An efficient procedure for the preparation of (1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentanes

Article abstract of DOI:10.1248/cpb.51.1153

Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl) cyclopentanes have been efficiently synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucleoside analogs with important antiviral

Full text of DOI:10.1248/cpb.51.1153

October 2003
Chem. Pharm. Bull. 51(10) 1153—1156 (2003)
1153
An Efficient Procedure for the Preparation of (1S,3R)- and
(1S,3S)-1-Amino-3-(hydroxymethyl)cyclopentanes
Henry RAPOPORT,a Yuewu CHEN,a Rafat M. MOHAREB,b Jin Hee AHN,c Tae Bo SIM,d and
,e
*
Jonathan Z. HO
a Department of Chemistry, University of California; Berkeley, California 94720, U.S.A.: b Department of Chemistry,
Faculty of Science, Cairo University; Giza, A.R. 1510 Egypt: c Department of Chemistry, Medicinal Science Division, Korea
Research Institute of Chemical Technology; Taejon, 305–600 S. Korea: d Genomics Institute of the Novartis Resarch; 10675
John Jay Hopkins Drive, F219, San Diego, California 92121, U.S.A.: and e Merck & Co., Inc., 126 E. Lincoln Avenue, P.O.
Box 2000, Mail Stop RY80R, Rahway, New Jersey 07065, U.S.A. Received June 12, 2003; accepted July 14, 2003
Enantiomerically pure (1S,3S)- and (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentanes have been efficiently
synthesized from L-aspartic acid. The title compounds are isosteres of ribose and may be used to construct nucle-
oside analogs with important antiviral and antineoplastic activities as demonstrated by a concise total synthesis
of (؉)-4؅-deoxycarbapentostatin nucleoside.
Key words amino acid; heterocycle; carbocycle; enantioselectivity; nucleoside
Methods for the synthesis of carbanucleoside building
blocks have drawn considerable attention1—3) because carbo-
cyclic nucleosides exhibit greater chemical and enzymatic
stability relative to their analogs with sugar moities.4—7)
(1S,3R)- and (1S,3S)-1-amino-3-(hydroxymethyl)cyclopentane
(1, 2) (Fig. 1) have been used as ribose motifs for the prepa-
ration of many biologically active compounds, such as ino-
sine analogs,8) nucleobases for DNA polymerase,9) human
immunodeficiency virus (HIV) inhibitors,10) purine nucleo-
sides,11) thimine nucleosides,12) carbocyclic thymidines,13) and
others.14—17)
Fig. 1
Previously, compound 1 was prepared from L-aspartic acid
via 2-aminoadipic acid using a 15-step sequence with less
than 10% overall yield.18) An alternate route19) that involved
an activated aziridine intermediate resulted in a similar yield
for 1. Cyclopentane 2 was also generated as a minor product
during the synthesis of 1. To the best of our knowledge, there
is no specific preparation of (1S,3S)-1-amino-3-(hydroxy-
methyl)cyclopentane (2). In our preparation of carbapento-
statine, we developed an efficient method to synthesize enan-
tiomerically pure 4 (36% overall yield) from L-aspartic acid
derivative 3 (Chart 1).20) This prompted us to develop a pro-
cedure to use 4 as a precursor to obtaining either 1 or 2 as a
major product.
Results and Discussion
In the synthesis of 1 (Chart 1), hydrogenation of 4 led to a
1 : 1 ratio of syn and anti esters 6 and 7. Without separation,
the mixture was hydrolyzed with aqueous LiOH to form a
mixture of lithium carboxylate 8 and 9, which was treated
with acetic anhydride in the presence of sodium acetate.
