168.9, 168.8,
167.6, 137.8, 135.2, 129.2, 128.9, 128.3, 127.6, 127.6, 75.3, 73.4,
72.4, 71.4, 70.6, 68.2, 50.5, 50.0, 20.9, 20.6, 20.5, 20.3; IR
(CDCl3) 3450, 2870, 1760, 1680 cm-1; MS (FAB) 556, 496, 468,
309; HRMS (FAB) for C29H34NO10 (M + 1), calcd 556.2183,
found 556.2185.
Hyd r ogen olysis of 14: Syn th esis of 16. To a solution of
14 (256 mg, 0.46 mmol) in absolute ethanol (50 mL) was added
Pd(OH)2 on carbon (50 mg). The system was flushed with
hydrogen and the reaction mixture stirred under a balloon of
hydrogen. After 8 h at room temperature, ethyl acetate (25
mL) was added, and the mixture was filtered through Celite.
The filtrate was concentrated in vacuo to give 16 (187 mg,
100%) as a white solid: [R]25D +15.0° (c 1.0, CH2Cl2); 1H NMR
(CDCl3, 300 MHz) δ 7.49-7.21 (m, 5 H), 5.95 (d, 1 H, J ) 7.8
Hz), 5.31 (t, 1 H, J ) 4.2 Hz), 5.15 (dd, 1 H, J ) 3.7, 6.8 Hz),
4.93 (dd, 1 H, J ) 5.0, 7.8 Hz), 4.30 (dd, 1 H, J ) 7.6, 15.3
Hz), 3.75-3.55 (m, 2 H), 2.21-2.11 (m, 1 H), 2.00, 1.89 (2 s,
each 3 H), 1.88 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 171.4,
170.1, 169.1, 168.8, 134.3, 129.6, 129.2, 127.7, 71.5, 70.8, 70.4,
61.3, 53.4, 50.1, 43.5, 20.5, 20.3, 20.2; IR (CDCl3) 3430, 2920,
1750, 1650 cm-1; FABMS m/e 408 (M + 1, 100).
Exp er im en ta l Section 27
Syn th esis of Tr isu bstitu ted Cyclop en ten e 11. (Benzyl-
oxy)methyl chloride (PhCH2OCH2Cl, 3.48 g, 22.3 mmol) was
added dropwise to a suspension of freshly sublimed cyclopen-
tentadienylthallium (4 g, 14.8 mmol) in diethyl ether (150 mL)
at -30 °C under Ar, and the mixture was stirred for 30 h at
-20 °C. The suspension was rapidly filtered at -30 °C into a
500 mL flask, and to the resulting yellow filtrate were added
n-Bu4NIO4 (6.44 g, 14. 87 mmol) and cold methanol (50 mL).
The mixture was warmed to -20 °C, and a solution of (S)-
mandelohydroxamic acid (2.48 g, 14.8 mmol) in methanol (20
mL) was added dropwise under Ar. The reaction mixture was
stirred at -20 °C for 24 h and then slowly warmed to room
temperature over 20 h and filtered through a short silica gel
column. The filtrate was concentrated to give impure 10 (5
g), which was carried on directly to the next step.
To a suspension of 10 and Na2HPO4 (10.1 g) in 2:1 THF/
methanol (120 mL) at 0 °C was added sodium amalgam (22 g,
6% w/w). After the mixture was stirred for 8 h at 0 °C, 1:1
THF/EtOAc (200 mL) was added, and the mixture was filtered
through Celite. The filtrate was concentrated in vacuo and
purified by silica gel chromatography (50:1 CH2Cl2/CH3OH)
Deh yd r a tion of 16: Syn th esis of 17. To a solution of
alcohol 16 (124 mg, 0.30 mmol) and o-nitrophenylselenocyan-
ate (138 mg, 0.61 mmol) in dry THF (3 mL) at room temper-
ature was added n-Bu3P (148 mg, 0.73 mmol 182 µL) dropwise
under Ar. After 4 h, the solvent was removed in vacuo, and
the residue was filtered through a short column of silica gel
eluting with 1:1 hexanes/EtOAc to afford impure selenide (162
mg), which was immediately dissolved in THF (3 mL) and
treated with H2O2 (0.13 mL, 30% w/w) dropwise at room
to give 11 (1.98 g, 40% for three steps) as a clear oil: [R]25
D
1
+25.7° (c 0.3, CH3OH); H NMR (CDCl3, 300 MHz) δ 7.41-
7.25 (m, 10 H), 6.36 (d, 1 H, J ) 7.8 Hz), 5.97-5.91 (m, 1 H),
5.70-5.65 (m, 1 H), 5.01 (d, 1 H, J ) 3.3 Hz), 4.59-4.51 (m, 3
(27) For general experimental procedures, see ref 19.

