Practical enantiospecific synthesis of an orthogonally protected 1,4- trans -1,5- cis - 4,5-diamino-2-cyclopenten-1-ol derivative

Article abstract of DOI:10.1021/jo1009118

An enantiospecific synthesis of an orthogonally protected 1,4-trans-1,5-cis-4,5-diamino-2-cyclopenten-1-ol derivative 16 is reported. The trans-diamine moiety was established by anti-specific vinyl addition to a novel threitol-derived tert-butanesulfinylimine 2 and Overman rearrangement. The cyclopentene skeleton was constructed via RCM reaction of a key 1,6-diene intermediate 11.

Full text of DOI:10.1021/jo1009118

pubs.acs.org/joc
synthesis employed Sharpless-Kresze allylic amination for
Practical Enantiospecific Synthesis of an
Orthogonally Protected 1,4-trans-1,5-cis- 4,5-
Diamino-2-cyclopenten-1-ol Derivative
the introduction of the C-4 amino group.4a,b Hale prepared a
derivative of I in 17 steps starting from D-glucosamine.4c
[3,3]-Rearrangement of allylic isocyanate was used twice by
Ichikawa to deliver an orthogonally protected intermediate
in 20 steps from L-arabitol.4d Recently, Chida’s synthesis fea-
tured sequential sigmatropic rearrangement to provide an ana-
logue of I in 15 steps from D-tartaric acid.4e Focusing on the
chemistry of R-chiral amines,5 herein we report a practical
and enantiospecific synthesis of a precursor for 1,4-trans-1,5-
cis-4,5-diamino-2-cyclopenten-1-ol I.
Bing Wang*
Shanghai Boramino Chemicals Co., Ltd., Room 202, Unit 5,
Building 1, 688 Qiushi Road, Shanghai 201512, China
boramino10@yahoo.com
Received May 13, 2010
We envisaged that Overman rearrangement6 could be emp-
loyed not only as an ideal protocol for the chiral allylic amine
motif in I but also as a strategic solution to the starting
material (Scheme 1). In fact, the trans-diol moiety of II map-
ped nicely onto the skeleton of L-(þ)-tartaric acid, an in-
expensive and readily available starting material. Next, the
1,6-diene III, a key precursor to the cyclopentene ring via
RCM reaction,7 was to be procured by Wittig methylenation
and vinyl addition to a tert-butanesulfinylimine.8 With regard
to the latter process, the R-alkoxyl group of imine was expec-
ted to favor the desired anti- diastereoselectivity. Overall,
this approach was totally different from that of Chida and
co-workers4e in terms of tailoring of the threitol topology.
Since a priori stereochemical prediction for organometal-
lic additions to N-tert-butanesulfinyl-R-alkoxyaldimines has
often been difficult,9 both (SS)- and (RS)-imines were prepa-
red at the outset (Scheme 2). Monosilylated diol 110 under-
went Swern oxidation11 and condensation with (SS)- and
(RS)-tert-butanesulfinamide, respectively, to furnish novel
threitol-derived N-t-BS-imines 2 and 3 in both the same 77%
overall yields. CuSO4 and Ti(OEt)412 gave comparable results
in imine formation, although the former required 2-3 days
for complete conversion. Under both conditions, epimeriza-
tion of imine R-position was not detected.
An enantiospecific synthesis of an orthogonally protected
1,4-trans-1,5-cis-4,5-diamino-2-cyclopenten-1-ol derivative
16 is reported. The trans-diamine moiety was established
by anti-specific vinyl addition to a novel threitol-derived
tert-butanesulfinylimine 2 and Overman rearrangement.
The cyclopentene skeleton was constructed via RCM
reaction of a key 1,6-diene intermediate 11.
Chiral 1,2-amino alcohols are essential structural features
in natural products, therapeutics, as well as chiral ligands
and auxiliaries.1 Similarly, chiral 1,2-diamines are also pivo-
tal to these fields.2 4,5-Diamino-2-cyclopenten-1-ol (I), a
cyclic variant incorporating both 1,2-amino alcohol and
1,2-diamine moieties, has been a challenging target due to
its dense functionalization, yet its synthetic utility has been
highlighted by several total syntheses of the antitumor oroidin
alkaloid (-)-agelastatin A.3 For example, Weinreb’s racemic
Subsequent Grignard additions to t-BS-imines 2 and 3 re-
vealed some interesting stereochemical outcomes (Table 1).