Epimerization of 9 to 8 followed by cyclization to form lac-
tam 10 in an excellent yield. The Pf-group was replaced with
an N-Boc group to form lactam 11. The amide carbonyl
group of 11 had a great deal of imide character, as evidenced
by its reduction to alcohol 12 using NaBH4. Upon treatment
with HCl, compound 12 was transformed to the desired prod-
uct 1.21)
Reagents and conditions: (a) DIBAL-H, THF, 94%; (b) H2, Pd/C, MeOH, 99%,
6 : 7ϭ1 : 1; (c) LiOH, water, MeOH; (d) Ac2O, AcONa, 95% from 4; (e) Boc2O, H2,
Pt/C, MeOH, 97%, (f) NaBH4, MeOH, 91%; (g) 1.0 M HCl in ether, 99%.
Chart 1
genation with different catalysts proceeded rapidly; however,
the cis-isomer 13 was usually the predominant product ex-
cept in the case of the nickel catalyst which yielded an 18 : 82
ratio of cis : trans products. Reductions with diimide and
ionic hydrogenation with nBuSiH3 gave higher selectivity for
the trans-isomer 14 with better overall yields. Hydrogenation
of 14 with 5% Pt/C resulted in the removal of N-Pf protect-
ing group to give the desired product 2 (Table 1).
To synthesize 2, DIBAL reduction of 4 gave the allyllic al-
cohol 5 (Chart 1). A variety of reduction methods was then
attempted to convert 5 to 14 selectively (Table 1). Hydro-
The utility of 1, was demonstrated by the synthesis of
deoxycarbapentostatin (Chart 2). Protection of 12 with
To whom correspondence should be addressed. e-mail: jonathan_ho@merck.com
© 2003 Pharmaceutical Society of Japan

1154
Vol. 51, No. 10
Table 1
for 4 h. NaOH (6 M, 3 ml) was added and mixture was partitioned between
water (300 ml) and EtOAc (200 ml). Aqueous phase was extracted with
EtOAc (200 mlϫ2). Combined organic layers were washed with water
(100 ml) and brine (50 ml), dried (Na2SO4), and concentrated. The residue
was purified by flash chromatography (30% EtOAc : hexaneϭ30 : 70) to
give alcohol 5 as a thick oil (3.3 g, 93%): [a]D Ϫ4.4° (cϭ0.037, CHCl3); 1H-
NMR d: 2.01 (m, 4H), 3.07 (q, 1H, Jϭ7.7 Hz), 3.95 (s, 3H), 5.31 (m, 1H),
7.33 (m, 11H), 7.69 (d, 2H, Jϭ7.5 Hz); 13C-NMR d: 41.5, 41.6, 54.7, 62.1,
73.2, 119.8, 119.9, 123.5, 125.2, 126.2, 217.0, 127.6, 127.7, 128.0, 128.1,
128.2, 142.3, 145.3, 150.5. Anal. Calcd for C25H23NO: C, 84.95; H, 6.56; N,
3.96. Found: C, 84.64; H, 6.48; N, 3.80.
Run
Method
13 : 14
Yield of 13 (%) Yield of 14 (%)
Synthesis of (1S,3R)-1-(N-Boc-amino)-3-(hydroxymethyl)cyclopentane
(12) A slurry of 4 (4 g, 10.5 mmol), MeOH (50 ml), and 10% Pd/C (0.5 g)
was hydrogenated in a Parr shaker under 45 psi of H2 at rt for 24 h. The reac-
tion mixture was filtered, and the filtrate was evaporated to give a 1 : 1 mix-
ture (3.95 g, 99%) of cis ester 6 and trans ester 7. Lithium hydroxide (1.0 M
solution, 11 ml, 11 mmol) was added to a solution of 6 and 7 (3.95 g,
10.4 mmol) in THF (40 ml). The mixture was stirred at rt for 4 h then con-
centrated. Toluene (5 mlϫ3) was used to azeotrope water. Ac2O (50 ml) and
NaOAc (5 g, 61 mmol) were added and the mixture was heated at its reflux
temperature under nitrogen atmosphere. After 18 h, the mixture was concen-
trated then saturated NaHCO3 (100 ml) was added. The aqueous phase was
extrated with EtOAc (100 mlϫ3). The combined organic layer was washed
with brine (100 ml), dried (MgSO4), filtered, and concentrated to dryness.