3408 J . Org. Chem., Vol. 63, No. 10, 1998
Li et al.
temperature. After 5 h, the solvent was removed at reduced
pressure, and the residue was flash chromatographed (1:1
hexanes/EtOAc) to afford methylenecyclopentane 17 (100 mg,
84% from 16) as a syrup: [R]25D -21.3° (c 1.9, CH2Cl2); 1H NMR
(CDCl3, 300 MHz) δ 7.45-7.22 (m, 5 H), 5.55-5.65 (m, 2 H),
5.41-5.36 (m, 2 H), 5.31 (dd, 1 H, J ) 3.7, 4.8 Hz), 5.24 (dd,
1 H, J ) 3.3, 5.8 Hz), 5.17-5.07 (m, 1 H), 3.66 (s, 2 H), 2.05,
1.91, 1.87 (3 s, each 3 H); 13C NMR (CDCl3, 75 MHz) δ 170.5,
169.6, 169.1, 169.0, 145.5, 134.5, 129.5, 129.0, 127.5, 115.7,
70.9, 70.3, 70.2, 50.1, 43.8, 20.6, 20.34, 20.32; IR (CDCl3) 3460,
2920, 1750, 1670 cm-1; FABMS m/e 390 (M + 1).
137.3, 137.1, 128.5, 128.4, 128.4, 128.3, 128.2, 128.0, 128.0,
127.9, 127.6, 83.8, 82.3, 81.6, 78.4, 77.5, 76.5, 76.5, 75.6, 75.0,
73.8, 73.4, 72.3, 69.8, 69.2, 62.4; IR (film) 3350, 1660, 1550
cm-1; FABMS m/e 727 (M + 1, 100).
H yd r ogen olysis of 21: Syn t h esis of 6-E p it r eh a zolin
(5). To a solution of 21 (40 mg, 0.055 mmol) in dry EtOH (5
mL) was added Pd(OH)2 on carbon (200 mg), and the mixture
was stirred under hydrogen (1 atm) at room temperature for
24 h. The reaction was filtered through Celite, and the filtrate
was concentrated. The impure product was chromatographed
on Dowex 50WX 2-200 and eluted with deionized water and
0.5 N aqueous ammonia. The desired product was contained
in the first few fractions, which were lyophilized to afford
Osm yla tion of 17: Syn th esis of 19. Aqueous OsO4 (0.32
mL, 5% w/w in H2O) was added to a solution of methylenecy-
clopentane 17 (130 mg, 0.33 mmol) and N-methylmorpholine
N-oxide (117 mg, 1.10 mmol) in 10:1 acetone/H2O (6.6 mL) at
0 °C. The reaction was warmed to room temperature and
monitored by TLC. After 36 h, the solvent was removed in
vacuo, and the resulting cyclopentanediol was dissolved in
pyridine (3 mL) to which were added DMAP (16 mg, 0.13
mmol) and acetic anhydride (0.50 mL, 5.3 mmol) under Ar.
The solution was stirred at room temperature for 24 h and
then concentrated in vacuo. The residue was flash chromato-
graphed (1:1 hexanes/EtOAc) to afford pentaacetate 19 (163
6-epitrehazolin ((+)-5) as a white solid (17 mg, 82%): [R]25
D
+135.6° (c 0.67, H2O) (lit.9b [R]D +130°); H NMR (D2O, 500
1
MHz) δ 5.14 (d, 1 H, J ) 5.5 Hz), 4.89 (dd, 1 H, J ) 6.5, 6.5
Hz), 4.28 (dd, 1 H, J ) 4.5, 5.5 Hz), 3.99 (d, 1 H, J ) 7.5 Hz),
3.74, 3.78 (AB q, 2 H, J ) 3.5, 12.5 Hz), 3.67-3.53 (m, 3 H),
3.49 (dd, 1 H, J ) 9.0, 10.0 Hz), 3.39 (m, 1 H), 3.23 (dd, 1 H,
J ) 9.0, 10.0); 13C NMR (D2O, 75 MHz) δ 161.0, 83.4, 82.3,
80.4, 75.8, 72.9, 72.6, 71.7, 69.8, 69.5, 61.5, 60.5; IR (KBr) 3370,
2930, 1670 cm-1; FABMS m/e 367 (M + 1, 55), 119 (100).
