Unexpected ring expansion of the (3aS,6aR)-γ-thiolactone moiety during the introduction of the (+)-biotin side chain

Article abstract of DOI:10.1002/hlca.200800435

The reaction of vinylmagnesium bromide with the (3aS,6aR)-γ- thiolactone 2 in THF afforded, after unexpected ring expansion of the g-thiolactone moiety, the seven-membered-ring ketone 5 in excellent yield, instead of the expected tertiary alcohol 3.

Full text of DOI:10.1002/hlca.200800435

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Unexpected Ring Expansion of the (3aS,6aR)-g-Thiolactone Moiety during
the Introduction of the (þ)-Biotin Side Chain
by Jian Huanga), Fei Xionga)b), Zhong-Hua Wanga), and Fen-Er Chen*a)b)
a) Fudan-DSM Joint Laboratory for Synthetic Method and Chiral Technology, Department of Chemistry,
Fudan University, 220 Handan Road, Shanghai 200433, P. R. China
b) Institute of Biomedical Science, Fudan University, Shanghai 200433, P. R. China
(fax: þ 86-21-65643811; e-mail: rfchen@fudan.edu.cn)
The reaction of vinylmagnesium bromide with the (3aS,6aR)-g-thiolactone 2 in THF afforded, after
unexpected ring expansion of the g-thiolactone moiety, the seven-membered-ring ketone 5 in excellent
yield, instead of the expected tertiary alcohol 3.
Introduction. – (þ)-Biotin (1) is an important water-soluble B-complex vitamin
bearing a cis-fused cyclic urea and tetrahydrothiophene ring, to which is attached a
pentanoic acid side chain (cf. Scheme 1). Due to its useful biological properties for
human nutrition and animal health [1], this vitamin has attracted considerable
attention from both industries and academia for more than 60 years1). A great number
of approaches to 1 have been reported so far [2]. However, the introduction of the
pentanoic acid side chain at C(4) of the (3aS,6aR)-g-thiolactone 2 still remains a
challenging task.
As a continuation of our interest in the total synthesis of (þ)-biotin (1) [3], we
devised different Grignard reagents to realize the installation of the pentanoic acid side
chain on 2. For example, the reaction of (3-ethoxyprop-1-ynyl)magnesium bromide
[3b] or (methoxymethyl)magnesium iodide [3h] with 2 introduced part of the side
chain affording the corresponding tertiary alcohol with good yield. The Grignard
reagent derived from 2-(4-bromobutyl)-2-methyl-1,3-dioxolane and magnesium [3c]
also reacted well with 2 allowing a direct introduction of the side chain of biotin.
In an exploration for a new synthesis of (þ)-biotin (1), our plan involved a Grignard
reaction of vinylmagnesium bromide with 2 to introduce a C2 side chain, followed by an
Et3SiH-mediated ionic hydrogenation [4]2) to establish the third chiral center [5]3),
and subsequent chemical manipulation at the terminal olefin could install the full biotin
side chain with correct configuration (Scheme 1).
Results and Discussion. – With these considerations in mind, we attempted the
reaction of 2 with vinylmagnesium bromide in THF. The reaction proceeded smoothly
1
)
)
)
For reviews about the synthesis of (þ)-biotin, see [2].
For a review about ionic hydrogenation, see [5].
2
3
We have developed an efficient method to establish the third chiral center of (þ)-biotin via a mild
ionic hydrogenation, see [3k].
ꢀ 2009 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 92 (2009)
Scheme 1. Planned Synthetic Approach toward 1
under stirring at room temperature for 4 h, and to our surprise only the ring expansion
product 5 was isolated in 86% yield, and no expected 3 could be detected (Scheme 2).
Scheme 2. The Unexpected Ring Expansion of Thiolactone 2
The fundamental architecture of compound 5 was unambiguously confirmed by the
X-ray crystallographic analysis of alcohol 6 (Fig.), which was obtained by reduction of
5 via an Et3SiH-mediated ionic hydrogenation (Scheme 2).
Figure. ORTEP Drawing of the X-ray structure of 6
Next, we investigated an analogous reaction of ethylmagnesium bromide with 2.
The reaction proceeded via tertiary alcohol 7 as expected to furnish the desired
compound 8 in 96% yield, and no ring-expansion product was detected (Scheme 3).