Purification of this residue by flash chromatography (EtOAc : hexaneϭ
15 : 85) afforded 10 (3.4 g, 95% from 4) as a white solid (mp 222 °C; lit18)
mp 220 °C). A mixture of 10 (3.4 g, 10.0 mmol), Boc2O (3.0 g, 13.8 mmol)
and 5% Pt/C (0.5 g) was hydrogenated in a Parr shaker under 15 psi of H2 at
rt for 24 h. The reaction mixture was filtered, and filtrate was evaporated. Pu-
rification of the residue by flash chromatography (EtOAc : hexaneϭ15 : 85)
1
2
3
4
5
H2, Pd/C, MeOH
H2, Rh/C, MeOH
H2, Ni, PhH
Diimide
TFA, nBuSiH3
55 : 45
34 : 66
18 : 82
3 : 97
46
29
11
1
40
52
78
92
93
2 : 98
1
Reagents and conditions: (a) H2, Pt/C, MeOH, 98%.
1
afforded 11 (3.3 g, 97%): [a]D25 Ϫ30.3° (cϭ1.7, CHCl3); H-NMR (CDCl3)
d: 1.40 (d, Jϭ6.0 Hz, 1H), 1.52 (s, 9H), 1.78 (m, 5H), 2.84 (s, 1H), 4.52 (s,
1H); 13C-NMR (CDCl3) d: 23.8, 28.1, 28.4, 37.8, 46.7, 58.9, 149.4, 175.6;
Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.55; H,
8.31; N, 6.88. A solution of 11 (3.0 g, 14.2 mmol) in MeOH (100 ml) was
cooled in an ice bath as NaBH4 (1.1 g, 28.9 mmol) was added in 3 portions.
The mixture was warmed to room temperature and stirred for 3 h. Solvent
was evaporated under vacuum, and the mixture was partitioned between sat-
urated aq KH2PO4 (500 ml) and EtOAc (250 ml). Aqueous phase was ex-
tracted with EtOAc (200 ml) twice and combined organic layers were
washed with brine (100 ml), dried, and filtered. The filtrate was evaporated
and purified by flash chromatography (EtOAc : hexaneϭ30 : 70) to give alco-
hol 12 as an oil (2.9 g, 97%): [a]D25 Ϫ21.2° (cϭ1.3, CHCl3); 1H-NMR
(CDCl3) d: 1.11 (m, 1H), 1.38 (m, 12H), 1.69 (m, 2H), 1.92 (m, 2H), 2.13
(m, 2H), 3.70 (m, 2H); 13C-NMR (CDCl3) d: 26.3, 28.4, 33.0, 36.3, 39.8,
52.0, 66.4, 79.0, 155.6; Anal. Calcd for C11H21NO3: C, 61.37; H, 9.83; N,
6.51. Found: C, 61.28; H, 9.85; N, 6.35.
Reagents and conditions: (a) TBDPS-Cl, pyr, rt, 18 h, then 1.0 M HCl in ether, 12 h,
83%; (b) ClCH2CH2Cl, CF3CH2OH, 80 °C, 4 h, then, DMF dimethyl acetyl, 80 °C, 74%
from 15; (c) Propanedithiol, Et3N, 67%; (d) Aqueous HF (49%), 1,4-dioxane, 3 h, 72%.
Chart 2
TBDPS-Cl followed by Boc removal with HCl in ether af-
forded amine 15 which was treated with enantiomerically
pure nitrile 1620) to give imidazole 17. Treatment of 17 with
N,N-dimethylformamide dimethyl acetal yielded stable ami-
dine 18. The azide was reduced and cyclized to azepine 19,
which upon removal of the silyl groups with aqueous HF fur-
nished deoxycarbapentostatin (20).