Syn th esis of Br om oh yd r in 26. N-Bromosuccinimide (378
mg, 2.1 mmol) was added to a solution of cyclopentene 11 (626
mg, 1.8 mmol) in 1,4-dioxane (50 mL) and H2O (5 mL) at room
temperature. After the reaction mixture was stirred at room
temperature for 18 h, the solvents were removed in vacuo, and
the residue was purified by flash chromatography on silica gel
(10:1 CH2Cl2/CH3OH) to afford 26 (677 mg, 85%) as a white
solid: mp 128-135 °C; 1H NMR (acetone-d6, 500 MHz) δ 7.61
(d, 1 H, J ) 7.0 Hz), 7.48 (d, 2 H, J ) 6.5 Hz), 7.35-7.20 (m,
8 H), 5.31 (d, 1 H, J ) 4.5 Hz), 5.07 (d, 1 H, J ) 4.5 Hz), 4.96
(d, 1 H, J ) 5.0 Hz), 4.61 (d, 1 H, J ) 6.0 Hz), 4.34 (m, 1 H),
4.42 (s, 2 H), 4.18 (m, 1 H), 4.22 (m, 1 H), 4.00 (dd, 1 H, J )
5.5, 6.5 Hz), 3.62 (dd, 1 H, J ) 4.0, 9.5 Hz), 3.54 (dd, 1 H, J )
4.0, 9.5 Hz), 2.15 (m, 1 H); 13C NMR (acetone-d6, 75 MHz) δ
173.2, 141.9, 139.6, 128.9, 128.8, 128.3, 128.2, 127.5, 78.1, 77.3,
74.8, 73.6, 68.8, 61.6, 51.9, 51.2; IR (film) 3400, 1710, 1670
cm-1; HRMS (FAB) for C21H25BrNO5 (M + 1) calcd 450.0916,
found 450.0916.
mg, 96%) as a syrup: [R]25 -9.1° (c 2.0, CH2Cl2); 1H NMR
D
(CDCl3, 300 MHz) δ 7.50-7.24 (m, 5 H), 5.82 (d, 1 H, J ) 10.0
Hz), 5.57 (d, 1 H, J ) 5 Hz), 5.50 (t, 1 H, J ) 4.6 Hz), 5.37 (dd,
1 H, J ) 4.3, 6.9 Hz), 5.11 (dd, 1 H, J ) 6.8, 10.0 Hz), 4.37,
4.49 (AB q, 2 H, J ) 12.5 Hz), 3.59, 3.66 (AB q, 2 H, J ) 16.6
Hz), 2.09, 2.06, 1.96, 1.94, 1.75 (5 s, each 3 H); 13C NMR
(CDCl3, 100 MHz) δ 170.4, 170.2, 169.9, 168.6, 168.4, 168.3,
134.2, 129.6, 129.1, 127.6, 87.7, 73.8, 71.6, 68.5, 60.3, 54.9, 43.7,
21.5, 20.6, 20.1, 20.1, 20.0; IR (CDCl3) 3450, 2925, 1760, 1680
cm-1; FABMS (M + 1) 508.3; HRMS (FAB) for C24H30NO11 (M
+ 1) calcd 508.1819, found 508.1822.
Hyd r olysis of 19: Syn th esis of 7. A solution of pentaac-
etate 19 (158 mg, 0.31 mmol) in anhydrous HCl-CH3OH (0.5
M, 5 mL) was stirred and heated at 90 °C in a sealed tube for
24 h. The solvent was removed in vacuo, and the residue was
dissolved in H2O (2.5 mL) and then extracted with ether (3 ×
2.5 mL) and ethyl acetate (1 × 2.5 mL). The aqueous layer
was lyophilized to afford 7‚HCl (64 mg, 96%) as a syrup: [R]25
Syn th esis of Br om otr ia ceta te 27. A mixture of bromo-
hydrin 26 (761 mg, 1.7 mmol), acetic anhydride (15 mL), and
DMAP (30 mg, 0.25 mmol) was stirred overnight. The mixture
was concentrated in vacuo at room temperature to give a
brown solid that was purified by flash chromatography on
silica gel (20:1 CH2Cl2/CH3OH) to afford 27 (916 mg, 94%) as
D
1
) -13.0° (c 2.0, CH3OH); H NMR (D2O, 300 MHz) δ 4.27 (t,
1 H, J ) 5.9 Hz), 4.11 (t, 1 H, J ) 4.9 Hz), 3.82 (d, 1 H, J )
4.6 Hz), 3.72 (s, 2 H), 3.41 (d, 1 H, J ) 6.4 Hz); 13C NMR (D2O,
100 MHz) δ 80.6, 77.8, 72.2, 68.5, 62.7, 59.9; IR (film) 3300
cm-1; FABMS m/e 180 (M + 1).
1
Cou p lin g of 7 w ith Isoth iocya n a te 6: Syn th esis of 20.
Isocyanate 6 (118 mg, 0.20 mmol) in THF (1.5 mL) was added
to a solution of 7‚HCl (29 mg, 0.14 mmol) and Et3N (0.1 mL)
in 10:3 THF/H2O (1.3 mL). The reaction was stirred at room
temperature for 4 h, and the solvent was removed in vacuo.