(5) (a) Chen, B.-L.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2010, 75, 941.
(b) Wang, B.; Wang, Y.-J. Org. Lett. 2009, 11, 3410. (c) Wang, B.; Zhong, Z.;
Lin, G.-Q. Org. Lett. 2009, 11, 2011. (d) Wang, B.; Lin, G.-Q. Eur. J. Org.
Chem. 2009, 5038. (e) Wang, B.; Liu, R.-H. Eur. J. Org. Chem. 2009, 2845.
(f) Liu, R.-H.; Fang, K.; Wang, B.; Xu, M.-H.; Lin, G.-Q. J. Org. Chem.
2008, 73, 3307.
(6) For an excellent review, see: (a) Overman, L. E.; Carpenter, N. E. Org.
React. 2005, 66, 1. For an improved protocol, see: (b) Nishikawa, T.; Asai,
M.; Ohyabu, N.; Isobe, M. J. Org. Chem. 1998, 63, 188.
(1) For excellent reviews, see: (a) Ager, D. J.; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 835. (b) Reetz, M. T. Chem. Rev. 1999, 99, 1121.
(c) Bergmeier, S. C. Tetrahedron 2000, 56, 2561. (d) Burchak, O. N.; Py, S.
Tetrahedron 2009, 65, 7333.
(7) For excellent reviews, see: (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc.
€
Chem. Res. 1995, 28, 446. (b) Furstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012.
(2) For excellent reviews, see: (a) Kizirian, J.-C. Chem. Rev. 2008, 108,
140. (b) Viso, A.; de la Pradilla, R. F.; Garcıa, A.; Flores, A. Chem. Rev. 2005,
´
105, 3167. (c) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des.
2006, 67, 101.
(3) Isolation of (-)-agelastatin A: (a) D’Ambrosio, M.; Guerriero, A.;
Debitus, C.; Ribes, O.; Pusset, J.; Leroy, S.; Pietra, F. J. Chem. Soc., Chem.
Selected applications in total synthesis: (c) Martin, S. F.; Humphrey, J. M.; Ali,
A.; Hillier, M. C. J. Am. Chem. Soc. 1999, 121, 866. (d) Garg, N. K.; Hiebert, S.;
Overman, L. E. Angew. Chem., Int. Ed. 2006, 45, 2912.
(8) For an excellent comprehensive review on tert-butanesulfinylimine
chemistry, see: Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev.
2010, 110, 3600.
Commun. 1993, 1305. (b) Hong, T. W.; Jı
´
menez, D. R.; Molinski, T. F. J. Nat.
(9) (a) Evans, J. W.; Ellman, J. A. J. Org. Chem. 2003, 68, 9948.
(b) Harried, S. S.; Croghan, S. D.; Kaller, M. R.; Lopez, P.; Zhong, W.;
Hungate, R.; Reider, P. J. J. Org. Chem. 2009, 74, 5975.
(10) Martin, S. F.; Chen, J.-H.; Yang, C.-P. J. Org. Chem. 1993, 58, 2867.
(11) (a) Huang, S. L.; Swern, D. J. Org. Chem. 1978, 43, 4537. For an
excellent review, see: (b) Tidwell, T. T. Org. React. 1990, 39, 297.
(12) (a) Cogan, D. A.; Ellman, J. A. J. Am. Chem. Soc. 1999, 121, 268.
(b) Liu, G.; Cogan, D. A.; Owens, T. D.; Tang, T. P.; Ellman, J. A. J. Org.
Chem. 1999, 64, 1278.
Prod. 1998, 61, 158. For total syntheses, see ref 4 and references cited therein.
(4) (a) Anderson, G. T.; Chase, C. E.; Koh, Y.-H.; Stien, D.; Weinreb,
S. M.; Shang, M. J. Org. Chem. 1998, 63, 7594. (b) Stien, D.; Anderson, G. T.;
Chase, C. E.; Koh, Y.-H.; Weinreb, S. M. J. Am. Chem. Soc. 1999, 121, 9574.
(c) Hale, K. J.; Domostoj, M. M.; Tocher, D. A.; Irving, E.; Scheinmann, F.