Synthesis of (1S,3R)-1-Amino-3-(hydroxymethyl)cyclopentane (1)
A
solution of 12 (2.8 g, 13.2 mmol) in CH2Cl2 (40 ml) was cooled in an ice
bath as HCl (1.0 M solution in ether, 26.5 ml, 26.5 mmol) was added. The
mixture was stirred at room temperature for 18 h, and concentrated to a
white solid 1 (1.75 g, 99%) with 100% ee. The spectral data were identical
with those previously reported.18)
Generation Procedure for Hydrogenation A slurry of 5, MeOH
(10 ml), and catalyst (0.1 g) was hydrogenated in a Parr shaker under 45 psi
of H2 at rt for 24 h. The reaction mixture was filtered, and the filtrate was
evaporated to give an oil. The ratio of 13 : 14 in the reaction mixture was de-
termined by analytical RPHPLC (Zorbax RX C-18 column; MeCN : water :
In summary, an efficient approach to cyclopentane amino
alcohols 1 and 2 was developed using a common intermedi-
ate 4 derived from L-aspartic acid. By employing D-aspartic
acid, this route would also provide access to enantiomerically
pure (1R,3S)-, and (1R,3R)-1-amino-3-(hydroxymethyl)cy- TFAϭ49 : 51 : 0.1).
Synthesis of (1S,3R)-1-[N-(9-Phenyl-9-fluorenyl)amino]-3-cyclopen-
tanemethanol (13) and (1S,3S)-1-[N-(9-Phenyl-9-fluorenyl)amino]-3-cy-
clopentanemethanol (14) The title compounds were prepared from 5
clopentanes.
Experimental
General All reactions were conducted under a nitrogen atmosphere. All (353 mg) by the procedure mentioned above with 10% Pd/C as catalyst, and
NMR data were obtained at 400 MHz for proton and 100 MHz for carbon the ratio of 13 : 14 in the reaction mixture was 55 : 45. Compound 13 and 14
spectra, in CDCl3 unless otherwise noted, using TMS as an internal stan- were then separated by preparative RP-HPLC (Zorbax RX C-18 column;
dard. Specific rotations were measured at 25 °C. Melting points are uncor- MeCN : water : TFAϭ42 : 58 : 0.1) to give 13 (163 mg, 46%), and 14
rected. Column chromatography was performed using 230—400 mesh silica (141 mg, 40%). For compound 13: [a]D25 Ϫ7.1° (cϭ1.6, CHCl3); 1H-NMR
gel. Enantiomeric excess was determined by chiral HPLC (Chiralpak AD (CDCl3) d: 0.98 (m, 1H), 1.20 (m, 1H), 1.33 (m, 1H), 1.45 (m, 1H), 1.58 (m,
column 250ϫ4.6) with isoocratic mobile phase (hexane : isopropanolϭ 2H), 1.98 (m, 1H), 2.65 (m, 1H), 3.50 (m, 2H), 7.35 (m, 13H), 7.68 (m, 2H);
97 : 3).