The residue was flash chromatographed (25:2 CH2Cl2/CH3OH)
a white solid: mp 114-115 °C; H NMR (CDCl3, 300 MHz) δ
7.50-7.25 (m, 10 H), 6.28 (d, 1 H, J ) 7.5 Hz), 6.01 (s, 1 H),
5.35-5.15 (m, 2 H), 4.57 (m, 1 H), 4.49 (s, 2 H), 4.16 (t, 1 H,
J ) 4.5 Hz), 3.59 (d, 2 H, J ) 5.1 Hz), 2.43 (m, 1 H), 2.16,
2.05, 1.93 (3 s, each 3 H); 13C NMR (CDCl3, 75 MHz) δ 169.8,
169.2, 169.1, 168.1, 137.7, 135.0, 129.1, 128.8, 128.3, 127.6,
127.5, 127.3, 79.5, 78.0, 75.2, 73.4, 69.0, 51.5, 50.0, 49.2, 20.8,
to give thiourea 20 (81 mg, 80%) as a syrup: [R]25 +140.4° (c
D
1.0, CH2Cl2); H NMR (CDCl3, 300 MHz) δ 7.72 (d, 1 H, J )
20.3; IR (film) 3300, 1750, 1620, 1590 cm-1; [R]25 +17.2° (c
1
D
7.4 Hz), 7.38-7.18 (m, 20 H), 7.07-7.14 (m, 2 H), 6.87 (br, 1
H), 5.20 (bs, 1 H), 4.71-4.96 (m, 4 H), 4.62 (s, 2 H), 4.56-4.38
(m, 4 H), 4.13 (bs, 2 H), 4.02-3.83 (m, 3 H), 3.43-3.82 (m, 10
H); 13C NMR (CDCl3, 75 MHz) δ 184.2, 138.1, 137.6, 137.1,
136.7, 128.6, 128.4, 128.4, 128.4, 128.3, 128.2, 128.1, 127.9,
127.9, 127.8, 127.8, 83.0, 81.6, 79.4, 78.8, 76.9 75.9, 75.1, 73.4,
73.1, 72.4, 71.1, 70.4, 68.3, 64.6, 63.3; IR (film) 3400, 3350,
1525 cm-1; FABMS m/e 761 (M + 1, 100).
1.1, CH2Cl2); HRMS (FAB) for C27H31BrNO8 (M + 1) calcd
576.1233, found 576.1230.
Deben zyla tion of 27: Syn th esis of 28. Benzyl ether 27
(343 mg, 0.60 mmol) was dissolved in anhydrous EtOH (25
mL), and Pd(OH)2 on carbon (110 mg, Aldrich) was added. The
solution was stirred at room temperature under a balloon of
hydrogen for 4 h and then filtered through Celite and solvent
removed to afford 318 mg of impure product. Purification by
flash chromatography on silica gel (1:1 hexanes/EtOAc) af-
forded 28 (252 mg, 99%) as a white foam: 1H NMR (CDCl3,
300 MHz) δ 7.50-7.20 (m, 5 H), 5.77 (d, 1 H, J ) 8.1 Hz), 5.18
(dd, 1 H, J ) 3.9, 6.9 Hz), 5.07 (dd, 1 H, J ) 2.7, 5.4 Hz), 4.63
(ddd, 1 H, J ) 5.4, 8.4, 10.2 Hz), 3.97 (dd, 1 H, J ) 2.7, 3.9
Hz), 3.69 (d, 2 H, J ) 4.2 Hz), 3.64 (s, 2 H), 2.05 (m, 1 H),
2.05, 1.87 (2 s, each 3 H); 13C NMR (CDCl3, 75 MHz) δ 171.9,
170.0, 169.1, 134.2, 129.5, 129.3, 127.7, 79.7, 79.3, 60.1, 52.5,
Cycliza t ion of 20: Syn t h esis of 21. Freshly prepared
yellow HgO (3 g, 14.4 mmol) was added in three portions to a
solution of thiourea 20 in 5:1 ether/THF (6 mL) at room
temperature. The reaction was stirred at room temperature
for 2 d, and then the mixture was filtered through Celite. After
the filtrate was concentrated, the residue was purified by silica
gel chromatography (10:1 CH2Cl2/CH3OH) to afford aminoox-
azoline 21: [R]25D +91.0° (c 1.0, CH2Cl2); 1H NMR (CDCl3, 300
MHz) δ 7.38-7.18 (m, 20 H), 7.10-7.00 (m, 2 H), 5.31 (d, 1 H,
J ) 4.6 Hz), 4.91 (d, 1 H, J ) 10.9 Hz), 4.80-4.70 (m, 3 H),
4.66-4.34 (m, 6 H), 4.32 (t, 1 H, J ) 4.3 Hz), 4.12 (d, 1 H, J )
6.4 Hz), 4.04-3.70 (m, 5 H), 3.50-3.69 (m, 2 H), 3.45-3.23
(m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 160.2, 137.7, 137.4,
50.0, 49.7, 43.5, 20.7, 20.3; IR (film) (3500, 1750, 1680 cm-1
;
[R]25 -11.9° (c 0.5, CH2Cl2); HRMS (FAB) for C18H23BrNO6
D
(M + 1) calcd 428.0709, found 428.0706.