Org. Lett. 2003, 5, 2927. (d) Ichikawa, Y.; Yamaoka, T.; Nakano, K.;
Kotsuki, H. Org. Lett. 2007, 9, 2989. (e) Hama, N.; Matsuda, T.; Sato, T.;
Chida, N. Org. Lett. 2009, 11, 2687.
6012 J. Org. Chem. 2010, 75, 6012–6015
Published on Web 08/09/2010
DOI: 10.1021/jo1009118
r
2010 American Chemical Society

Wang
JOCNote
SCHEME 1. Retrosynthetic Plan for I
SCHEME 3. Synthesis of 1,6-Diene
SCHEME 2. Synthesis of Threitol-Derived t-BS-Imines
major vinyl adducts 4 and 6 were anti-β-amino alcohols,
regardless of the sulfinyl chirality.13 Nevertheless, it should
be emphasized that the unique stabilizing and electron-
withdrawing effects of t-BS are irreplaceable.14
Having one olefin double bond in place, we proceeded to
modify the other end of the threitol skeleton. Deblocking the
TBDPS group of 4 with TBAF, Dess-Martin oxidation15 of
the resulting primary alcohol, and standard Wittig olefina-
tion of the crude aldehyde afforded diene 8 in 73% yield over
three steps (Scheme 3). This process demonstrated the com-
patibility of t-BS with the hypervalent iodine reagent Dess-
Martin periodinane, which may even qualify it as a protect-
ing group proper in the multistep synthesis of complex mole-
cules. Acidic hydrolysis of both the acetonide and t-BS
followed by selective N-protection with Cbz in one pot pro-
vided the RCM precursor 9 in high yield. However, unlike its
homologue which cyclized smoothly,4d the RCM reaction of
diene 9 using Grubbs’ first-generation catalyst was sluggish
and complex, nor could Neolyst solve the problem. We assu-
med that intramolecular hydrogen bonding between the
polar functionalities might lock 9 in an unfavorble confor-
mation for ring-closure.
To circumvent this difficulty, the diol was acetylated, and
diene 11 proved to be an excellent substrate for RCM. With
the original Grubbs catalyst (2.5-3.5 mol %) in DCM, a
typical gram-scale run furnished cyclopentene 12 in 91%
yield, plus 6% unreacted diene, under diluted conditions
(Scheme 4). The Ac protections were conveniently removed
by mild alcoholysis using a catalytic amount (20 mol %) of
K2CO3, with concomitant cyclization to yield a carbamate
intermediate. In view of its low solubility and potential hydro-
philicity, the crude product was used directly without aque-
ous workup, and its reaction with trichloroacetonitrile pro-
ceeded smoothly under conventional conditions. The Overman
rearrangement (with Isobe’s modification6b) of the resulting
trichloroacetimidate 13 was uneventful, affording amide 14
with a trans- diamine substitution pattern in excellent yields
(up to 95%).
TABLE 1. Anti-Selective Vinyl Addition to 2 and 3a
entry
imine
solvent
adductb (%)
anti/sync
1d
2
(SS)-2
(SS)-2
(RS)-3
(RS)-3
(RS)-3
THF
4 þ 5, 86
4 only, 94
6 þ 7, 85
6 þ 7, 82
6 þ 7, 93
1.5:1
>99:1
4.8:1
7.3:1
9.6:1
DCM
DCM
THF
3
4d
5d
DCM
aConditions: To a solution of imine (5.0 mmol, 0.2 M) at -78 °C was
added dropwise 2.5 equiv of vinylmagnesium bromide, except as indi-
cated otherwise. bIsolated yields. Determined by 1H NMR spectros-
c
copy of the crude adducts. dThe Grignard reagent was precomplexed
with TMEDA.
Addition of vinylmagnesium bromide TMEDA complex9
;
to 2 at -78 °C produced inseparable epimers 4 and 5 in a
disappointing 1.5:1 ratio. However, this scenario was funda-
mentally changed by shifting the solvent to DCM and omit-
ting the additive, yielding diastereospecifically a single adduct 4
1
as judged by the diagnostic olefinic region of the H NMR
spectroscopy of the crude product (entry 2). On the other
hand, using the same protocol, the addition to (RS)-imine 3
yielded a pair of separable epimers 6/7 in a useful 4.8:1 ratio.