Synthesis of (1S)-1-[N-(9-Phenyl-9-fluorenyl)amino]-3-(hydroxymethyl)-
13C-NMR (CDCl3) d: 25.7, 34.7, 38.8, 39.4, 84.7, 66.7, 73.1, 119.7, 119.8,
124.8, 125.5, 125.6, 125.9, 127.1, 127.7, 127.8, 127.9, 128.2, 128.3, 128.4,
140.1, 140.8, 144.8, 145.6, 150.1. Calcd for C25H25NO: C, 84.47; H, 7.09;
cyclopentene (5) A solution of DIBAL-H (1.0 M solution in THF, 21 ml,
21 mmol) was added to a solution of ester 420) (4.0 g, 10.5 mmol) in THF N, 3.94. Found: C, 84.11; H, 7.39; N, 3.66. For compound 14: [a]D25 Ϫ16.3°
(100 ml) at 0 °C, and the reaction mixture was stirred at room temperature (cϭ1.6, CHCl3); 1H-NMR (CDCl3) d: 0.94 (m, 1H), 1.18 (m, 2H), 1.39 (m,

October 2003
1155
2H), 1.72 (m, 1H), 1.82 (br s, 2H), 2.18 (m, 1H), 2.70 (m, 1H), 3.25 (d, methyl acetal (0.5 ml, 3.77 mmol) was added and the resulting mixture was
Jϭ7.0 Hz, 2H), 7.25 (m, 5H), 7.40 (m, 4H), 7.45 (d, Jϭ7.8 Hz, 2H), 7.75 (d, heated at 80 °C for 13 h. Purification by flash chromatography on SiO2
Jϭ7.5 Hz, 2H); 13C-NMR (CDCl3) d: 27.3, 35.4, 37.6, 39.9, 54.5, 67.2, (EtOAc : hexane : Et3Nϭ30 : 70 : 0.1) gave imidazole 18 (510 mg, 74% from
73.3, 119.8, 119.9, 125.1, 125.2, 125.3, 126.2, 127.0, 127.6, 127.7, 128.0,
128.1, 128.2, 140.3, 140.4, 145.5, 150.5, 150.6. Calcd for C25H25NO: C,
84.47; H, 7.09; N, 3.94. Found: C, 84.17; H, 6.99; N, 4.04.
15): [a]D25 ϩ4.8° (cϭ0.6, CHCl3); 1H-NMR (CDCl3) d: Ϫ0.10 (s, 3H), 0.01
(s, 3H), 0.85 (s, 9H), 1.05 (s, 9H), 1.45—2.30 (m, 6H), 3.30 (s, 6H), 3.35
(m, 2H), 3.64 (m, 3H), 4.50 (m, 1H), 4.82 (m, 1H), 7.12 (s, 1H), 7.19—7.66
Hydrogenation of 5 with Rh/C as a Catalyst Compounds 13 and 14 (m, 10H), 7.78 (s, 1H). Calcd for C36H55N7O2Si2: C, 64.15; H, 8.22; N,
were prepared from 5 (353 mg) by the general procedure mentioned above 14.55. Found: C, 64.50; H, 8.13; N, 14.37.
with Rh/C as catalyst, and the ratio of 13 : 14 in reaction mixture was 34 : 66.
Compound 13 and 14 were separated by preparative RP-HPLC to give 13
(102 mg, 29%), and 14 (184 mg, 52%).
Synthesis of (8R)-3-[3-(tert-Butyldiphenylylsilyl)oxy]methyl]cyclopentyl-
8-[(tert-butyldimethylsilyl)oxy]-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]-
diazepine (19) A solution of imidazole 18 (500 mg, 0.72 mmol), pro-
Hydrogenation of 5 with Re Ni as a Catalyst Compounds 13 and 14 panedithiol (0.5 ml, 5 mmol) and triethylamine (1 ml, 7.2 mmol) in methanol
were prepared from 5 (353 mg) by the general procedure mentioned above (5 ml) was heated at 50 °C. After 13 h the solvent was evaporated to give a
with Re Ni as catalyst, and the ratio of 13 : 14 in reaction mixture was yellow oil which was purified by flash chromatography (EtOAc : hexane :
18 : 82. Compound 13 and 14 were separated by preparative RP-HPLC to Et3Nϭ50 : 50 : 0.1) to afford diazepine 19 (291 mg, 67%): [a]D ϩ11.2°
give 13 (39 mg, 11%), and 14 (276 mg, 78%).