Deh yd r a tion of 28: Syn th esis of 29. To a mixture of
alcohol 28 (170 mg, 0.40 mmol) in anhydrous THF (20 mL)

Enantioselective Approaches to Aminocyclopentitols
J . Org. Chem., Vol. 63, No. 10, 1998 3409
stirring over 4 Å molecular sieves (1 g) was added 2-nitrophen-
yl selenocyanate (136 mg, 0.60 mmol). The reaction mixture
was stirred under argon while n-Bu3P (150 µL, 0.60 mmol)
was added dropwise. After being stirred overnight at room
temperature, the intermediate selenide was treated with 30%
H2O2 (0.7 mL) at room temperature for 50 h. The reaction
mixture was filtered through Celite and the filtrate concen-
trated in vacuo. Purification of the impure alkene by flash
chromatography afforded 29 (124 mg, 80%) as a white solid:
Closu r e of 32 to Ep oxid e 33. Finely powdered K2CO3 (30
mg) was added to a solution of bromohydrin 32 (4 mg, 0.005
mmol) in CH3OH (2 mL). The heterogeneous reaction mixture
was stirred at room temperature for 60 h, and the solvent was
removed in vacuo. After the residue was triturated with CH2-
Cl2, the solvent was removed in vacuo and the soluble residue
purified by flash chromatography to give epoxide 33 (3 mg,
81%): 1H NMR (CDCl3, 500 MHz) δ 7.40-7.10 (m, 20 H), 4.97
(d, 1 H, J ) 9.0 Hz), 4.91 (d, 1 H, J ) 11.0 Hz), 4.85 (d, 1 H,
J ) 11.0 Hz), 4.80 (d, 1 H, J ) 10.5 Hz), 3.36 (t, 1 H, J ) 9.0
Hz), 3.80-3.50 (m, 8 H), 4.02 (d, 1 H, J ) 10.5 Hz), 4.79 (d, 1
H, J ) 11.0 Hz), 4.75 (d, 1 H, J ) 11.5 Hz), 4.58 (d, 1 H, J )
12.5 Hz), 4.50 (d, 1 H, J ) 11.0 Hz), 4.48 (d, 1 H, J ) 11.5 Hz),
4.40 (d, 1 H, J ) 1.5 Hz), 4.20 (d, 1 H, J ) 11.5 Hz); IR (film)
3400, 2750, 1700, 1080 cm-1; FABMS m/e 709 (M + 1, 100).
Ep oxid a tion of 11: Syn th esis of 35. To a solution of
cyclopentene 11 (636 mg, 1.80 mmol) in 1,4-dioxane (20 mL)
was added m-CPBA (374 mg, 2.16 mmol) at room temperature.
The reaction mixture was stirred at room temperature over-
night and the solvent was removed in vacuo. The residue was
purified by flash chromatography on silica gel to give 35 (637
mg, 96%) as an oil: 1H NMR (CDCl3, 300 MHz) δ 7.42-7.25
(m, 10 H), 6.58 (d, 1 H, J ) 7.5 Hz), 5.06 (d, 1 H, J ) 3.6 Hz),
4.47 (s, 2 H), 4.31 (dt, 1 H, J ) 8.4, 1.5 Hz), 4.10 (dt, 1 H, J )
8.1, 1.4 Hz), 3.61-3.42 (m, 4 H) 3.22 (d, 1 H, J ) 3.3 Hz), 2.17
(d, 1 H, J ) 6.6 Hz), 1.61 (m, 1 H); 13C NMR (CDCl3, 75 MHz)
δ 172.4, 139.2, 137.7, 128.8, 128.6, 128.4, 127.8, 127.6, 126.7,
74.3, 73.9, 73.4, 68.6, 57.3, 56.1, 50.6, 45.7; IR (film) 3300, 1650,
1500 cm-1; FABMS m/e 370 (M + 1, 98), 119 (100%).
1
mp 128-130 °C; H NMR (CDCl3, 500 MHz) δ 7.40-7.20 (m,
5 H), 5.66 (s, 1 H), 5.49 (d, 1 H, J ) 5.4 Hz), 5.45 (m, 1 H),
5.37 (t, 1 H, J ) 2.4 Hz), 5.24 (t, 1 H, J ) 2.1 Hz), 5.12 (dd, 1
H, J ) 2.1, 5.4 Hz), 4.03 (t, 1 H, J ) 2.1 Hz), 3.66 (s, 2 H),
2.06, 1.86 (2 s, each 3 H); 13C NMR (CDCl3, 75 MHz) δ 170.7,
169.7, 169.2, 145.2, 134.5, 129.5, 129.2, 127.6, 115.3, 78.4, 77.7,
51.7, 48.3, 43.8, 20.9, 20.5; IR (film) 3320, 1750, 1680, 1580
cm-1; HRMS (FAB) for C18H21BrNO5 (M + 1) calcd 410.0603,
found 410.0598.
Osm yla tion of 29: Syn th esis of 30. A solution of N-
methylmorpholine N-oxide (98 mg, 0.84 mmol) and 2% aqueous
OsO4 (178 µL, 5 mol %) was added to cyclopentene 29 (110
mg, 0.28 mmol) dissolved in acetone (10 mL) and H2O (1 mL).
The reaction mixture was stirred at room temperature for 40
h, and then the solvents were removed in vacuo and the
residue was combined with Ac2O (10 mL) and DMAP (20 mg).