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Scheme 3. The Grignard Reaction of 2 with Ethylmagnesium Bromide
Although the mechanistic details for the formation of compound 5 are not known, a
plausible mechanism may be advanced to rationalize the ring expansion reaction
(Scheme 4). Presumably, nucleophilic attack of the CO group of 2 by vinylmagnesium
bromide produced the a,b-unsaturated keto compound 9, and subsequent intra-
molecular Michael addition led to the seven-membered ring ketone 5 (Scheme 4).
Scheme 4. Plausible Mechanism for the Formation of 5
All products were new and were unequivocally characterized by IR, mass, and
NMR spectra (1H, 13C, 1H,1H-COSY, 13C,1H-COSY, and HMBC). For compound 5, the
MS (m/z 367 ([M þ H]þ) and 389 ([M þ Na]þ)) and elemental analysis were in accord
with the molecular formula C21H22N2O2S. The DEPT spectrum revealed the presence
of five CH2 groups. The 13C-NMR data indicated the presence of two CO groups with
signals at d(C) 159 and 206. The atom numbering used for NMR assignment along with
2
all diagnostic COLOC correlations between various H- and C-atoms via J(C,H) and
3J(C,H) couplings are presented in the Table.
Conclusions. – From the investigated reactions, the following conclusion can be
drawn. Instead of the expected alcohol 3, a seven-membered-ring ketone 5 can be
conveniently obtained with high yield in the Grignard reaction of (3aS, 6aR)-g-
thiolactone 2 with vinylmagnesium bromide, most probably because of an intra-
molecular 1,4-conjugated addition. Further studies on the introduction of the pentanoic
acid side chain via a Grignard reaction and the chemistry of the novel compound 5 are
under investigation.