Interestingly, contrary to the case of 2, the additive TMEDA
enhanced the dr to 9.6:1 for the mismatched substrate 3
under optimized conditions (entry 5). Gratifyingly, the newly
formed stereogenic centers in 4 and 6 were unamibiguously
determined to be of the desired S- configuration, by X-ray
analysis of the crystalline desilylation products (see the Sup-
porting Information). Thus, for both imines 2 and 3, the
Further transformation of the trichloroacetamide turned
out to be nontrivial (Scheme 5). Initial attempts at selective
removal of this N-acyl group in the presence of the carbamate
(14) Analogous N-Ts-imines were unstable, while N-benzylimines gave
ꢀ
lower (35-84%) yields: (a) Cossy, J.; Pevet, I.; Meyer, C. Eur. J. Org. Chem.
2001, 2841. In contrast to t-BS imines, the drs for p-toluenesulfinylimines
were controlled by the sulfur chirality: (b) Zhou, D.; Staake, M.; Patterson,
S. E. Org. Lett. 2008, 10, 2179.
(13) Precedences of diastereoconvergent additions to t-BS imines are very
rare: (a) McMahon, J. P.; Ellman, J. A. Org. Lett. 2004, 6, 1645. (b) Risseeuw,
M. D. P.; Mazurek, J.; van Langenvelde, A.; van der Marel, G. A.; Overkleeft,
H. S.; Overhand, M. Org. Biomol. Chem. 2007, 5, 2311.
(15) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155. For
reviews, see: (b) Speicher, A.; Bomm, V.; Eicher, T. J. Prakt. Chem. 1996,
338, 588. (c) Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346, 111.
J. Org. Chem. Vol. 75, No. 17, 2010 6013

Wang
JOCNote
SCHEME 4. Synthesis of 4,5-Diamino-2-cyclopenten-1-ol
(2 ꢀ 30 mL), and the combined organic layer was washed with
brine, dried (Na2SO4), and concentrated under reduced pres-
sure. The residue was purified by silica gel flash column chro-
matography (EtOAc/hexane =1/6 to 1/3) to afford 4 (4.410 g,
94%) as a colorless oil: [R]24D þ30.9 (c 1.09, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.71-7.65 (m, 4H), 7.45-7.35 (m, 6H),
5.54 (ddd, 1H, J=17.2, 10.4, 8.0 Hz), 5.35 (d, 1H, J=17.2 Hz),
5.23 (d, 1H, J=10.4 Hz), 4.24 (dd, 1H, J=7.9, 3.6 Hz), 4.19 (dt,
1H, J=8.2, 3.0 Hz), 4.11-4.07 (m, 1H), 3.82 (d br, 1H, J=2.4
Hz), 3.81-3.78 (AB-d, 1H, JAB = 11.3 Hz, J = 4.0 Hz),
3.71-3.68 (AB-d, 1H, JAB = 11.3 Hz, J = 4.2 Hz), 1.42 (s,
3H), 1.41 (s, 3H), 1.21 (s, 9H), 1.06 (s, 9H); 13C NMR (125 MHz,
CDCl3) δ 135.6 (4C), 133.7, 133.0 (2C), 129.7 (2C), 127.7 (4C),
120.1, 109.1, 79.6, 77.0, 64.6, 57.6, 55.6, 27.3, 27.0, 26.8 (3C),
22.6 (3C), 19.2; HR-ESI-MS m/z calcd for C29H44NO4SSi (M þ
Hþ) 530.2760, found 530.2753.