After the mixture was stirred overnight at room temperature,
excess Ac2O was removed in vacuo and the residue purified
by flash chromatography on silica gel (1:1 hexanes/EtOAc) to
afford 30 (96 mg, 65%) as a white solid: mp 70-72 °C; [R]25
D
+8.9° (c 1.5, CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.40-7.20
(m, 5 H), 5.87 (d, 1 H, J ) 5.7 Hz), 5.61 (d, 1 H, J ) 10.2 Hz),
5.55 (dd, 1 H, J ) 6.9, 8.1 Hz), 5.34 (dd, 1 H, J ) 8.1, 9.6 Hz),
4.44, 4.24 (AB q, 2 H, J ) 12 Hz), 3.88 (dd, 1 H, J ) 6.0, 6.3
Hz), 3.65, 3.60 (AB q, 2 H, J ) 13.4 Hz), 2.08, 1.97, 1.96, 1.95
(4 s, each 3 H); 13C NMR (CDCl3, 75 MHz) δ 170.5, 170.1, 169.9.
168.9, 168.8, 134.7, 129.7, 128.1, 87.2, 79.1, 77.0, 59.9, 54.2,
49.5, 44.1, 22.0, 21.1, 20.7, 20.6; IR (film) 1750, 1700, 1650
cm-1; HRMS (CI) for C22H27NO9Br (M + 1) calcd 528.0869,
found 528.0856.
Cou p lin g of 30 w ith Isoth iocya n a te 6: Syn th esis of 31.
A mixture of tetraacetate 30 (20 mg, 0.038 mmol) and 0.5 M
HCl in CH3OH (20 mL) was heated at reflux for 60 h. The
solvent was removed in vacuo, and the residue was dissolved
in H2O (2 mL) and Et3N (30 µL) and then added to a solution
of isothiocyanate 6 (33 mg, 0.057 mmol) in THF (4 mL) with
stirring at room temperature for 5 d. Evaporation of the
solvents and purification by flash chromatography on silica
gel gave 30 (17 mg, 55%) as a yellow gum: 1H NMR (CDCl3,
500 MHz) δ 7.63-7.05 (m, 21 H), 6.76 (br, s, 1 H), 5.10 (br, s,
1 H), 4.90-4.15 (m, 11 H), 3.85-3.40 (m, 10 H); 13C NMR
(CDCl3, 75 MHz) δ 186.1, 138.4, 137.9, 137.5, 137.0, 129.0,
128.8, 128.7, 128.6, 128.5, 128.2, 128.1, 82.0, 80.9, 80.2, 79.9,
77.6, 77.1, 76.3, 75.5, 73.8, 73.7, 71.5, 68.3, 65.7, 58.9, 56.1;
IR (film) 3300 cm-1; FABMS m/e 743 (M + 1 - HBr, 50), 709
(M + 1 - HBr and H2S, 65).
Cycliza tion of 31: Syn th esis of 32. To a solution of
thiourea 31 (17 mg, 0.021 mmol) in anhydrous THF (5 mL)
were added 4 Å molecular sieves (0.5 g) and purified yellow
HgO (75 mg). The reaction mixture was protected from light,
stirred at room temperature for 16 h, and then filtered through
Celite. The solvent was removed in vacuo and the residue
purified by flash chromatography to afford 32 (14 mg, 86%)
as a white solid: [R]25D +61° (c 0.42, CH2Cl2); 1H NMR (CDCl3,
500 MHz) δ 7.35-7.05 (m, 20 H), 5.22 (d, 1 H, J ) 5.0 Hz),
4.90 (d, 1 H, J ) 11.0 Hz), 4.74 (t, 2 H, J ) 11.0 Hz), 4.68 (d,
1 H, J ) 11.5 Hz), 4.55 (d, 1 H, J ) 5.0 Hz), 4.52 (d, 1 H, J )
4.5 Hz), 4.44 (d, 1 H, J ) 10.5 Hz), 4.39 (d, 1 H, J ) 12.0 Hz),
4.36 (d, 1 H, J ) 1.5 Hz), 4.21 (d, 1 H, J ) 11.5 Hz), 4.09 (d,
1 H, J ) 11.5 Hz), 3.80-3.70 (m, 3 H), 3.66-3.50 (m, 5 H),
3.44 (d, 1 H, J ) 1.5 Hz); 13C NMR (CDCl3, 125 MHz) δ 168.4,
139.1, 138.6, 138.3, 138.2, 129.3, 129.1, 129.08, 129.06, 129.0,
128.88, 128.85, 128.7, 128.58, 128.56, 128.44, 128.36, 82.3,
79.2, 79.1, 78.6, 76.2, 75.6, 74.0, 73.9, 73.1, 71.6, 71.0, 69.2,
60.3, 56.7, 55.6; IR (film) 3450, 2900, 1700 cm-1; FABMS m/e
709 (M + 1 - HBr, 100).