(cϭ0.5, CHCl3). 1H-NMR (CDCl3) d: 0.09 (s, 3H), 0.14 (s, 3H), 0.92 (s,
Reduction of 5 with Diimide A solution of acetic acid (1.23 ml, 9H), 1.06 (s, 9H), 1.27—2.20 (m, 6H), 3.36—3.50 (m, 3H), 3.60 (m, 3H),
21 mmol) in MeOH (10 ml) was added to a solution of 5 (353 mg, 1.0 mmol) 4.25 (m, 1H), 4.95 (m, 1H), 7.11 (s, 1H), 7.38—7.65 (m, 10H), 7.72 (s, 1H).
and dipotassium azodicarboxylate (4.1 g, 21 mmol) in MeOH (10 ml) using a Calcd for C34H50N4O2Si2: C, 67.73; H, 8.36; N, 9.29. Found: C, 67.44; H,
syringe pump over 6 h. The resulting mixture was stirred at room tempera- 8.01; N, 9.62.
ture for 18 h. Solvent was evaporated under vacuum, and the mixture was
Synthesis of (8R)-3-[3-(Hydroxymethyl)]cyclopentyl-8-hydroxy-3,6,7,8-
partitioned between saturated aq KH2PO4 (500 ml) and EtOAc (250 ml). tetrahydroimidazo[4,5-d][1,3]diazepine (20) A solution of silyl ether 19
Aqueous phase was extracted with EtOAc (200 ml) twice and combined or- (250 mg, 0.42 mmol) in 1,4-dioxane (30 ml) in a Teflon container was cooled
ganic layers were washed with brine (100 ml), dried, and filtered. The ratio by an ice bath as aqueous HF (49%, 10 ml) was added slowly. The mixture
of 13 : 14 in reaction mixture was 3 : 97. The filtrate was evaporated and 13
was stirred at rt for 3 h, diluted with CHCl3 (100 ml), and washed with satu-
and 14 were separated by preparative RP-HPLC to give 13 (3 mg, 1%), and rated aqueous Na2CO3 (200 ml). The aqueous phase was extracted with
14 (327 mg, 92%).
CHCl3/IPA (3/1, 100 mlϫ5), and the combined organic layers were dried
Reduction of 5 with nBuSiH3 A solution of nBuSiH3 in THF (0.5 M,
(Na2SO4) and concentrated to a yellow oil. Purification was effected by flash
5 ml, 2.5 mmol) was added to a solution of 5 (353 mg, 1.0 mmol) and TFA chromatography (IPA : CHCl3 : Et3Nϭ10 : 90 : 0.1) followed by RP-HPLC
(123 ml, 2 mmol) in THF (10 ml) using a syringe pump over 2 h. The result- (Zorbax RX C-18 column; MeCN : water : TFAϭ34 : 66 : 0.1) to give 20
1
ing mixture was stirred at rt for 18 h. Solvent was evaporated under vacuum, (83 mg, 72%): [a]D ϩ14.1° (cϭ0.4, CHCl3). H-NMR (CDCl3) d: 1.26 (m,
and the mixture was partitioned between saturated aq. KH2PO4 (500 ml) and 2H), 1.74 (m, 3H), 2.16 (m, 2H), 3.43 (m, 2H), 3.70 (br s, 2H), 4.02 (m, 2H),
EtOAc (250 ml). Aq phase was extracted with EtOAc (200 ml) twice and 4.77 (m, 1H), 5.10 (m, 1H), 5.60 (br s, 1H), 7.13 (s, 1H), 7.36 (s, 1H). Anal.
combined organic layers were washed with brine (100 ml), dried, and fil- Calcd for C12H18N4O2·H2O: C, 53.72; H, 7.51; N, 20.88. Found: C, 53.58;
tered. The ratio of 13 : 14 in reaction mixture was 2 : 98. The filtrate was H, 7.90; N, 20.96.
evaporated and 13 and 14 were separated by preparative RP-HPLC to give
13 (3 mg, 1%), and 14 (330 mg, 93%).