SCHEME 5. Functional Group Manipulations
(SS)-N-((S)-1-((4S,5S)-2,2-Dimethyl-5-vinyl-1,3-dioxolan-4-yl)-
allyl)-2-methylpropane-2-sulfinamide (8). Compound 4 (7.870 g,
14.88 mmol) in THF (40 mL) was treated with TBAF (1.0 M in
THF, 16.4 mL, 16.4 mmol) for 1 h at rt, and the solvent was
removed under reduced pressure. The residue was purified by
silica gel flash column chromatography (EtOAc/hexane=1/2 to
EtOAc) to afford the desilylation product (4.290 g, 99%) as
colorless crystals. To a cooled (0 °C) solution of the above
alcohol (625 mg, 2.15 mmol) and pyridine (0.34 mL, 4.3 mmol)
in CH2Cl2 (10 mL) was added Dess-Martin periodinane (1.64 g,
3.87 mmol), and the solution was warmed to rt and stirred at this
temperature for 1 h, diluted with ether, quenched with 10% aq
Na2S2O3 and satd aq NaHCO3, and stirred for 15 min. The
aqueous layer was extracted with ether (4 ꢀ 30 mL), and the
combined organic layer was washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. Under a N2 atmos-
phere, a suspension of methyltriphenylphosphonium bromide
(2.30 g, 6.45 mmol) in THF (30 mL) was treated with KHMDS
(0.91 M in THF, 6.85 mL, 6.23 mmol) at rt for 1 h and cooled to
-78 °C. To the yellow ylide solution was added the above crude
aldehyde in THF (6 mL), and the mixture was warmed to room
temperature, stirred for 4 h, and then heated at 50 °C for 2 h. The
cooled mixture was quenched by addition of satd aq NH4Cl, the
aqueous layer was extracted with ether (2 ꢀ 30 mL), and the
combined organic layer was washed with brine, dried (Na2SO4),
and concentrated under reduced pressure. The residue was
purified by silica gel flash column chromatography (EtOAc/
using literature protocols were unsuccessful (aq NaOH, or
NaBH4/EtOH) or low yielding (Cs2CO3, DMF, 100 °C).16
Fortuitously, when we turned to acidic hydrolysis (6 N HCl,
reflux),17 a clean global deprotection of both the trichloro-
acetamide and carbamate was achieved. After evaporation
of the volatiles, the resulting diamine bis-HCl salt was neut-
ralized and protected with Boc2O. To differentiate the two
amino groups again, compound 15 was treated with NaH in
THF to effect a smooth cyclization, yielding carbamate 16
(95%), whose functionalities were orthogonally protected.
In conclusion, we have developed a practical and enantio-
specific access to an orthogonally protected 1,4-trans-1,5-cis-
4,5-diamino-2-cyclopenten-1-ol derivative 16 using inexpensive
starting materials such as L-(þ)-tartaric acid, (SS)-tert-buta-
nesulfinamide, and accessible reagents and catalysts. The
overall yield is 34% from imine 2 in 14 steps, and all opera-
tions are convenient. In addition, we have identified a simple
protocol for efficient synthesis of chiral β-hydroxy-R-branched
allylic amines18 via a highly diastereoselective vinyl addition
to threitol-derived t-BS-imines. Other features of the present
route include a RCM reaction to construct the cyclopentene
ring and an Overman rearrangement to install the C-4 amino
group. Finally, the N-tert-butanesulfinyl auxiliary was shown
to be compatible with Dess-Martin oxidation and Wittig
olefination.
hexane =1/4 to 1/2) to afford 8 (459 mg, 74%) as a yellow oil:
1
[R]25 þ81.3 (c 0.76, CHCl3); H NMR (500 MHz, CDCl3) δ
D
5.83 (ddd, 1H, J=17.3, 10.0, 7.2 Hz), 5.67 (ddd, 1H, J=17.0,
10.2, 8.4 Hz), 5.38 (d, 1H, J=17.3 Hz), 5.38 (d, 1H, J=17.0 Hz),
5.32 (d, 1H, J=10.3 Hz), 5.28 (d, 1H, J=10.5 Hz), 4.39 (t, 1H,
J=7.9 Hz), 4.15-4.10 (m, 1H), 3.92 (dd, 1H, J=8.1, 3.8 Hz),
3.78 (d br, 1H, J=2.5 Hz), 1.43 (s, 3H), 1.40 (s, 3H), 1.23 (s, 9H);
13C NMR (125 MHz, CDCl3) δ 135.9, 133.8, 120.3, 119.3, 109.3,
82.6, 78.0, 57.6, 55.7, 26.9, 26.8, 22.6 (3C); HR-ESI-MS m/z
calcd for C14H26NO3S (M þ Hþ) 288.1633, found 288.1620.