Hyd r olysis of 35 to Tetr ols 39 a n d 40. To an ice-cold
suspension of epoxide 35 (180 mg, 0.49 mmol) in water (2 mL)
was added CF3CO2H (1.0 mL), and the resulting mixture was
stirred at 0 °C for 1 h and then warmed to room temperature.
When TLC analysis indicated that no starting material
remained (48 h at room temperature), the solvents were
removed in vacuo and the residue was dissolved in 5:1 CH2-
Cl2/CH3OH (10 mL) containing suspended NaHCO3 (0.5 g).
After filtration through Celite, the organic phase was concen-
trated and the residue was purified by flash chromatography
(20:1 CH2Cl2/CH3OH) to afford 39 (62 mg, 32%) and 40 (103
mg, 52%) as pale oils. Because of low solubility and broad
NMR line widths, both 39 and 40 were directly acetylated
(pyridine, 20 equiv of Ac2O, 0.4 equiv DMAP) and character-
ized as the corresponding peracetates 43 (93% yield) and 44
(90% yield). For 43: 1H NMR (CDCl3, 300 MHz) δ 7.40-7.31
(m, 10 H), 6.33 (d, NH, J ) 7.5 Hz), 6.01 (s, 1 H), 5.18-5.16
(m, 2 H), 5.07-5.03 (m, 1 H), 4.47 (br d, 2 H), 4.42-4.46 (m,
1 H), 3.56 (d, 2 H, J ) 4.5 Hz), 2.38-2.35 (m, 1 H), 2.17, 2.03,
2.02, 1.94 (4 s, each 3 H); 13C NMR (CDCl3, 100 MHz) δ 170.2,
169.8, 169.2, 169.0, 168.1, 137.8, 135.2, 129.1, 128.9, 128.4,
127.7, 127.4, 79.2, 76.4, 75.3, 74.9, 73.5, 68.6, 51.1, 47.9, 20.9,
20.8, 20.7, 20.5; IR (film) 3450, 1750, 1690 cm-1; FABMS m/e
556 (M + 1, 38), 119 (100). For 44: 1H NMR (CDCl3, 300 MHz)
δ 7.45-7.30 (m, 10 H), 6.88 (d, NH, J ) 6 Hz), 6.01 (s, 1 H),
5.40-5.24 (m, 3 H), 4.57, 4.48 (AB q, 2 H, J ) 12 Hz), 4.14 (br
q, 1 H), 3.75, 3.64 (ABX, J ) 3.6, 3.9, 9.0 Hz), 2.24 (s 3 H),
2.19-2.10 (m, 1 H), 2.06, 2.04, 2.03 (3 s, each 3 H); 13C NMR
(CDCl3, 100 MHz) δ 171.8, 169.7, 169.5, 169.4, 169.1, 138.0,
135.2, 129.0, 128.8, 128.3, 127.5, 127.2, 77.6, 75.3, 73.4, 72.6,
72.5, 69.1, 53.2, 49.3, 21.0, 20.84, 20.80, 20.6; IR (film) 3400,
1745, 1675 cm-1; FABMS m/e 556 (M + 1, 100).
Hyd r ogen olysis of 43 to Alcoh ol 45. A mixture of benzyl
ether 43 (163 mg, 0.29 mmol), anhydrous ethyl alcohol (10 mL),
and Pd(OH)2 on carbon (Pearlman’s catalyst, 25 mg) was
stirred under a balloon of hydrogen at room temperature for
4 h. The reaction mixture was filtered through Celite and
solvent evaporated to afford 45 (120 mg, quantitative), which
was used without further purification in the next reaction. For
analytical purposes, a sample of the product was purified by
flash chromatography on silica gel to give 45 as a white solid:
1H NMR (CDCl3, 300 MHz) δ 7.43-7.32 (m, 3 H), 7.29-7.21
(m, 2 H); 5.75 (d, NH, J ) 8.4 Hz), 5.10-4.97 (m, 3 H), 4.49-
4.39 (br m, 1 H), 3.63 (s, 2 H), 3.60 (d, 2 H, J ) 5.4 Hz), 2.10-
1.98 (br m, 1 H), 2.06, 2.05, 1.86 (3 s, each 3 H); 13C NMR
(CDCl3, 100 MHz) δ 172.0, 170.2, 169.5, 168.9, 134.0, 129.5,

3410 J . Org. Chem., Vol. 63, No. 10, 1998
Li et al.
129.2, 127.7, 79.6, 75.6, 75.1, 57.9, 49.9, 48.3, 43.3, 20.7, 20.6,
20.4; IR (film) 3580-3400, 1750, 1660 cm-1; FABMS m/e 408
(M + 1, 100).