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Table. COLOC Correlation Between Various H- and C-Atoms of Ketone 5. Arbitrary atom numbering.
H-atom
COLOC with C-atom
HꢂC(1)
HꢂC(2)
HꢂC(3)
HꢂC(4)
HꢂC(5)
HꢂC(6)
HꢂC(7)
C(6)
C(3), C(5), C(7)
C(2), C(4)
C(1), C(2)
C(3)
C(1), C(7), C(8), C(2’), C(6’)
C(2), C(6), C(8), C(2’’), C(6’’)
Experimental Part
General. THF was distilled over Na/benzophenone, and toluene over CaH2. Other reagents were
obtained from commercial sources and used as such. FC ¼ Flash chromatography. M.p.: WRS-1B digital
melting-point apparatus; uncorrected. Optical rotations: Jasco-P1020 digital polarimeter. IR Spectra:
Jasco-FT/IR-4200 spectrometer. 1H- and 13C-NMR Spectra: Bruker-Avance-400 spectrometer; at 400
(1H) and 100 MHz (13C); CDCl3 solns.; d in ppm with CHCl3 (d(H) 7.26) and CDCl3 (d(C) 77.0) as
internal standards, J values in Hz. ESI-MS: Waters-Quattro-Micromass instrument. Elemental analyses:
Carlo-Erba-1106 instrument; results for C, H, N, and S within ꢀ 0.4% of the theoretical values.
(3aR,8aS)-Tetrahydro-1,3-bis(phenylmethyl)-1H-thiepino[3,4-d]imidazole-2,8(3H,4H)-dione (5).
Bromoethene gas was introduced at r.t. into a mixture of Mg turnings (0.19 g, 7.6 mmol) in THF
(10 ml) until the Mg turnings disappeared. Then, the resulting soln. was cooled to 08, and a soln. of
thiolactone 2 (1 g, 2.95 mmol) in THF (10 ml) was added dropwise. Then the mixture was allowed to
warm to r.t. and stirred at r.t. for 4 h. The reaction was quenched by sat. aq. NH4Cl soln. (20 ml), and the
mixture was extracted with AcOEt (3 ꢁ 20 ml). The combined org. phase was washed with brine, dried
(MgSO4), and concentrated, and the residue purified by FC: pure 5 (0.92 g, 86%). White solid. M.p.
1
143.4 – 145.38. IR (KBr): 2906, 1659, 1604, 1451, 1359, 1246, 1148, 1086, 744, 701. H-NMR (400 MHz,
CDCl3): 2.42 (dd, J ¼ 15.2, 9.2, 1 H); 2.53 – 2.61 (m, 3 H); 2.72 (dd, J ¼ 15.2, 3.2, 1 H); 2.83 – 2.88 (m,
1 H); 3.76 (td, J ¼ 9.6, 3.2, 1 H); 3.98 (d, J ¼ 14.8, 1 H); 4.11 (d, J ¼ 15.2, 1 H); 4.21 (d, J ¼ 10.4, 1 H); 4.79
(d, J ¼ 15.2, 1 H); 4.97 (d, J ¼ 14.8, 1 H); 7.19 – 7.34 (m, 10 H). 13C-NMR (100 MHz, CDCl3): 28.23; 32.77;
44.46; 45.80; 46.91; 53.04; 65.04; 127.70; 127.85; 127.91; 128.71; 128.78; 136.05; 136.59; 159.93; 206.12. ESI-
MS: 367.2 ([M þ H]þ), 389.2 ([M þ Na]þ). Anal. calc. for C21H22N2O2S (366.483): C 68.82, H 6.05, N
7.64, S 8.75; found: C 68.73, H 6.14, N 7.76, S 8.66.
(3aR,8S,8aS)-Hexahydro-8-hydroxy-1,3-bis(phenylmethyl)-1H-thiepino[3,4-d]imidazol-2(3H)-one
(6). BF3 · Et2O (2.78 ml, 22 mmol) was added dropwise at 08 to a soln. of 5 (0.2 g, 0.55 mmol) and Et3SiH
(1.765 ml, 10.9 mmol) in CH2Cl2 (5 ml). Then, the mixture was allowed to warm to r.t. and stirred at r.t.
for 12 h. The reaction was quenched by addition of sat. aq. NaHCO3 soln. to adjust the pH to 7, and the
resulting mixture was extracted with AcOEt (3 ꢁ 20 ml). The combined org. phase was washed with
brine, dried (MgSO4), and concentrated, and the residue purified by FC: pure 6 (0.18 g, 92%). Colorless
1
solid. M.p. 186.1 – 187.28. IR (KBr): 3321, 2919, 1664, 1473, 1261, 1071, 968, 701. H-NMR (400 MHz,
CDCl3): 1.97 – 2.06 (m, 2 H); 2.15 – 2.21 (m, 1 H); 2.50 – 2.61 (m, 2 H); 2.67 – 2.73 (m, 1 H); 2.88 (dd, J ¼
15.2, 7.2, 1 H); 3.59 (t, J ¼ 8.0, 1 H); 3.69 (td, J ¼ 8.8, 2.8, 1 H); 3.98 (d, J ¼ 15.2, 1 H); 4.09 – 4.11 (m, 1 H);
4.25 (d, J ¼ 15.2, 1 H); 4.92 (d, J ¼ 14.8, 2 H); 7.25 – 7.31 (m, 10 H). 13C-NMR (100 MHz, CDCl3): 28.74;