Acknowledgments J.Z.H. dedicates this paper to his Ph.D. advisor, Pro-
Synthesis of (1S,3R)-1-Amino-3-(hydroxymethyl)cyclopentane (1) from
fessor Robert M. Coates, Ph.D., Department of Chemistry, University of Illi-
Hydrogenation of 13 A slurry of 13 (355 mg, 1 mmol), MeOH (10 ml), nois at Urbana-Champaign, Urbana, Illinois 61801, U.S.A., on the occasion
HCl (1.0 M solution in ether, 2 ml, 2 mmol) and 5% Pt/C (0.1 g) was hydro- of his 65th birthday. J.Z.H thanks Dr. Charles S. Elmore and Dr. Terry A.
genated in a Parr shaker under 45 psi of H2 at room temperature for 24 h. Lyle who have assisted greatly in the use of clear and proper written English.
The reaction mixture was filtered, and the filtrate was evaporated to give 1
(149 mg, 98%). Chiral HPLC analysis (Chiralpak AD column 250ϫ4.6; References
hexane : isopropanolϭ97 : 3) indicated that enantiomeric excess for 1 was
99.9%.
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Synthesis of (1S,3S)-1-Amino-3-(hydroxymethyl)cyclopentane (2)
A
slurry of 14 (355 mg, 1 mmol), MeOH (10 ml), HCl (1.0 M solution in ether,
2 ml, 2 mmol) and 5% Pt/C (0.1 g) was hydrogenated in a Parr shaker under
45 psi of H2 at rt for 24 h. The reaction mixture was filtered, and the filtrate
was evaporated to give 2 (149 mg, 98%). Chiral HPLC analysis indicated
that enantiomeric excess for 2 was 100%. A solution of BDCS silylation
reagent (Aldrich, 0.5 M TBDMS-Cl and 1.0 M imidazole solution in DMF,
37 ml) was added to a solution of 12 (2 g, 9.3 mmol) in DMF (10 ml). The
mixture was stirred at rt for 18 h then partitioned between saturated aq
KH2PO4 (500 ml) and EtOAc (250 ml). Aq phase was extracted with EtOAc
(200 mlϫ2) and combined organic layers were washed with brine (100 ml),
dried, and filtered. Solvent was removed and HCl (5.0 M solution in EtOAc,
10 ml) was added. After the mixture was stirred at rt for 12 h, solvent was
evaporated to give 15 as HCl salts (1.4 g, 83%): [a]D25 Ϫ4.1° (cϭ1.2,
CHCl3); 1H-NMR (CDCl3) d: 1.05 (s, 9H), 1.35 (m, 2H), 1.55 (m, 2H), 1.71
(m, 1H), 1.86 (m, 1H), 2.11 (m, 2H), 2.75 (br s, 2H), 3.32 (q, Jϭ7.0 Hz,
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1 mmol) and imidate 1620) (297 mg, 1 mmol) in 2,2,2-trifluoroethanol (1 ml)
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and 1,2 dichlorethane (10 ml) was stirred at 80 °C for 4 h to yield 17. An an- 14) Santan L., Teijeira M., Uriarte E., Teran C., Casellato U., Graziani R.,
A
alytical sample was obtained by flash chromatography (EtOAc : Et3Nϭ
99 : 1): [a]D25 ϩ2.9° (cϭ1.0, CHCl3); 1H-NMR (CDCl3) d: 0.09 (s, 9H), 0.12
(s, 3H), 0.91 (s, 9H), 1.03 (s, 3H), 1.30—2.20 (m, 7H), 3.34 (m, 3H), 3.70
(m, 3H), 4.25 (m, 1H), 4.95 (m, 1H), 7.11 (s, 1H), 7.38—7.72 (m, 10H).
Calcd for C33H50N6O2Si2: C, 64.04; H, 8.14; N, 13.58. Found: C, 64.04; H,
8.14; N, 13.58. Without purification of 17, N,N-dimethylformamide di-
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403—407 (1986).

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