Benzyl N-[(1S,4S,5S)-4,5-Diacetoxy-2-cyclopenten-1-yl]carb-
amate (12). Under a N2 atmosphere, to a solution of diene 11
(1.010 g, 2.80 mmol) in DCM (140 mL) was added Grubbs’ first-
generation catalyst (57 mg, 0.07 mmol, 2.5 mol %) at rt, the solu-
tion was stirred overnight, an additional amount (23 mg, 1.0 mol %)
of catalyst was added, and stirring was continued for 5 h. The
solvent was removed under reduced pressure, and the residue
was purified by silica gel flash column chromatography (EtOAc/
hexane = 1/3 to 1/2) to recover a small amount of 11 (61 mg,
6%), followed by 12 (848 mg, 91%) as a pale yellow oil which
Experimental Section
(SS)-N-((S)-1-((4S,5S)-5-((tert-Butyldiphenylsilyloxy)methyl)-
2,2-dimethyl-1,3-dioxolan-4-yl)allyl)-2-methylpropane-2-sulfin-
amide (4). Under a N2 atmosphere, to a cooled (-78 °C) solution
of imine 2 (4.445 g, 8.87 mmol) in CH2Cl2 (45 mL) was added
dropwise vinylmagnesium bromide (0.7 M in THF, 31.7 mL,
22.2 mmol) over 5 min, and the solution was stirred at this tem-
perature for 1 h, quenched by addition of satd aq NH4Cl,
and warmed to rt. The aqueous layer was extracted with ether
(16) (a) Nomura, H.; Richards, C. J. Org. Lett. 2009, 11, 2892. (b) Weygand,
F.; Frauendorfer, E. Chem. Ber. 1970, 103, 2437. (c) Urabe, D.; Sugino, K.;
Nishikawa, T.; Isobe, M. Tetrahedron Lett. 2004, 45, 9405.
crystallized on standing: mp 63-65 °C; [R]23 þ175.5 (c 0.42,
D
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.39-7.30 (m, 5H),
(17) Casara, P. Tetrahedron Lett. 1994, 35, 3049.
6.04-5.98 (m, 1H), 5.98-5.92 (m, 1H), 5.66 (s br, 1H), 5.31-
5.27 (m, 1H), 5.15-5.03 (m, 3H), 4.85 (d br, 1H, J = 8.4 Hz),
2.06 (s, 3H), 1.99 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 170.4,
(18) For recent synthetic methods for chiral R-branched allylic amines,
see: (a) Ni, C.; Liu, J.; Zhang, L.; Hu, J. Angew. Chem., Int. Ed. 2007, 46, 786.
(b) Brak, K.; Ellman, J. A. J. Am. Chem. Soc. 2009, 131, 3850. (c) Reference 5a.
6014 J. Org. Chem. Vol. 75, No. 17, 2010

Wang
JOCNote
169.6, 155.7, 136.3, 135.6, 131.5, 128.5 (2C), 128.2 (3C), 81.0, 75.1,
67.0, 55.6, 20.9, 20.6; HR-ESI-MS m/z calcd for C17H19NNaO6
(M þ Naþ) 356.1110, found 356.1092.
up in DCM-MeOH (1:1, 20 mL), Et3N (0.95 mL, 6.9 mmol) was
added follwed by Boc2O (1.248 g, 5.72 mmol), and the solution was
stirred for 4 h at rt. The solvent was removed under reduced pres-
sure, and the residue was purified by silica gel flash column chro-
matography (EtOAc/hexane =1/2) to afford 15 (622 mg, 85%) as
a white solid: mp 145-146 °C; [R]22D -103.9 (c 0.92, CHCl3); 1H
NMR (500 MHz, CDCl3) δ 6.01 (s br, 2ꢀ1H), 5.57-5.33 (m, 1H),
5.17-4.89 (m, 1H), 4.70-4.45 (m, 2H), 3.83-3.71 (m, 1H),
2.70-2.15 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H); peaks broadened
due to rotamers; 13C NMR (125 MHz, CDCl3) δ 156.4, 156.1,
137.7, 132.7, 79.7 (2C), 73.2, 60.3, 59.8, 28.4 (6C); HR-ESI-MS m/z
calcd for C15H27N2O5 (M þ Hþ) 315.1920, found 315.1914.