Helvetica Chimica Acta – Vol. 92 (2009)
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31.03; 37.62; 45.14; 48.19; 57.30; 61.06; 70.71; 127.53; 127.59; 128.04; 128.12; 128.69; 137.5; 138.2; 161.7.
ESI-MS: 369.2 ([M þ H]þ). Anal. calc. for C21H24N2O2S (368.4988): C 68.44, H 6.56, N 7.60, S 8.70;
found: C 68.63, H 6.44, N 7.74, S 8.62.
(3aS,4Z,6aR)-4-Ethylidenetetrahydro-1,3-bis(phenylmethyl)-1H-thieno[3,4-d]imidazol-2(3H)-one
(8). To a mixture of Mg turnings (0.18 g, 7.6 mmol) in THF (3 ml) was added a soln. of bromoethane
(0.57 ml, 7.6 mmol) in THF (4 ml), and the mixture was stirred at r.t. until the Mg turnings had
disappeared. The soln. was cooled to 08, a soln. of 2 (1 g, 2.95 mmol) in THF (11 ml) added dropwise, and
the resulting mixture stirred at 158 for 3 h. Then, sat. aq. NH4Cl soln. (10 ml) was added and the mixture
extracted with AcOEt (3 ꢁ 20 ml). The combined org. phase was washed with brine, dried (MgSO4), and
concentrated to afford crude 7 (ESI-MS: 369.5 ([M þ H]þ) and 391.5 ([M þ Na]þ)). To the crude 7, 2m
HCl (6 ml) and toluene (6 ml) were added, and the soln. was heated to reflux for 1 h. Cooled to r.t., the
aq. phase was extracted with toluene (3 ꢁ 10 ml), and the combined org. phase was washed with sat.
NaHCO3 soln. and brine, dried (MgSO4), and concentrated: 8 (1.0 g, 96%). White solid. M.p. 132 – 1348.
1
IR (KBr): 2930, 1695, 1470, 1250, 1158, 1025, 756. H-NMR (400 MHz, CDCl3): 1.70 (d, J ¼ 6.8, 3 H);
2.92 – 3.00 (m, 2 H); 4.03 (d, J ¼ 15.2, 1 H); 4.06 – 4.09 (m, 1 H); 4.21 (d, J ¼ 15.2, 1 H); 4.27 (d, J ¼ 7.6,
1 H); 4.82 (d, J ¼ 15.2, 1 H); 4.96 (d, J ¼ 7.6, 1 H); 5.52 (dt, J ¼ 6.8, 6.8, 1 H); 7.24 – 7.37 (m, 10 H).
13C-NMR (100 MHz, CDCl3): 46.78; 46.85; 53.15; 56.51; 57.04; 128.00; 128.60; 128.67; 128.84; 135.36;
135.48; 159.52; 167.37; 171.56. ESI-MS: 351.6 ([M þ H]þ), 373.6 ([M þ Na]þ). Anal. calc. for C21H22N2OS
(350.4836): C 71.96, H 6.33, N 7.99, S 9.15; found: C 71.81, H 6.45, N 7.85, S 9.26.
X-Ray Crystallographic Data of 6. Crystals of 6 suitable for X-ray analysis were obtained by
recrystallization from AcOEt/cyclohexane 2 :1 at r.t. CCDC-689299 contains the supplementary
crystallographic data (excluding structure factors) for the structure of 6 in this article. These data can
be obtained free of charge via http://www.ccdc. cam.ac.uk/data_request/cif. Structure-determination and
refinement data: C21H24N2O2S, Mr 368.48; crystal size 0.30 ꢁ 0.15 ꢁ 0.12 mm; orthorhombic; a ¼ 8.261(4),
b ¼ 14.045(6), c ¼ 32.656(15) ꢂ; a ¼ 90, b ¼ 90, g ¼ 908; space group P212121, Z ¼ 8, V¼ 3789(3) ꢂ3,
Dcalc. ¼ 1.292 g/cm3; R ¼ 0.0599, Rw ¼ 0.1052; ꢂ 9 ꢃ h ꢃ 10, ꢂ 17 ꢃ k ꢃ 15, ꢂ 40 ꢃ l ꢃ 41; MoKa radiation
(l 0.71073 ꢂ); T 293(2) K.
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Received December 5, 2008