(dd, 1 H, J ) 4.6, 5.4 Hz), 4.41, 4.28 (AB q, 2 H, J ) 12 Hz),
3.66, 3.60 (AB q, 2 H, d, J ) 16.8 Hz), 2.07, 2.04, 1.97, 1.94,
1.92 (5 s, each 3 H); 13C NMR (CDCl3, 100 MHz) δ 170.6, 170.1,
169.9, 169.8, 169.1, 134.6, 129.8, 129.5, 128.0, 87.0, 79.2, 75.8,
73.4, 59.6, 52.5, 43.9, 21.9, 21.0, 20.9, 20.8, 20.6; IR (film) 1750,
1700 cm-1; HRMS (CI) for C24H30NO11 (M + 1) calcd 508.1819,
found 508.1813.
Syn th esis of Am in ocyclop en titol 22. A solution of
pentaacetate 48 (18 mg, 0.036 mmol) in 0.5 M HCl/MeOH (0.5
mL) was heated to reflux for 4 d. The solvent was removed in
vacuo and the residue dried in vacuo overnight to afford
aminocyclopentitol 22‚HCl as a white solid (5 mg, 87%). The
1H and 13C NMR spectral data of 22, as well as of its
hexaacetylated derivative, matched values previously reported
by Shiozaki.12b In addition, the specific rotation of 22‚HCl
[+2.1° (c 0.2, H2O)] was in good agreement with the values
previously reported for both synthetic [+1.7° (c 0.41, H2O)] and
naturally derived [4.5° (c 1.1, H2O)] samples.12b
Deh yd r a tion of 45: Syn th esis of 46. To a solution of
alcohol 45 (119 mg, 0.29 mmol) and 2-nitrophenyl selenocy-
anate (132 mg, 0.58 mmol) in anhydrous THF (5 mL) stirring
over 4 Å molecular sieves (1 g) under argon was added
tributylphosphine (175 µL, 0.70 mmol) dropwise via syringe.
After 4 h at room temperature, the solvent was evaporated
and the residue filtered through a plug of silica gel to elute
the intermediate selenide, which was dissolved in THF (5 mL)
and treated with 30% H2O2 (164 µL, 1.4 mmol) for 5 h at room
temperature. Solvent evaporation followed by flash chroma-
tography on silica gel (1:1 hexanes/ethyl acetate) gave 46 (107
mg, 95%) as a white solid: mp 128-130 °C; [R]27 ) -53.3° (c
D
1
1.07, CH2Cl2); H NMR (CDCl3, 500 MHz) δ 7.45-7.25 (m, 5
H), 5.53 (d, 1 H, J ) 8.5 Hz), 5.48 (dd, 1 H, dd, J ) 1.0, 2.0
Hz), 5.22 (dd, 1 H, J ) 2.5, 5.5 Hz), 5.19 (dt, 1 H, J ) 3.0, 8.5
Hz), 5.09 (t, 1 H, J ) 2.5 Hz), 5.07 (dd, 1 H, J ) 2.5, 5.5 Hz),
4.99 (t, 1 H, J ) 3.0 Hz), 3.68 (d, 1 H, J ) 16.5 Hz), 3.65 (d, 1
H, J ) 16.5 Hz), 2.10, 2.09, 1.86 (3 s, each 3 H); 13C NMR
(CDCl3, 75 MHz) δ 170.9, 170.2, 169.7, 145.2, 134.8, 129.8,
129.5, 128.0, 112.7, 78.4, 75.6, 74.7, 51.7, 44.0, 21.1, 21.0, 20.8;
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (GM 35712) for generous financial
assistance, Professor Masao Shiozaki for reference
spectra, and Mr. Darren Kassab for helpful experimen-
tal assistance. Support of the Cornell Nuclear Magnetic
Resonance Facility by the NSF (CHE 7904825; PGM
8018643) and NIH (RR02002) is gratefully acknowl-
edged.
IR (film) 3320, 1750, 1680, 1580 cm-1; HRMS (CI) for C20H24
-
NO7 (M + 1) calcd 390.1553, found 390.1542.
Osm yla tion of 46: Syn th esis of P en ta a ceta te 48. To
an ice-cold solution of alkene 46 (38 mg, 0.098 mmol) in 10:1
acetone/water (1.1 mL) were added N-methylmorpholine N-
oxide (30 mg, 0.29 mmol) and 2% aqueous OsO4 (62 µL, 5 mol
%). After being stirred at room temperature for 24 h, the
reaction mixture was concentrated in vacuo, and the residue
was treated with acetic anhydride (1.0 mL) and DMAP (10
mg). The mixture was stirred at room temperature overnight,
the solvents were removed, and the residue was purified by
flash chromatography (1:1 hexanes/ethyl acetate) to afford 48
(32 mg 65%) as a clear gel: [R]26D ) +8.6° (c 0.88, CH2Cl2); 1H
NMR (CDCl3, 400 MHz) δ 7.45-7.20 (m, 5 H), 5.79 (d, 1 H, J
) 5.6 Hz), 5.68 (d, 1 H, J ) 8.8 Hz), 5.41-5.33 (m, 2 H), 5.10
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra for
5, 7, 12, 14, 16, 17, 19-21, 26-28, 30-32, 35, 43-46, 48,
and 22 and 1H NMR spectra for 29 and 33 (33 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
J O980050A