tert-Butyl (3aS,4R,6aR)-2-Oxo-3,3a,4,6a-tetrahydro-2H-cyclo-
penta[d]oxazol-4-ylcarbamate (16). Under a N2 atmosphere, to a
cooled (0 °C) solution of 15 (109 mg, 0.35 mmol) in THF (5 mL)
was added NaH (60%, 28 mg, 0.70 mmol) in one portion, and
the suspension was warmed to rt and stirred overnight, quen-
ched by addition of satd aq NH4Cl, and extracted with DCM
(3 ꢀ 10 mL). The combined organic phase was dried (Na2SO4)
and concentrated under reduced pressure. The residue was puri-
fied by silica gel flash column chromatography (EtOAc/hexane =
(3aS,6S,6aS)-2-Oxo-3,3a,6,6a-tetrahydro-2H-cyclopenta[d]-
oxazol-6-yl 2,2,2-Trichloroacetimidate (13). A solution of 12
(112 mg, 0.34 mmol) in MeOH (5 mL) was treated with K2CO3
(10 mg, 0.072 mmol) at rt overnight, and the solvent was com-
pletely removed under reduced pressure. To the residue were
added DCM (5 mL) and DBU (0.02 mL), the suspension was
cooled to 0 °C, and Cl3CCN (0.15 mL) was added dropwise. The
suspension was slowly warmed to rt, stirred for 2 h, and con-
centrated. The residue was purified by silica gel flash column
chromatography (EtOAc/hexane =2/1) to afford 13 (81 mg,
84%) as white crystals: mp 140-152 °C dec; [R]24 þ233.8
D
(c 0.81, CHCl3); 1H NMR (500 MHz, CDCl3) δ 8.55 (s, 1H), 6.60
(s br, 1H), 6.23-6.17 (m, 2H), 5.91 (s, 1H), 5.10 (d, 1H, J=7.0
Hz), 4.92 (d, 1H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3)
δ 161.5, 158.2, 137.4, 130.9, 90.8, 86.4, 82.2, 60.4; HR-ESI-MS
m/z calcd for C8H8Cl3N2O3 (M þ Hþ) 284.9601, found 284.9611.
2,2,2-Trichloro-N-((3aS,4R,6aR)-2-oxo-3,3a,4,6a-tetrahydro-
2H-cyclopenta[d]oxazol-4-yl)acetamide (14). Under a N2 atmos-
phere, a mixture of 13 (372 mg, 1.30 mmol) and K2CO3 (28 mg,
0.21 mmol) in xylene (30 mL) was heated at 140 °C for 9 h,
cooled to rt, and concentrated under reduced pressure. The
residue was purified by silica gel flash column chromatography
(EtOAc/hexane =1/1 to 2/1) to afford 14 (355 mg, 95%) as a
white foam: mp 179-181 °C; [R]20D -116.0 (c 0.42, CHCl3); 1H
NMR (500 MHz, CD3OD) δ 6.16 (dt, 1H, J = 5.8, 1.8 Hz),
6.10-6.07 (m, 1H), 5.73-5.70 (m, 1H), 4.73 (s br, 1H), 4.19 (d,
1H, J=7.3 Hz); 13C NMR (125 MHz, CD3OD) δ 163.9, 160.5,
134.9, 134.3, 93.6, 86.5, 65.3, 61.7; HR-ESI-MS m/z calcd for
C8H8Cl3N2O3 (M þ Hþ) 284.9601, found 284.9587.
1/1 to 2/1) to afford 16 (79 mg, 95%) as a white solid: mp 127-
D
1
129 °C; [R]25 -109.6 (c 0.79, CHCl3); H NMR (500 MHz,
CDCl3) δ 6.10-6.06 (m, 1H), 6.02 (dd, 1H, J=5.7, 2.2 Hz), 5.97
(s br, 1H), 5.61 (d, 1H, J = 7.3 Hz), 5.22-4.70 (m, 1H), 4.57-
4.40 (m, 1H), 4.10 (d, 1H, J = 7.4 Hz), 1.45 (s, 2 ꢀ 9H); peaks
broadened due to rotamers; 13C NMR (125 MHz, CDCl3) δ
157.8, 155.2, 134.9, 132.8, 84.3, 80.3, 63.8, 61.5, 28.3 (3C); HR-
ESI-MS m/z calcd for C11H17N2O4 (M þ Hþ) 241.1118, found
241.1136.
Acknowledgment. I thank Mr. Guang-Bing Wang (Shanghai
Boramino Chemical Co., Ltd.) for reliable technical assistance.
C,C0-Bis(1,1-dimethylethyl) N,N0-[(1R,2S,3R)-3-Hydroxy-
4-cyclopenten-1,2-diyl]biscarbamate (15). Compound 14 (665 mg,
2.29 mmol) was suspended in 6 N HCl (15 mL), the mixture was
refluxed for 12 h, and the resulting solution was concentrated and
dried under high vacuum. The white solid thus obtained was taken
Supporting Information Available: Characterization data
and experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 17, 2010 6015